ABSTRACT

 

Obesity is pandemic and a multidisciplinary approach is critical for its management. Anti-obesity treatment includes lifestyle modifications combined with anti-obesity medications. Anti-obesity drugs target either central nervous system pathways, which regulate sensations of satiety and fullness, or peripheral modulators of digestion, metabolism and lipogenesis. Combined anti-obesity agents is a novel, promising field, especially the co-administration of gut hormone analogues with centrally acting molecules. Consequently, it is hoped that in the near future, individualized pharmacological management of obesity could be meaningfully achieved by targeting different pathways governing energy homeostasis and weight regulation.  This chapter reviews potential molecular targets of the energy homeostasis system along with new anti-obesity drugs currently under investigation.

INTRODUCTION                                                                                                                      

 

The pathophysiology that leads to obesity is considered a novel field for research. Understanding human metabolism and the homeostatic mechanisms of weight regulation includes comprehension of the interaction between central nervous system and peripheral modulators of weight maintenance. Current anti-obesity molecular pharmacotherapy is based on single molecule anti-obesity drugs that act either via enhancement of satiety feeling, inhibition of hunger, or triggering of catabolism. However, on average, the weight-lowering effects of these medications are modest at best and side effects are common.

 

According to current clinical practice guidelines for pharmacological management of obesity published in 2015 by The Endocrine Society, if a patient’s weight is not responsive to lifestyle intervention, weight loss pharmacotherapy can be offered for a BMI ≥27kg/m2 when an obesity-related comorbidity is present, or when the BMI is ≥30kg/m2 (1). In fact, pharmacologic weight management should be considered in patients who meet these weight criteria and have any of a number of chronic conditions in which obesity is considered to play a major role, including type 2 diabetes mellitus (T2DM), cardiovascular disease, hypertension, dyslipidemia, obstructive sleep apnea, nonalcoholic fatty liver disease, certain cases of malignancies (i.e. endometrial, breast, colon) (2), osteoarthritis, depression (3), and infertility (4).

 

Currently, there are six anti-obesity medications that have received US Food and Drug Administration (FDA) approval: orlistat, phentermine, phentermine/topiramate extended release (ER), lorcaserin, naltrexone sustained release (SR)/bupropion SR, and liraglutide (the only injectable formulation). At the same time, the European Medicines Agency (EMA) has approved only three of these: orlistat, bupropion/naltrexone and liraglutide.

 

Considering the extent to which obesity impairs health alone or through expression of one or more of these comorbidities, the need for new molecular pharmaceutic agents is crucial. As detailed below, future weight-loss medications will be based on our knowledge of key regulatory sites of weight regulation and energy homeostasis so as to achieve greater efficacy while minimizing off-target side effects, characteristics that are necessary for approval by both American and European drug regulatory agencies.

 

TARGETS OF PHARMACOTHERAPY IN THE MANAGEMENT OF OBESITY

 

Novel insights provided by pathophysiology indicate the presence of a complex homeostatic system in which information about the energy reserve status and the meal quality and content is relayed from the periphery (gastrointestinal tract, pancreas, and adipose tissue) via specific orexigenic and anorexigenic peptides and hormones to the central nervous system (CNS). Peripheral peptide hormones are released postprandially and travel in the circulation to bind to their receptors in the homeostatic regulatory centers in the CNS, notably the arcuate nucleus (ARC) of the hypothalamus and the dorsal vagal complex (DVC) in the brainstem medulla. The ARC contains neurons expressing key orexigenic neurotransmitters, agouti-related peptide (AgRP) and neuropeptide Y (NPY), as well as anorexigenic neurotransmitters, proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART). Food intake is thus modulated by complementary mechanisms so as to maintain energy and weight homeostasis. New drug therapies have begun to focus on combination therapy using medications that target more than one of these central pathways, thereby achieving more favorable weight loss outcomes. In addition, combining treatments may provide a better safety profile given that lower doses of each drug when used together may achieve better weight loss than higher doses of a single agent (see Figure 1 below).

 

Factors That Influence Appetite

 

The regulation of satiety and appetite depends on the interaction of three major factors: biological systems, modern macro-environmental exposures, and micro-environmental influences. Biological systems are shaped by genetic and epigenetic influences from early-life events that govern development of orexigenic and anorexigenic neuro-hormonal pathways involved in the pathophysiology of obesity. Modern macroenvironment (food production, consumption, availability, social structure, weather influencing physical activity, television and technology, cultural norms, endocrine disruptors) and microenvironment (nutrition, exercise, sleep, stressful lifestyle, circadian rhythm) play an important role in the conformational development of cognitive and emotional brain regions, thus predisposing to the obese phenotype.

 

Genetic Factors of Physical Activity

 

Specific genes predict to what extent adults remain active. This is evidenced in a study examining identical twins in which environmental factors shared by children at age 13 accounted for 78% to 84% of sport participation, whereas genetic differences provided no contribution at all. At the age of 17 to 18 the genetic influences represented 36% of the variance in the level of participation in sports, and by age 18 to 20, genetic factors were responsible for almost all (85%) of the differences in participation in sports.

CENTRALLY-ACTING ANTI-OBESITY DRUGS

 

Monoamine Neurotransmitter Modulators

 

With the exception of the glucagon-like peptide 1 (GLP-1) receptor agonist liraglutide, currently available weight loss medications act on the central nervous system to enhance dopamine, norepinephrine, and serotonin action to enhance satiety, diminish hunger, and consequently affect weight loss. Drug combinations have opened new horizons as they use multiple neural pathways, leading to better results with less adverse events. Recently, a review of fifty reports involving 43,443 subjects compared the efficacy of the central acting anti-obesity drugs lorcaserin (5HT2c receptor agonist), naltrexone-bupropion (opioid receptor antagonist combined with a norepinephrine releasing agent that stimulates POMC neuronal firing), phentermine-topiramate (a norepinephrine and dopamine modulator plus a carbonate anhydrase inhibitor), and liraglutide. It was found that the maximal mean weight loss relative to placebo was -3.06, -6.15, -7.45, and -5.5kg after 1 year with mean weight regain +0.48kg, +0.91kg, +1.27kg, +0.43kg the following year, respectively.  In these studies, the one-year drop-out rate was 40.9%, 49.1%, 34.9%, 24.3%, respectively (5).

 

Leptin, Leptin Analogues and Leptin Sensitizers

 

Leptin is a protein secreted primarily by white adipose tissue (WAT). It directly stimulates anorexigenic POMC neurons and inhibits adjacent orexigenic NPY neurons in the ARC of the hypothalamus, thus promoting satiety, increasing energy expenditure, and resulting in weight loss (6). Circulating levels of leptin increase with adiposity and decline following body weight reduction; the latter might be implicated in the total and resting energy expenditure reduction seen after weight loss. The discovery of leptin in 1994 was a seminal event in obesity research. It helped to establish that body weight should be viewed as a disorder with a strong biological basis rather than simply the result of poor lifestyle choices. Studies with congenitally leptin-deficient, severely obese subjects revealed that administration of physiological doses of leptin decreased food intake and body weight (7). Obese individuals, however, are leptin-resistant and have increased circulating leptin levels. Whether administration of leptin could overcome leptin resistance and exert an anti-obesity effect was tested in a placebo-controlled study with 47 obese men and women given varying doses of recombinant human leptin (0.03 mg/kg and 0.30 mg/kg, respectively) for 24 weeks and advised to eat 500 kcal less than body requirements each day. A dose-dependent decrease in body weight was shown, ranging from -1.3 kg in the placebo group to -1.4 kg in the 0.03 mg/kg leptin-treated group, and to -7.1 kg in the 0.30 mg/kg leptin-treated group (8). These results suggested that leptin resistance can be overcome with high doses of leptin but resulting in only modest weight loss similar to currently approved medications.  In addition, whether these effects can be sustained long-term is not known. Reports were similar from animal studies testing the effect of leptin sensitizers targeting the protein tyrosine phosphatase-1B (PTP1B)(9)(10) or the chemical chaperones that repair ER stress, including 4-phenyl butyric acid (PBA) and tauroursodeoxycholic acid (TUDCA) (11), each of which demonstrated reduced food intake and body weight. Like leptin treatment, sustainability of these anti-obesity effects is still not clear.

 

Weight loss is associated with reduction in energy expenditure, which makes long term weight loss maintenance difficult (12). Furthermore, 6 days of high fat diet in mice suffice to dramatically decrease the levels of phosphorylated signal transducer and activator of transcription 3 (p-STAT3) in the arcuate nucleus (13) while short term overfeeding of normal weight mice can lead to an increase of leptin resistance (14). Besides the inefficiency of leptin analogues as monotherapy, combinations of leptin with amylin (15), fibroblast growth factor 21(FGF21), exendin4, (16), or a GLP-1/glucagon co-agonist (17) were proposed. Only the combination with the GLP-1/glucagon co-agonist has shown improvement of leptin sensitivity (18). Apart from diet, stress of endoplasmic reticulum contributes to leptin resistance (19). Several plant-derived substances, such as celastrol (20) and withaferin (21) have been tested in diet-induced obese rodents for improvement of this pathway that leads to leptin resistance.

 

METRELEPTIN

 

Metreleptin (MYALEPT) is an injectable human recombinant leptin analogue approved in Japan for metabolic disorders including lipodystrophy and in USA as first-line treatment for non-HIV related forms of generalized lipodystrophy (leptin deficiency, congenital/acquired lipodystrophy) (22). A previous indication for hypothalamic amenorrhea has been withdrawn (23). (see Table 1)

 

Table 1. Metreleptin (MYALEPT)
FDA approved/Phase	Approved in Japan for lipodystrophy disorders and in USA for non-HIV lipodystrophy
Mechanism of action	Human recombinant leptin injectable analogue
Clinical Benefits	↓blood glucose, triglycerides, hepatic fatty steatosis
Adverse events	Headache, hypoglycemia, decreased weight, abdominal pain -previous indication for hypothalamic amenorrhea discontinued

 

PRAMLINTIDE/METRELEPTIN

 

The combination of amylin-leptin (pramlintide-metreleptin) has been shown to be effective in the treatment of obesity. The anti-obesity properties of the combined treatment with pramlintide and metreleptin (pramlintide/metreleptin) were tested and showed a significant weight reduction of 12.7 ± 0.9% (11.5 ± 0.9 kg) without plateauing in obese patients during a 20-week trial period (24). The sponsors subsequently announced positive results from a 28-week proof-of-concept study with pramlintide and metreleptin combination treatment in overweight or obese subjects. The combination treatment reduced body weight on average by 12.7%, significantly more than treatment with pramlintide alone (8.4%), which is interpreted as 10 pounds more weight loss with the combined treatment. Remarkably, subjects receiving pramlintide/metreleptin continued to lose weight until the end of the study, compared to those treated with pramlintide alone, whose weight loss had stabilized towards the end of the study. The magnitude of weight loss was found to be dose-dependent and baseline BMI-dependent. Patients with a starting BMI less than 35 kg/m2 experienced the best weight loss efficacy with the combined treatment. A year later, the results of the 52-week blinded, placebo-controlled Phase II extension study of pramlintide/metreleptin were announced. The results indicated sustained and robust weight loss through the combined treatment; again, the most robust efficacy was seen in patients with a BMI less than 35 kg/m2 (25). Although the pramlintide/metreleptin combination seemed to be the next promising anti-obesity drug to be marketed, the sponsors discontinued its development in 2011, following commercial reassessment of the program (26).

 

Melanocortin-4 Receptor Agonists

 

The melanocortin system has a highly significant role in the hypothalamic regulation of body weight and energy expenditure. Leptin inhibits the release of the orexigenic neuropeptides orexin and melanocortin-concentrating hormone (MCH) in the lateral hypothalamic area (LHA) through the release of CART and melanocyte-stimulating hormone (α-MSH). The latter derives from the cleavage of POMC by prohormone convertase-1 and acts via melanocortin-3 and -4 receptors (MC3R, MC4R) activation. α-MSH emerged as a promising novel anti-obesity drug, and intranasal administration of the melanocortin sequence MSH/ACTH4-10 to normal-weight subjects was shown to acutely increase subcutaneous WAT lipolysis (27) and decrease body fat by 1.7 kg, when administered for six weeks (28). It eventually proved not to induce any significant reduction in body weight or body fat when compared with placebo in a 12-week study of 23 overweight men.

 

In preclinical studies, obese primates treated for eight weeks with the MC4R agonist RM-493 (Setmelanotide) lost an average of 13.5% of their body weight, with significant improvements in both insulin sensitivity and cardiovascular function. In June 2014, the results from the first human Phase II trial were released, testing the hypothesis that an MC4R agonist increases resting energy expenditure in obese subjects. A total of 12 obese but otherwise healthy individuals were randomized and completed both RM-493 and placebo periods in this double-blind, placebo-controlled, two-period crossover study. Analysis of the data indicates that short-term treatment with RM-493 increased resting energy expenditure significantly (by 6.4% vs placebo), thus suggesting RM-493 may be clinically effective for treating obesity. In 2015, administration of Setmelanotide to obese individuals for a limited time increased resting energy expenditure (REE) by 6.4% and shifted substrate oxidation to fat (29). Currently, Setmelanotide is being tested as a therapeutic option for rare genetic disorders of obesity such as POMC deficiency, heterozygous deficiency obesity, and POMC epigenetic disorders (30-32). (see Table 2)

 

Table 2. Setmelanotide (RM-493)
FDA approved/Phase	Phase II
Mechanism of action	MC4R-agonist
Weight loss vs placebo	13.5%
Clinical Benefits	↑insulin sensitivity, cardiovascular function, energy expenditure, ↓ body weight -tested for POMC deficiency, heterogenous deficiency obesity, POMC epigenetic disorders
Adverse events	Headache, arthralgia, nausea, spontaneous penile erection, female genital sensitivity

 

Melanin-Concentrating Hormone (MCH) Antagonists

 

The melanocortin-concentrating hormone (MCH) is an important orexigenic neuropeptide in the LHA. Its release is stimulated by NPY and inhibited by leptin, exerting its orexigenic effects through the MCH1 receptor (MCHR1) (33). Like NPY, MCH exerts pleiotropic effects on locomotor activity, sensory processing, anxiety, aggression, and learning. Thus, despite the role of MCH in hunger stimulation, MCHR1 blockade as an anti-obesity target is questionable because such inhibition could elicit undesirable side effects. In animal models, MCH antagonists have consistently demonstrated efficacy in reducing food intake acutely and in inhibiting body weight gain when given chronically (34). Five compounds have reached testing in human subjects. Although they were reported as well-tolerated, none has proceeded to Phase II studies. A major issue with many lead compounds is increased cardiovascular risk due to drug-induced QTc prolongation (35). Among others, the MCHR1 antagonist AMG 076 entered Phase I safety and tolerability testing in 2004, but there have been no subsequent reports of its status since 2005. The MCHR1 antagonist GW-856464 also entered Phase I studies in 2004; however, in 2010 it was reported that low bioavailability precluded further development. The MCHR1 antagonist NGD-4715 was safe and well-tolerated in a Phase I clinical trial, but its development ceased in 2013. Similarly, despite the reported tolerability and indication of efficacy of the MCHR1 antagonist ALB-127158, its development was terminated before the initiation of Phase II studies. Finally, the longest (28-day) Phase I study with BMS-830216, a pharmacological antagonist of MCH signaling (36) produced no indications of weight loss or reduced food intake and the compound did not proceed to Phase II studies.

 

Subtype-Selective Serotonin-Receptor Agonists

 

Central serotonin participates in feeding behavior and energy balance modulation, reducing food intake in animals and human beings.  This finding was supported by reports of two selective serotonin reuptake inhibitors (SSRIs) developed to treat depression, fluoxetine and sertraline, being associated with non-sustained weight loss in obese subjects. Thus, agonists to appropriate serotonin receptors are potentially valuable drugs. The serotonin (5-HT) system directly modulates the hypothalamic POMC (anorexigenic) and NPY (orexigenic) networks, enhancing satiety and causing hypophagia. These effects are mediated by 5-HT2C and 5-HT1B receptors, located on hypothalamic POMC and NPY neurons, respectively. Through the 5-HT1B receptors, serotonin inhibits the NPY/Agrp neurons, thereby decreasing the GABAergic inhibitory input to POMC cells; while through the 5-HT2C receptors it directly activates the anorexigenic POMC neurons. Via these actions, serotonin increases α-MSH and decreases AgRP release into the hypothalamic melanocortin system, promoting satiety. Between 1973 and 2000 there was an explosion in the pharmaceutic industry regarding central acting anti-obesity drugs. Three non-selective serotonin-receptor agonists were approved by FDA: fenfluramine (1973-1997), the combination phentermine-fenfluramine (1992-1997), and dexfenfluramine (1996-1997). These were all 5-HT1b agonists characterized for their ability to inhibit food consumption, but also had effects on other serotonin receptors that lead to unacceptable side effects (cardiac valvular thickening) and were voluntarily withdrawn from the market.

 

In 1997, when fenfluramine and dexfenfluramine were discontinued by the manufacturer, sibutramine, a serotonin and norepinephrine reuptake inhibitor emerged. Sibutramine has only little clinical relevance as an antidepressant but enhances weight loss due to an increase in energy expenditure and inhibition of food intake (37). In addition to weight loss, sibutramine was found to improve fasting levels of insulin, triglycerides, and high-density lipoprotein cholesterol. Sibutramine was also associated with increase of blood pressure, cardiovascular events, and cardiac arrhythmias (38). For these reasons, FDA withdrew it in 2010.

 

LORCASERIN

 

As activation of the 5-HT1B receptor has been implicated in both primary pulmonary hypertension (39) and valvopathy (40), the 5-HT2C receptor subtype has been proposed as a target for therapeutic intervention to allow weight loss. Several potent and selective 5-HT2Creceptor agonists proved to be effective in suppressing food intake and inducing weight loss in rodents, including WAY-163909 (41), CP-809101 (42), and vabicaserin (43). However, only lorcaserin (APD356) moved into clinical testing. Lorcaserin (Belviq) is a selective 5-HT2c receptor agonist, which belongs in the third generation of 5-HT-based anti-obesity drugs (44). It activates hypothalamic POMC neurons to induce satiety and decrease food intake but does not affect energy expenditure. Through actions on midbrain dopaminergic tone, it has been shown to suppress binge- food behaviors. Its action in addictive disorders is currently under investigation (45). Based on the outcome of the BLOOM (46) and BLOSSOM trials (47), in 2012 the FDA approved lorcaserin as an addition to a reduced-calorie diet and exercise for eligible patients (48). The efficacy of lorcaserin appears similar to that of orlistat (mean difference in weight loss between active and placebo treated groups approximately 3 to 4 kg) and perhaps slightly less than that of phentermine-topiramate. The impact of lorcaserin in patients with T2DM and BMI: 27-45kg/m2 was examined in the BLOOM-DM trial which showed a reduction of body weight by approximately 5kg versus 1.6kg in the placebo group, as well as significant decreases in heart rate, HDL levels, and waist circumference. Valvopathy was shown not to occur in excess with treatment and lorcaserin was generally well tolerated, with a low incidence of side effects such as headache, dizziness, fatigue, nausea. After the results of BLOOM-DM trial, a potential combination of GLP-1RA and 5-HT2A/C is now under investigation (49).

 

In a multicenter, randomized, double-blind, placebo-controlled, parallel-group study involving12,000 overweight and obese patients with cardiovascular disease or multiple cardiovascular risk factors (CAMELLIA-TIMI 61), the effect of long-term treatment with lorcaserin on major cardiovascular events and conversion to T2DM over a 5-year period were examined. After one year of treatment, 5% weight loss was observed in 38.7% and 17.4% in the lorcaserin and the placebo groups, respectively. Regarding cardiac risk, the lorcaserin group was non-inferior to the placebo group with slightly better values in cardiac risk factors (blood pressure, heart rate, glycemic control, lipid profile). Adverse events were rare in both groups, apart from the incidence of serious hypoglycemia in the lorcaserin group in those with diabetes managed using insulin or sulfonylureas (50, 51). In addition, lorcaserin administration decreased the incidence of T2DM by 19% in patients with prediabetes and by 23% in patients without diabetes. In patients with T2DM, lorcaserin resulted in a reduction of 0.33% in HbA1c compared with placebo at 1 year from a mean baseline of 7.0%. (see Table 3, 4)

 

Table 3. Lorcaserin (Belviq)
FDA approved/Phase	2012
Mechanism of action	Selective Serotonin 2C agonist
Weight loss vs placebo	3-4kg
Clinical Benefits	↓food intake, heart rate, HDL levels, waist circumference, HbA1c
Adverse events	Headache, dizziness, fatigue, nausea, dry mouth, constipation, heart valvopathy -In diabetics: hypoglycemia, headache, back pain, cough, fatigue, risk of serotonin syndrome/neuroleptic malignant syndrome, valvular heart disease

 

 

Table 4. Clinical Trials of Lorcaserin
Clinical trial	Patients	Dose	Treatment, placebo from baseline	% of patients losing ≥5% of baseline weight	Comment
BLOSSOM 1-year randomized, double-blind, placebo-controlled trial (2011)	4008 patients (18-65 y.o., BMI- 30-45kg/m2 or 27-29.9kg/m2 with comorbidity) randomized in a 2:1:2 ratio	i.10mg x2 po   ii.10mg x1 po   iii.placebo	i.-5.8kg     ii.-4.7kg     iii.-2.9kg	i.47.2%     ii.40.2%     iii.25%	Exclusion criteria: recent cardiovascular events, diabetes mellitus, BP >150/95mmHg
BLOOM 2-year randomized, double-blind, placebo-controlled trial (2010)	3182 adults (mean BMI-36.2kg/m2) randomized to lorcaserin twice daily or placebo group. After 52 weeks, the placebo group continued placebo and lorcaserin group selected placebo or lorcaserin for 52 weeks	i.10mg x2 po   ii. placebo	i.-5.8kg     ii.-2.2kg	i.47.5%     ii.20.3%	Weight loss was greater in the group which continued lorcaserin for the second year
BLOOM-DM 1-year randomized, double-blind, placebo-controlled trial (2012)	604 patients (HbA1c: 7-10%, BMI-27-45kg/m2, treatment with metformin, sulfonylurea or both)	i.10mg x2 po   ii.10mg x1 po   iii.placebo	i.-4.7kg     ii.-5.0kg     iii.-1.6kg	i.37.5%     ii.44.7%     iii.16.1%	↓heart rate, HDL levels, waist circumference in lorcaserin treated groups NO valvopathy was statistically significant
CAMELLIA-TIMI 61 3.3-year randomized, placebo-controlled trial (2018)	12,000 patients overweight/obese-three subgroups A. diabetes B. prediabetes C. normoglycemic	i.10mg x2/day   ii. placebo	At 1 year the mean treatment difference:  A: -2.6kg  B: -2.8kg  C: -3.3kg	At 1 year compared with placebo: A: 37.4% B: 39.7% C: 42.3%	↓ BMI, waist circumference, waist-to-hip ratio, HbA1c, reduced microvascular complications

 

Bupropion

 

Bupropion is a dopamine and norepinephrine-reuptake inhibitor that has been marketed as an anti-depressant and for smoking cessation. Previous animal studies have clearly shown a dose-dependent satiety effect of bupropion following intraperitoneal injection (52). The acute effects of dopamine and noradrenaline reuptake inhibition on energy homeostasis demonstrated their additive effects on short-term food intake (53). Bupropion increases dopamine activity and POMC neuronal activation, thereby reducing appetite and increasing energy expenditure (54). Whether the acute meal terminating effects of bupropion documented in animal studies could be translated into long-term weight loss efficacy in humans was addressed by three clinical trials with overweight and obese adults (55, 56, 57) using different treatment doses (100 to 400 mg/d) and duration (up to 24 weeks). They have all shown bupropion to have dose-dependent modest weight reducing efficacy, plus a safe profile. One study that assessed the anti-obesity efficacy of bupropion over two years reported maintenance of weight loss during the continuation phase, while another demonstrated its efficacy even in depressed patients. Although the weight loss effect of bupropion was superior in non-depressed patients compared to those suffering from depression, the fact that bupropion was well-tolerated and effective in this group of patients provides a potential valuable adjunctive therapy to elevate mood in depressed subjects in whom weight gain secondary to antidepressant therapy is an issue. Cardiovascular effects, such as a rise in blood pressure and tachycardia, were usually mild, while the risk of seizure, which was high with the original bupropion formulation, has been significantly reduced with the advent of bupropion-SR and bupropion-ER.

 

An interesting finding of the previous studies was that the rather modest weight loss effect of bupropion reached a plateau by 24 weeks of treatment. This could be explained by the molecular pathophysiology of the weight reducing effects of bupropion, which directly stimulates the hypothalamic POMC neurons that in turn release α-MSH and β-endorphin. α-MSH mediates the anorectic effect of POMC activation, whereas β-endorphin exerts negative feedback on POMC neurons via opioid receptors (58). The latter possibly points to one of the compensatory mechanisms that limits long-term efficacy of bupropion and other weight loss modalities.

 

Naltrexone

 

Naltrexone is an opioid receptor antagonist. By blocking opioid receptors on the POMC neurons, feedback inhibition is prevented further increasing POMC activity. Monotherapy with opioid antagonists to decrease short-term food intake has been tested (59). Naltrexone failed to produce consistent or clinically meaningful weight loss, even at large doses (300 mg/d) (60), implying that a single opioid mechanism is unlikely to explain all aspects of ingestive behavior.

 

Bupropion/Naltrexone Sustained Release (SR)

 

The combined bupropion/naltrexone (NB) therapy induced significantly greater weight loss on a diet and exercise program over 56 weeks compared to monotherapy and placebo (61). In 2014, the FDA approved this combination (Contrave, Mysimba) for body weight management in adults who are overweight and obese. This combined therapy of opioid antagonist and aminoketone antidepressant is titrated over four weeks to the maximum dose. NB has shown remarkable benefit in patients with binge-eating disorder (BED) and concomitant alcohol abuse, but this result needs further evaluation (62). Four major 56-week phase III randomized, double-blind, placebo-controlled trials have shown the therapeutic effect of ΝΒ SR (COR-I, COR-II, COR-BMOD, COR-DIABETES) in different dosage combinations (see Table 6). In COR-I, the weight loss ratio on NB 16/360mg, NB 32/360mg or placebo was -5.0%, -6.1%, -1.3% (P<0.00) respectively. In COR-II, the weight loss ratio on NB 32/360mg or placebo was -6.4%, -1.2% (P<0.001) (63). In COR-BMOD, NB SR 32/360mg plus intensive behavioral modification was compared with the behavioral modification alone as a therapeutic option. The weight loss ratio was -11.5% versus -7.3% (P<0.001), respectively (64). Recently, COR-Diabetes has included patients with T2DM with or without antidiabetic treatment. The NB SR 32/360mg treatment resulted in -5.1% weight loss versus -1.8% in the placebo group (P<0.001). NB treatment resulted in a HbA1c reduction, cardiovascular benefit, and lipid profile improvement (65). Due to FDA request for further investigation of the effect of NB on major cardiovascular events, the LIGHT trial was created. Unfortunately, this trial terminated early following recommendation by the academic leadership of the study because confidential interim data were publicly released by the sponsor (66). (See Table 5, 6)

 

Table 5. Bupropion/Naltrexone Sustained Release (Contrave, Mysimba+
FDA approved/Phase	2014
Mechanism of action	Aminoketone antidepressant/Opioid antagonist
Weight loss vs placebo	4.8kg
Clinical Benefits	↓ appetite
Adverse events	Nausea, constipation, headache, vomiting, dizziness, insomnia, dry mouth, suicidal ideation, increase blood pressure/heart rate, hepatotoxicity, angle-closure glaucoma Uncontrolled hypertension, seizures, anorexia nervosa/bulimia, chronic opioid use, coadministration with MAO inhibitors

 

Table 6: Clinical trials of Naltrexone/Bupropion SR
Clinical trial	Patients	Dose	Treatment, placebo from baseline	% of patients losing ≥5% of baseline weight	Comment
COR I 1-year randomized, double-blind, placebo-controlled trial (2010)	1742 patients randomly categorized in a 1:1:1 ratio	i.16/360mg po   ii.32/360mg po   iii. placebo	i.-5.0%     ii.-6.1%     iii.-1.3%	i.39%     ii.48%     iii.16%
COR II 1-year randomized, double-blind, placebo-controlled trial (2013)	1496 patients randomly categorized in a 2:1 ratio to NB 32/360mg or placebo; patients on NB with <5% weight loss in 28-44 week were reassigned to continue 32/360mg or increase daily dose to NB 48/360mg	i.32/360mg (or increased daily dose 48/360mg)   ii.placebo	i.-6.4%           ii.-1.2%	i.50.5%           ii.17.1%	Random reassignment to higher dose did not change weight loss results
COR-BMOD 1-year randomized, double-blind, placebo-controlled trial (2011)	793 patients with obesity randomly categorized in a 1:3 ratio	i. BMOD+ NB (32/350mg)   ii. BMOD+ placebo	i.-11.5%       ii.-7.3%	i.66.4%       ii.42.5%	The efficacy of NB is obvious, and a lifestyle change can increase weight loss
COR-DIABETES 1-year randomized, double-blind, placebo-controlled trial (2013)	505 patients overweight/obese and T2DM with/without oral anti-hypoglycemic agents randomly categorized in a 2:1 ratio	i.32/360mg   ii. placebo	i.-5.0%   ii.-1.8%	i.44.5% ii.18.9%	↓HbA1c, certain improvements in CVD risk factors. ↑ nausea, constipation, vomiting

 

 

Zonisamide

 

Given the pathophysiology behind the anti-obesity efficacy of the selective serotonin-receptor agonists and the dopamine-reuptake inhibitors, an ideal drug would combine serotonergic and dopaminergic activity. This is exactly the case of Zonisamide, a marketed antiepileptic drug that exerts dose-dependent biphasic dopaminergic (67) and serotonergic (68) activity. Its weight loss efficacy was investigated by a double-blind, placebo-controlled trial which reported a 32-week mean weight loss of 9.2 kg (1.7 kg) (9.4% loss) for the Zonisamide group (dose administered up to 600 mg/d) compared with 1.5 kg (0.7 kg) (1.8% loss) for the placebo group (P<0.001); Zonisamide was generally well-tolerated with only a few adverse effects (69). The findings were similar when the long-term effectiveness and tolerability of Zonisamide for weight control was examined in psychiatric outpatients using various psychotropic medications; the mean BMI reduction achieved was 0.8±1.7 kg/m2 and ranged from -2.9 kg/m2 to 4.7 kg/m2 (p<0.001), while the drug was generally safe and well-tolerated (70). Zonisamide was also assessed in the treatment of binge-eating (BE) disorder where it proved to be effective in reducing binge-eating frequency, severity of illness, and weight; however, the reports regarding its tolerability were conflicting (71). (see Table 7).

 

Table 7. Zonisamide
Mechanism of action	Selective serotonin-receptor agonist and dopamine-reuptake inhibitor
Weight loss vs placebo	7.8kg
Clinical Benefits	Assess in the treatment of binge-eating disorder
Adverse events	Nausea, headache, insomnia

 

Zonisamide/Bupropion SR

 

Whether the anti-obesity efficacy of Zonisamide is increased when combined with bupropion (dopamine and norepinephrine -reuptake inhibitor) has been evaluated in a few Phase II clinical trials with different combined doses; the bupropion SR/Zonisamide SR combination is marketed under the trade name Empatic. In its 24-week, double-blind, placebo-controlled Phase IIb trial (72), patients completing 24 weeks of bupropion SR 360 mg/Zonisamide SR 360 mg therapy lost 9.9% of their baseline body weight, or 22 pounds, compared to 1.7% for placebo patients (p<0.001). Of patients who completed 24 weeks of therapy, 82.6% lost at least 5% of their baseline body weight and 47.7% lost at least 10% of their baseline body weight compared to 18.9% and 5.7% of placebo patients, respectively (p<0.001 for both). Patients experienced significant weight loss as early as by their first post-baseline visit at week four. Importantly, patients continued to lose weight until the end of the trial period with no evidence of a weight loss plateau. Early results showed that patients lost an average of 14% over 48 weeks. Improvements were observed in key markers of cardiometabolic risk such as waist circumference, triglycerides, fasting insulin, and blood pressure. The most commonly reported adverse events for all patients were headache, insomnia, and nausea. The most common adverse events leading to discontinuation were insomnia, headache, and urticaria (hives). There were no serious adverse events attributed by investigators to the study drug. There were no statistically or clinically meaningful differences between the drug and placebo on measures of cognitive function, depression, suicidality or anxiety. These reports revealed a significant weight-reduction effect for the combination Bupropion/Zonisamide. However, the safety concerns (73) will need to be addressed in the upcoming Phase III studies before firm conclusions about its safety profile can be drawn. (see Table 8)

 

Table 8. Zonisamide/Bupropion (Empatic)
FDA approved/Phase	Phase II completed
Mechanism of action	Selective serotonin-receptor agonist and dopamine-reuptake inhibitor/dopamine and norepinephrine reuptake inhibitor
Weight loss vs placebo	9.9% of their baseline weight
Clinical Benefits	↓cardiometabolic risk
Adverse events	Headache, insomnia, nausea, urticaria

 

Topiramate

 

Topiramate is another anticonvulsant agent associated with weight loss. It is a sulphamate-substituted fructose that is approved as an antiepileptic/antimigraine agent and has multiple effects on the CNS, including action on the orexigenic GABA systems causing appetite suppression (74). A 6-month dose-ranging study in obese human subjects addressing its anti-obesity efficacy at doses of 64, 96, 192, and 384 mg/day (in divided twice-daily dosing) concluded that all doses produced significantly greater weight loss compared to placebo, and that weight loss in the 192 mg/day group was similar to the 384 mg/day group (75). This is important as topiramate has been associated with several neuropsychiatric effects, especially when administered at high doses (of 192 mg/d or more). Another study investigating the weight loss efficacy and safety of topiramate doses of 96, 192, and 256 mg/day over a 1-year period in obese subjects using the immediate release form tablets (before the development of the controlled-release formulation). Clinically significant weight loss (7.0, 9.1, and 9.7% of their baseline body weight for the doses of 96, 192, and 256 mg/day, respectively), was reported compared to 1.7% body weight loss in the placebo group (P<0.001) plus improvements in blood pressure and glucose tolerance (76). Finally, several other studies investigated the therapeutic effect of topiramate in patients with BED and bulimia (77) that are both associated with obesity; the results were very promising regarding control of symptoms in both disorders. (see Table 9)

 

Table 9. Topiramate
FDA approved/Phase	Phase II completed
Mechanism of action	Sulphamate-substituted fructose acts on GABA system
Weight loss vs placebo	7.0%(96mg),9.1%(192mg), 9.7% (256mg/day)
Clinical Benefits	Assess in the treatment of binge-eating, bulimia
Adverse events	Headache, insomnia, nausea, urticaria

 

Phentermine

 

Phentermine is a sympathomimetic amine, which has anorexigenic action, that also releases insignificant quantities of dopamine. Thus, it is characterized by lower abuse potential (78). Its main mechanism of action involves catecholamine release in the hypothalamus resulting in enhanced satiety feeling and reduction of food intake (79). The most common side effects of phentermine as a sympathomimetic drug is heart rate increase, hypertension, dizziness, dry mouth, insomnia, irritability, and gastrointestinal disorders (80). Phentermine was the first FDA approved anti-obesity drug in 1959 for those aged >16 years old, but for only short-term use (maximum 3 months). The reason for the time limit is because the pharmaceutic industry had not updated labeling since 1959. In 1968, in a double-blind, placebo-controlled trial, 108 overweight or obese women were categorized into three groups that received continuously or intermittently (every 4 weeks) dosed phentermine or placebo, respectively. The weight loss was -12.2kg, -13.0kg or -4.8kg, respectively (81).

 

Currently, the off-label long-term use of phentermine is indicated only if there is clinical benefit, stable blood pressure and pulse rate in the absence of cardiovascular history or substance abuse disorders. In a recently published retrospective cohort study, 13,972 patients were observed for 6, 12 and 24 months after phentermine initiation. They were categorized in five groups based on the time of phentermine administration: short-term use, short-term intermittent use, medium-term continuous use, medium-term intermittent use, long-term continuous use. Weight-loss, changes in blood pressure, heart rate, and incidence of cardiovascular events (myocardial infarction, stroke, angina, coronary artery bypass grafting, carotid artery intervention, death) were examined. Weight loss was greater among off-label groups than referent group of short-term use with results depending on the duration of phentermine initiation. Specifically, at six months, short-term intermittent patients lost 1.8% further body weight relative to short-term single patients and medium-term intermittent patients lost 5.6% further body weight relative to short-term single patients. At twelve months, the medium-term intermittent use group lost further 5.6% body weight relatively to the short-term use group. At twenty-four months, long-term the continuous use group lost 7.4% additional body weight in comparison with the short-term use group. Concerning safety of phentermine, changes in heart rate and diastolic blood pressure were insignificant at six, twelve, and twenty-four months. Interestingly, although the referent group showed a slight increase in systolic blood pressure (+0.5-3.2 mmHg) at twenty-four months, all groups had slightly lower systolic blood pressure than the referent group at twelve- and twenty-four-months follow-up period. Lastly, the incidence of major cardiovascular events was low. So, it was shown that the off-label over three months therapy with phentermine was superior to short–term administration with greater weight-loss effect and cardiovascular safety. More studies with fewer limitations should follow in order to support these findings (82). In 2013, a clinical trial comparing phentermine as monotherapy or as part of a combined therapy, took place and resulted in a weight loss of 5.1% at 28 weeks follow-up period in favor of the combined phentermine/topiramate group.(see Table 10)

 

Table 10. Phentermine
FDA approved/Phase	1959
Mechanism of action	Norepinephrine release and minor dopamine release
Weight loss vs placebo	0.23kg/week
Clinical Benefits	Lower abuse potential
Adverse events	Stimulation, insomnia, dry mouth, constipation, primary pulmonary hypertension Contraindicated in cardiovascular disease, coadministration with MAO inhibitors, hyperthyroidism, glaucoma, drug abuse

 

Phentermine/Topiramate ER

 

Because of dose-related side effects seen with topiramate treatment including suicidality, metabolic acidosis, acute myopia, and secondary angle closure glaucoma, a lower dose of topiramate was used (in a special controlled release formulation) in a novel anti-obesity drug called Qsymia. The main mechanism of action of Phentermine/Topiramate extended release(ER) is possibly the alteration of various neurotransmitters, including inhibition of voltage-dependent sodium channels, glutamate receptors, and carbonic anhydrase as well as potentiation of γ-aminobutyrate activity (83).Two large randomized, double-blind, placebo-controlled trials took place (EQUIP and CONQUER) followed by a 2-year extension trial (SEQUEL). In the EQUIP trial 1,267 patients with BMI>35kg/m2were allocated in two groups and received phentermine/topiramate ER 3.75/23mg and 15/92mg, respectively, once daily. With 59.9% of the patients discontinuing, this trial found no statistically significant difference between the two groups regarding weight reduction (84). In the CONQUER trial 2,487 patients were allocated in three groups and received phentermine/topiramate ER 7.5/46mg, phentermine/topiramate ER 15/92mg, and placebo, respectively. The results were in favor of the combined therapy while the greater dosage resulted in greater weight loss with mean weight loss -7.8kg, -9.8kg, and -1.2kg in the three respective groups (85). Patients who completed the CONQUER trial entered the SEQUEL trial for 52 weeks. The weight loss as percentage of the initial weight was -9.3%, -10.5% and -1.8% in the three respective groups. A statistically significant improvement of lipid profile, glycemic control, and waist circumference in the phentermine/topiramate ER groups was reported (86). Based on the positive results from three Phase III studies, in 2012 FDA approved topiramate/phentermine extended-release as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in eligible adults. Meanwhile however, approval was denied by European regulatory authorities, who cited potential risk to the heart and blood vessels, psychiatric side effects, and cognitive side effects in explaining their decision (see Table 11, 12).

 

Table 11. Topiramate/Phentermine Extended Release (ER) (Qsymia)
FDA approved/Phase	2012
Mechanism of action	Norepinephrine release, GABA modulation, voltage-gated ion channel modulation, stop of AMPA/kainite excitatory glutamate receptors and carbonic anhydrase
Weight loss vs placebo	6,6kg
Clinical Benefits	↓ lipid profile, HbA1c, waist circumference
Adverse events	Paresthesia, dizziness, dysgeusia, insomnia, constipation, dry mouth, fetal toxicity, metabolic acidosis, cognitive impairment Contraindicated in: Glaucoma, hyperthyroidism, coadministration with MAO inhibitors

 

Table 12. Clinical Trials of Phentermine/Topiramate ER
Clinical trial	Administration	N	Treatment, placebo from baseline	% of patients losing ≥5% of baseline weight	Comment
CONQUER Double-blind, placebo-controlled trial over 1 year (2011)	4-week titration+ 52 weeks of treatment: 15/92mg po or 7.5/46mg po	2487 patients (BMI:27-45kg/m2 with 2+ risk factors i.15/92mg   ii.7.5/46mg   iii. placebo	i.-9.8kg   ii.-7.8kg   iii.-1.2kg	i.70%   ii.62%   iii.21%	↑improvement in blood pressure, waist circumference, lipid levels, fasting glucose and insulin
SEQUEL 2-year study overall;1-year extension of CONQUER (2012)	227 patients completed the original blinded treatment	i.15/92mg   ii.7.5/46mg   iii. placebo	i.-10.9kg   ii.-9.6kg   iii.-2.1kg	i.79.3%   ii.75.2%   iii.30%

 

Neuropeptide Y (NPY) Inhibitors

 

The ARC NPY neurons inhibit the anorexigenic POMC neurons (via NPY Y1 and Y5 receptors) and promote the release of the orexigenic neuropeptides orexin and MCH in the LHA, thus promoting food intake. Therefore, NPY blockade could be a promising target for body weight management. Animal experiments (in mice) have shown that pharmacologic blockade or genetic deletion of the Y1- and Y5-receptors reduces food intake and weight, with Y1-receptor signaling appearing to be the major mediator of the orexigenic effects of NPY. However, NPY is the most abundant central neuropeptide and regulates many functions beyond feeding; thus, targeting NPY neurons/Y receptors specifically for obesity is not easy and could result in unacceptable side effects. In addition, experimental medical blockade of NPY signaling with the Y5-receptor antagonist MK-0577 failed to cause any significant weight loss in a 1-year clinical trial (87). On the other hand, the oral, once-daily, centrally acting selective Y5-receptor antagonist velneperit, previously known as S-2367, induced a mean placebo-adjusted weight loss of 5.0% from initial weight (p <0.0001) over 54 weeks of therapy and was accompanied by improvement of lipid profile and waist circumference reduction (88).Nevertheless, velneperit did not proceed in markets due to disappointing results in phase IIb trials. However, the combined Y1/Y5-receptor antagonism may prove more effective, though we are not aware of any Y1/Y5-receptor antagonist in development to date. In contrast to Y1 and Y5, the Y2- and Y4-receptors are the targets of the satiety hormones PYY and pancreatic polypeptide (PP), respectively, and, as mentioned below, two drugs, a Y2/Y4-receptor agonist (obinepitide and a selective Y4-receptor agonist (TM30339)) are in Phase I/II clinical trials and are yielding results that appear quite promising as regards weight loss. A combined anti-obesity medication of velneperit/orlistat is under way (phase II clinical trial), also with promising results (89).

 

Dopamine antagonists

 

The mesolimbic dopamine system was proven to play a critical role in compulsive overeating or binge eating, which is one of the main reasons why people become overweight or obese. There is some evidence that blocking the action of dopamine in animals can reduce food intake, particularly of foods that are high in fat and sugar. GSK 598809 is a D3 antagonist that blocks dopamine. Preliminary data from human studies failed to show any significant effect on body weight control (90).

 

Tesofensine

 

Tesofensine (TE) is a presynaptic inhibitor of norepinephrine, dopamine, and serotonin. Like sibutramine, it suppresses appetite and may result in significant weight loss, as this was shown when given for the treatment of Parkinson’s disease, but also in a multi-dose, dose-ranging trial where 203 obese patients were randomly assigned to Tesofensine (0.25, 0.5, and 1.0 mg) or placebo once daily. Phase II testing of the drug has been completed. After 24 weeks, mean weight reduction was greater in the Tesofensine groups (-6.7, -11.3, -12.8 kg, for the three doses, respectively) compared with placebo (-2.2 kg). Additionally, an improvement in lipid profile and glycemic control was observed. A dose-dependent increase in blood pressure was observed along with a 7.4bpm increase in pulse rate in the 0.5mg/day group. Adverse events such as headache and mood alterations were also present in all groups especially in the 1mg/day group (91). In another trial, 32 males were allocated in two groups and received 2mg/day Tesofensine and placebo, respectively. The interesting point in this trial was that the patients were free to consume their usual amounts levels of food and exercise as usual. However, in the Tesofensine group they lost 1.8kg over 2 weeks because Tesofensine increased visual analog scale ratings of satiety and 24h fat oxidation in comparison with placebo. Even if an increase in total energy expenditure was not observed, an increase in sleeping energy expenditure was found. Altogether, Tesofensine induces weight loss by promoting the satiety feeling and slightly increasing metabolic rate (92). The effect of Tesofensine in appetite sensations was evaluated in another phase II trial, in which patients were allocated in 4 groups and received 0.25mg, 0.5mg, 1mg and placebo, respectively, for 24 weeks. For the first 12 weeks, a dose-dependent increase in the satiety feeling was noticed even though this feeling faded away as the trial was in progress (93). In 2010, a study on the abuse effect of Tesofensine, bupropion, atomoxetine, and placebo in comparison to d-amphetamine took place and concluded that the studied substances had no abusive action (94). Tesofensine has been shown to increase both blood pressure and pulse rate. In 2018, a phase III clinical trial was powered by the pharmaceutic industry producing Tesofensine. In this study 372 patients were allocated in three groups and received Tesofensine 0.25mg, 0.5mg and placebo. Furthermore, a combination of Tesofensine/metoprolol is recently being examined against hypothalamic injury-induced obesity and Prader-Willi syndrome (95). (see Table 13)

 

Table 13. Tesofensine
FDA approved/Phase	Phase III
Mechanism of action	Triple monoamine reuptake inhibitor of dopamine, norepinephrine, serotonin
Weight loss vs placebo	4.5-10.6%
Clinical Benefits	Pharmacological similar to sibutramine ↓ appetite, body weight, lipid profile, blood glucose
Adverse events	Headache, mood alterations, potentially increase heart rate, blood pressure, psychiatric disorders

.

Lisdexamfetamine dimesylate

 

Another sympathomimetic, Lisdexamfetamine dimesylate, at certain doses appears effective in decreasing binge-eating days in patients with BED compared with placebo, according to a study published online by JAMA Psychiatry (96). The study included 259 and 255 adults with BED in safety and intention-to-treat analyses, respectively. Patients received lisdexamfetamine 30, 50 or 70 mg/day or placebo. BE days per week decreased in the 50 mg and 70 mg groups but not in the 30 mg group compared with placebo. Confirmation of these findings in ongoing clinical trials may result in improved pharmacologic treatment for moderate to severe BED.

 

Cannabinoid-1 Receptor (CB1) Antagonists

 

Among other neurotransmitter systems, the cannabinoid system modulates the hypothalamic melanocortin and NPY feeding networks. It has been shown that administration of cannabinoid-1 receptor (CB1) agonists and antagonists induces hyperphagia and hypophagia, respectively. These observations led to development of rimonabant, a cannabinoid-1 receptor antagonist, for the treatment of obesity, which was shown quite effective in promoting weight loss; however, it increased the incidence of mood-related disorders (97). As a result, in 2009, rimonabant was withdrawn from the market and the development of other cannabinoid-1 receptor antagonists for the treatment of obesity has also been discontinued. Before withdrawal, rimonabant was shown to have advantages in glycemic control and cardiovascular events (98). In 2010, another CB1 antagonist (AM6545) was found to have less psychological side effects and to induce satiety feeling and weight loss in animal studies (99). (see Table 14)

 

Table 14. Cannabinoid Type-1 Receptor Antagonists (SR141716, AM251, AM6545)
Mechanism of action	Antagonism of cannabinoid type-1 receptors stimulates anorexigenic signaling
Clinical Benefits	↓ body weight, blood glucose, cardiovascular events -AM6545: has limited CNS penetration
Adverse events	Mood alterations

 

Human Chorionic Gonadotropin (hCG)

 

Human chorionic gonadotropin (hCG) in the form of subcutaneous injection and oral or sublingual diet drops has been advertised as aiding in weight loss of one to two pounds daily, absence of hunger, and maintenance of muscle tone. Clinical trials, however, failed to support this claim (100). In fact, FDA recommended avoiding buying over-the-counter weight loss products which contain hCG. One might ask why the hCG diet has so many enthusiastically supporting it. The reason may be that this diet needs to be accompanied by severe calorie restriction, to only 500-800 calories per day. Anyone following such recommendations is bound to lose weight, if only short-term. Most crucially, though, since hCG has been reported to induce serious side effects, this drug should not be used for the treatment of obesity. In addition, very low-calorie diets have not been shown to be superior to conventional diets for long-term weight loss, plus they have risks, such as gallstone formation, irregular heartbeat, and an imbalance of electrolytes. Therefore, if weight loss is the goal, there are safer ways to make it happen.

 

Nesfatin-1

 

Nesfatin-1 is a satiety molecule, which was first described in rats and is derived from its precursor molecule nucleobindin2 (NUCB2) (101). It is expressed both centrally in hypothalamic food intake-regulatory nuclei, the nucleus paraventricular and the arcuate nucleus, and peripherally, in the stomach, pancreas, adipose tissue, and testis. In the gastric oxyntic mucosa, nesfatin-1 is co-expressed with the orexigenic peptide ghrelin in X/A-like cell in rats and humans. The anorexigenic action of nesfatin-1 is based on its ability to cross the blood-brain barrier. It is notable that NUCB2/nesfatin-1 not only decreases food intake, gastric emptying, and small intestine motility, but also reduces glucose and increases insulin levels (102). Intracerebroventricular (icv) injection of full length nesfatin-1 caused a significant reduction of food intake in rats and mice (103). These findings suggest that downstream signaling might be altered, a hypothesis to be further investigated. The fact that nesfatin-1 acts in a leptin-independent way, indicates that it might be a new molecular target in the pharmacotherapy of obesity. The identification of the yet unknown nesfatin-1 receptor will allow the development of nesfatin-1 agonists and antagonists. Whether peripheral nesfatin-1 is primarily involved in the regulation of food intake is questionable and should be further investigated.

 

GASTROINTESTINAL AND PANCREATIC PEPTIDES THAT REGULATE FOOD INTAKE

 

The gut-brain axis plays an important role in food consumption regulation. During food intake, information regarding meal quality and content and short-term alterations in nutrient status is relayed from the gastrointestinal (GI) tract and pancreas to the brain which in turn determines meal size. Apart from feeding, a few satiation signals optimize these processes by influencing gastrointestinal motility and secretion. Several peptides have been identified that mediate this GI system-brain communication including satiety signals such as gastrin releasing peptide (GRP), cholecystokinin (CCK), peptide YY (PYY), glucagon-like peptide-1 (GLP-1), pancreatic polypeptide, glucagon, and amylin, as well as the orexigenic peptide ghrelin. While the anorexigenic peptides are secreted during feeding, ghrelin is secreted before meals and acts to increase hunger and meal initiation. Some of the GI and pancreatic peptides implicated in the regulation of food intake act directly on regions of the brain involved in the regulation of food intake, including the ARC in the hypothalamus and the area postrema, while others act outside of the CNS.  For example, modulating the activity of neurons such as the vagus nerve, which projects to the nucleus of the solitary tract in the brain stem.

 

CCK and CCK1R Agonists

 

CCK is the first described intestinal satiation peptide (104). It is produced by the mucosal I cell (105) of the duodenum and jejunum, and the enteric nervous system, in response to luminal nutrients, especially lipids and proteins. Through endocrine and/or neural mechanisms, CCK regulates numerous GI functions, including satiation, by acting on two CCK-specific receptors: the CCK receptor 1 (CCK1R), expressed mainly in the GI system, and the CCK2R that predominates in the brain. The vagus nerve plays a critical role in CCK-induced satiation as it contains CCK1R, indicating the afferent pathway through which CCK relays satiation signals from the GI to the hindbrain region. Corroborating this hypothesis is the well-documented attenuation of CCK-induced satiation following abdominal subdiaphragmatic vagotomy (106). In addition, CCK inhibits gastric emptying, thereby augmenting gastric distention and mechanoreceptor stimulation, which in turn augments the anorectic effects of CCK (107). Despite the satiety effect of CCK, its potential as an anti-obesity target is questionable. Human studies with intravenously infused CCK carboxy-terminal octapeptide (CCK-8) have shown decreases in meal size and duration in a dose-dependent manner (108). However, the CCK satiating effects were very short-lived, usually not lasting more than 30 minutes, which raises issues as to its importance in long-term body weight regulation. In an animal study, chronic CCK administration with up to 20 peripheral injections per day, although reducing meal size, was associated with increased meal frequency, leaving body weight unaffected (109). Finally, the reports from trials testing CCK1R agonists as potential anti-obesity drugs were disappointing (110). It is currently suggested that there might be a role for CCK in body weight regulation not as a monotherapy but possibly as an adjunctive/synergistic therapy to long-term adiposity signals, such as leptin (111).

 

Glucagon-Like Peptide-1 Analogues

 

The dominant role of GI in satiation (112) is mediated not only by the gastric mechanoreceptors and upper intestinal neuropeptides such as CCK, but also by gut satiation peptides that are secreted from lower-intestine enteroendocrine cells in response to ingested food. They in turn diffuse through interstitial fluids to activate nearby nerve fibers and/or enter the bloodstream to function as hormones and augment the perception of GI fullness by acting in specific parts of the CNS. There is a well-defined duodenal-ileal communication (the ileal brake) via which the proximal intestine informs the distal intestine as to meal quality and content so that the latter modulates/restricts feeding duration, proximal GI motility, and gastric emptying, while it also regulates metabolic responses to nutrient intake. GLP-1 appears to engage such a mechanical and behavioral brake effect on eating and is produced primarily by L cells in the distal small intestine and colon. Along with glucagon and oxyntomodulin, GLP-1 is cleaved from proglucagon, which is expressed in the gut, pancreas, and brain. The GLP-1 equipotent bioactive forms GLP17–36 and GLP17-37 are rapidly inactivated in the circulation by dipeptidyl peptidase-4 (DPP4). Therefore, GLP-1 analogues that have a slightly different molecular structure, but a significantly longer duration of action compared to wild GLP-1 have been used for therapeutic interventions in patients with diabetes, in whom they significantly improved glycemic control, fasting plasma glucose, β-cell function, and probably β-cell regeneration. Currently, the GLP-1 analogues used in clinical practice for diabetes control are exenatide, lixisenatide, dulaglutide, liraglutide, and semaglutide. Beyond the improved glycemic control achieved, clinical studies have also demonstrated anorectic effects and significant weight loss via these agents (113, 114). Although the exact mechanisms by which GLP1 induces anorexia are not yet fully known, it is suggested that vagal and possibly direct central pathways are involved (115). The GLP-1 receptor R (GLP1R) is the principle mediator of the anorectic effects of GLP-1 (116) and is expressed by the gut, pancreas, brainstem, hypothalamus, and vagal-afferent nerves (117).

 

LIRAGLUTIDE

 

Its mechanism of action is both central and peripheral targeting satiety centers of the brain and regulating glucose metabolism. It is the only injectable medication for obesity and is titrated from 0.6mg to 3.0mg over 4 weeks. The most common side effects of liraglutide and generally of GLP1 analogues are gastrointestinal (nausea, diarrhea, constipation, vomiting, dyspepsia, abdominal pain) and rarely pancreatitis. The product has a boxed warning stating that thyroid C-cell tumors have been seen in rodents but the relevance of this in humans is uncertain. The drug should not be used in patients with a personal or family history of medullary thyroid carcinoma (MTC) or in patients with multiple endocrine neoplasia syndrome type 2. Three major trials, SCALE-Obesity, Prediabetes, SCALE-Diabetes, SCALE-Maintenance, have established the therapeutic benefit of liraglutide for weight loss. The SCALE-Obesity, Prediabetes evaluated liraglutide in patients who were overweight and obese but did not have diabetes. The study included 3,731 individuals who were assigned to treatment with liraglutide 3 mg or a placebo. Patients were also counseled on diet and exercise. At the end of the 56-week trial, the liraglutide group lost an average 8% (7.2kg) of their body weight compared to 2.6% (2.8kg) in the placebo group (118); net weight loss was 4.4kg. In the SCALE-Diabetes trial, 846 adults who were overweight or obese and had T2DM were allocated to receive either daily 3.0mg liraglutide or placebo, with mean weight loss -6.0% and -2.0%, respectively (119). In the SCALE-Maintenance trial, 422 adults who were overweight or obese and had lost >5% of initial body weight with a calorie restriction diet were allocated to receive either liraglutide or placebo, respectively, with mean weight loss -6.2% and -0.2%, respectively (120).Recently, Saxenda (liraglutide 3.0mg) has asked for a label update based on the results of the LEADER trial, which studied the effects of the lower dose version of liraglutide (1.8 mg) used to treat diabetes. According to this trial, which examined a population with T2DM and established cardiovascular disease,1.8mg liraglutide daily showed statistically significant reduction of cardiovascular death, of non-fatal myocardial infarction (heart attack), and of non-fatal stroke by 13% versus placebo, when added to standard care. (121) (see Table 15, 16).

 

Table 15. Liraglutide (Saxenda)
FDA approved/Phase	2014
Mechanism of action	Glucagon-like peptide-1 agonist
Weight loss vs placebo	4.4kg
Clinical Benefits	↓cardiovascular death, non-fatal myocardial infarction, non-fatal stroke
Adverse events	Nausea, hypoglycemia (serious if co-administrated with insulin), gastrointestinal disorders, fatigue, dizziness, abdominal pain, increased lipase, acute pancreatitis, acute gallbladder disease, increase heart rate, suicidal ideation, thyroid c-cell tumors seen in mice Contraindicated in: History of medullary thyroid carcinoma or multiple endocrine neoplasia 2

 

Table 16. Clinical Trials of Liraglutide
Clinical trial	Patients	Dose	Treatment, placebo from baseline	% of patients losing ≥5% of baseline weight	Comment
SCALE-Obesity+Prediabetes 1-year randomized, double-blind, placebo-controlled trial (2015)	3731 patients overweight/obese without DM (61.2% had prediabetes) randomly divided into two groups	i.3.0mg sc once daily   ii. placebo	i.-8.4kg     ii.-2.8kg	i.63.2%     ii.27.1%	Improvement of body weight, glycemic index, blood pressure, waist circumference
SCALE-Diabetes 1-year randomized, double-blind, placebo-controlled trial (2015)	846 adults with T2DM overweight/obese	i.3.0mg sc once daily   ii. placebo	i.-6.0%     ii.-2.0%	i.54.2%     ii.21.4%	More GI disorders in the liraglutide group. No pancreatitis was reported
SCALE-Maintenance 1-year randomized, double-blind, placebo-controlled trial (2013)	422 adults overweight/obese who had lost ≥5% of initial body weight during a calorie-restriction period were randomized	i.3.0mg sc once daily     ii. placebo	i.-6.2%       ii.-0.2%	i.81.4%       ii.48.9%	A combination of liraglutide, diet, exercise induced further weight loss and improvement in certain cardiovascular risk factors

 

SEMAGLUTIDE

 

Semaglutide is a novel long-acting GLP1 analogue indicated for T2DM and awaiting approval for obesity at higher doses. The efficacy of this anti-obesity drug has been proven by the SUSTAIN 1-6 trials. In these trials, patients who were overweight or obese, with and without T2DM, with or without antidiabetic medications, were allocated in groups which received semaglutide in two different dosages (0.5mg or 1.0mg) or placebo or another anti-diabetic therapy. The superiority of semaglutide 1.0mg against semaglutide 0.5mg or placebo or another anti-diabetic agent was obvious (122). In SUSTAIN 7, Semaglutide administered in subcutaneous injections once weekly was compared with Dulaglutide. Mean weight loss was greater in the group which received 1.0mg semaglutide (-4.9kg) vs the groups that received 0.5mg semaglutide (-3.6kg), 1.5mg Dulaglutide (-3kg), and0.75mg Dulaglutide (-2.3kg). Additionally, oral semaglutide is currently approved for the treatment of T2DM. In order to avoid malabsorption, semaglutide is administrated 30 minutes before breakfast. Apart from semaglutide, other oral GLP-1 agonists, such as TTP054/TTP-054 and ZYOG1, are under investigation (122). Two other trials, STEP, which studies the effects of semaglutide in patients with obesity, and SELECT, which investigates the cardiovascular effects of semaglutide in patients with obesity are currently underway (123). PIONEER, which examines the cardiovascular safety of oral administration of semaglutide in patients with T2DM, recently showed the non-inferiority of this medication to placebo (124). (see Table 17).

 

Table 17. Clinical Trials of Semaglutide
Clinical trial	Study Design	Dose	Treatment, placebo from baseline	% of patients losing ≥5% of baseline weight
SUSTAIN 1	Double-blinded For 30 weeks	i.0.5mg sc once weekly ii.1.0mg sc once weekly iii. placebo	i. -3.7kg ii. -4.5kg iii. -1.0kg	i.37% ii.45% iii.7%
SUSTAIN 2	Double-blinded Duration: 56 weeks	i.0.5mg sc once weekly ii.1.0mg sc once weekly iii. sitagliptin 100mg per po once daily	i.-4.3kg ii.-6.1kg iii.-1.9kg	i.46% ii.62% iii.18%
SUSTAIN 3	Open-label Duration:56 weeks	i.1.0mg sc once weekly ii. exenatide extended release 2.0mg	i.-5.6kg ii.-1.9kg	i.52% ii.17%
SUSTAIN 4	Open-label Duration: 30 weeks	i.0.5mg sc once weekly ii.1.0mg sc once weekly iii. insulin glargine	i.-3.5kg ii.-5.2kg iii.+1.2kg	i.37% ii.51% iii.5%
SUSTAIN 5	Double-blinded Duration:30 weeks	ii.0.5mg sc once weekly ii.1.0mg sc once weekly iii. placebo	i.-3.7kg ii.-6.4kg iii.-1.4kg	i.42% ii.66% iii.11%
SUSTAIN 7	Open-label Duration: 40 weeks	i.0.5mg sc once weekly ii.0.75mg dulaglutide sc once weekly iii.1.0mg sc once weekly iv.1.5mg dulaglutide sc once weekly	i.-4.6kg ii.-2.3kg   iii.-6.5kg iv.-3.0kg	i.44% ii.23%   iii.63% iv.30%
SUSTAIN 6 (CVD outcomes)	Double-blinded Duration:104 weeks	i. 0.5mg sc once weekly ii.1.0mg sc once weekly iii. placebo 0.5mg iv. placebo 1.0mg	i.-3.6kg ii.-4.9kg iii.-0.7kg iv.-0.5kg	Non inferior
SUSTAIN 8	Phase 3b Semaglutide vs canagliflozin
SUSTAIN 9	Semaglutide as an add-on to SGLT2 monotherapy or in combination with either metformin or sulfonylurea

 

OTHER LONG-ACTING GLP-1 ANALOGUES

 

Other long-acting GLP-1 analogues are currently being investigated for weight loss in addition to diabetes treatment. Once-daily 13-week treatment with 20 μg or 30 μg of lixisenatide reduced body weight significantly more compared to placebo (-3 kg for lixisenatide 20 μg; p<0.01, -3.47 kg for lixisenatide 30 μg; p<.01, -1.94 kg for placebo) (125). Current findings regarding CJC-1134-PC, which is a conjugate of exendin-4 and recombinant human albumin and represents a once-weekly glucagon-like peptide-1 receptor agonist, suggest that it provides similar reduction in body weight compared with exenatide twice-daily. It may have a more favorable adverse event profile which might improve patient compliance and probably total weight loss in the long-term (126). Finally, albiglutide and taspoglutide are two novel GLP-1 analogues currently being investigated. A recent review that examined the efficacy, safety, and perspective for the future of the once-weekly GLP-1 receptor agonists exenatide, taspoglutide, albiglutide, LY2189265 and CJC-1134-PC, and compared them to the currently available agonists, exenatide BID and liraglutide QD, concluded that the long-acting agonists are not superior compared to the currently used exenatide BID and liraglutide QD regarding weight loss (127).In a separate development, an orally administered PYY3-36 and GLP-1 combination has been formulated using a sodium N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC) carrier (127). Early studies revealed that the neuropeptides delivered orally in this way had a pharmacodynamic profile consistent with the reported pharmacology, were rapidly absorbed by the gastrointestinal tract, and reached concentrations several-fold higher than those seen naturally postprandially (128). Oral GLP-1 (2-mg tablet) alone and in combination with PYY3-36 (1-mg tablet) showed enhanced fullness at meal onset and induced a significant reduction in energy intake. Exenatide-CCK (129) and Liraglutide-Setmelanotide (130) have been also introduced as different combined anti-obesity therapies which act synergistically on POMC-deficient patients.

 

Single Molecule Multi-Agonists

 

The main therapeutic idea of this category is based on the concept that a single molecule could target multiple receptors (at least two; multi-agonist), thus allowing synergistic action of both pharmaceutical agents.

 

GLUCAGON-LIKE PEPTIDE 1/GLUCAGON

 

As mentioned before, GLP-1 analogues are effective anti-obesity medications and improve glucose intolerance. Glucagon has direct action on the liver by stimulating gluconeogenesis and glycogenolysis (131). It can even result in hyperglycemia and T2DM. Of note, patients with T2DM are characterized by impaired glucagon secretion. However, glucagon in CNS decreases food intake, increases energy expenditure via brown fat thermogenesis, decreases fat accumulation via lipolysis and lipid synthesis inhibition, improves cardiac performance, inhibits gastric motility, and stimulates autophagy. In 2009, the first human study announced that low-dose co-infusion of GLP-1 and glucagon could decrease food intake and increase energy expenditure (132). Therapy with a GLP-1/glucagon multi-agonist was created when amino acids 17, 18, 20, 21, 23 of glucagon were substituted in the glucagon molecule by the respective GLP-1 residues (133). The alanine at position 2 of the peptide was substituted with Aminoisobuturic acid (Aib) to protect the molecule from DDP-IV inactivation, and a lactam bridge was introduced between amino acids 16 and 20 to stabilize the secondary structure to ensure glucagon receptor potency. Once weekly administration of this pharmaceutical agent, for 4 weeks, in diet-induced obesity in mice, resulted in improvement of obesity, hepatic steatosis, glucose control, and lipid profile. Increase in energy expenditure was observed only with the multi-agonist therapy, but not with the glucagon monotherapy. Moreover, it was found that therapy with the multi-agonist improved leptin sensitivity in DIO mice (134). Different GLP-1/glucagon multi-agonists are currently under investigation (135). Interestingly, an oxyntomodulin multi-agonist was under investigation concurrently with the GLP1/glucagon multi-agonist.

 

OXYNTOMODULIN

 

Oxyntomodulin (OXM) is a 37-amino acid anorexigenic peptide hormone produced in the L-cells of the distal small intestine and colon, where it co-localizes with GLP-1 and PYY. Animal studies have shown weight reduction and improved glucose metabolism following chronic OXM injections beyond that explained by food intake restriction, suggesting an additional effect of OXM on energy expenditure. Just like GLP1, OXM is a product of proglucagon gene believed to modulate energy homeostasis at least in part via GLP1R, although its GLP1R binding affinity is about 100 times lower than that of GLP1 (136). Centrally however, GLP1 and OXM have different targets, as OXM activates neurons in the hypothalamus (137), whereas GLP1 acts in the hindbrain and other autonomic control areas (138). In human studies, acute anorectic effect of OXM was demonstrated by intravenously infused OXM (139). A reduction in food intake was also seen and retained during chronic administration in a 4-week trial with OXM injections three times a day 30 minutes before meals in a group of overweight and obese volunteers (n = 14). OXM reduced nutrient intake (35% ± 9%) resulting in significant weight loss compared to placebo (2.3 ± 0.4 kg vs 0.5 ± 0.5 kg, respectively). The findings of another study with twelve overweight or obese human volunteers who underwent a randomized, double-blinded, placebo-controlled study were similar; an ad libitum test meal was used to measure energy intake during intravenous infusions of either PYY3-36 or OXM or combined PYY3-36/OXM. Again, OXM significantly reduced energy intake compared to placebo, although the combined treatment had superior effects compared to PYY3-36 or OXM monotherapy. Human studies have also clearly demonstrated the direct effect of OXM on energy expenditure (140); this effect was later confirmed by indirect calorimetry (141). These modest but favorable results suggest significant promise for OXM-based therapies for obesity. In addition to the established action of OXM on appetite, another mechanism that potentially plays a role in energy intake and glucose metabolism is gastric emptying. Intravenous infusion of OXM reduced gastric emptying in humans (142). Whether reduction in gastric emptying is involved in the acute and long-term metabolic effects of OXM is not yet clear. Nevertheless, the immediate future will reveal OXM’s role in obesity management. However, as for other peptide hormones, their clinical application is limited by their short circulatory half-life, a major component of which is cleavage by DPP-IV. Therefore, structurally modified analogues with an altered OXM pharmacological profile have been produced with longer duration of action, good safety profile, and positive effects on body weight (and glucose metabolism) management in animal studies (143). These findings bring closer their usage in human clinical trials. Furthermore, the crystal structure of OXM has been determined, and this advance should facilitate the rational design of oxyntomodulin peptidomimetics to be tested as oral anti-obesity pharmaceuticals. Even so, despite the promising weight reduction efficacy of OXM, only a small number of development projects appears to be at an advanced stage. TKS1225 is an OXM analogue. The present status of this molecule is unknown. OXY-RPEG has been engineered via its proprietary reversible pegylation technology to increase its half-life and increased potency. In preclinical testing, OXY-RPEG was significantly superior to twice daily injections of OXM in the reduction of food intake and the degree and durability of weight loss. In 2009, an oxyntomodulin-based multi-agonist peptide with glucagon and GLP-1 agonistic actions were created. This multi-agonist had advanced action comparing to the one that Day et al had introduced at the same year (144). A 2-weeks trial in DIO mice showed weight loss and glucose control improvement. This beneficial action was obvious even in mice without GLP1 or glucagon receptor confirming the superiority of this analogue. Oxyntomodulin functions endogenously as a physiologic co-agonist, but regarding its small bioactivity, it is mainly characterized by its function as biosynthetic precursor to glucagon.

 

GLUCAGON-LIKE PEPTIDE 1/AMYLIN

 

In 2010, salmon calcitonin-exendin-4 combined therapy achieved reduction of food intake and weight in non-human primates (145). Of note, the human amylin receptor subtypes consist of calcitonin receptor and receptor activity-modifying proteins. This observation was the first step in the development of multi-agonist molecules targeting GLP-1 and Amylin (146). Two of these peptide hybrids (phybrids) had a C-terminally truncated Exenatide, which was covalently linked to the N-terminus of an amylin analogue (Davalintide) through either a repeat β-ala-β-ala dipeptide, or through triple-glycine linear repeat. Administration of phybrids resulted in greater weight loss in non-human primates than monotherapy, although similar to that achieved by a physical commixture of the single hormones. Another GLP1/Amylin phybrid was introduced, which used a full-length Exenatide sequence linked to Davalintide viaan intervening 40-kDa PEG. This phybrid reduced both blood glucose and body weight in a dose-dependent fashion.    

 

GLUCAGON-LIKE PEPTIDE 1/GLUCOSE-DEPENDENT INSULINOTROPIC POLYPEPTIDE

 

This single-molecule multi-agonist was quite controversial. Glucose-Dependent Insulinotropic Polypeptide (GIP), is a 42-amino acid peptide, produced by K-cells in the duodenum and jejunum and released into the general circulation upon stimulation by dietary lipids (147). The investigation following the discovery of this new peptide, showed that GIP is the first incretin hormone. It acts directly on the pancreas augmenting glucose-stimulated insulin secretion (148). It is worth mentioning that GIP has the ability to enhance both insulin secretion in hyperglycemia and glucagon release in hypoglycemia (149). A few years later, the role of GIP in obesity development became apparent. GIP acts on adipocytes enhancing adipogenesis, inhibition of lipolysis, stimulation of de novo lipogenesis (150) and on chylomicrons stimulating triglyceride release. It also affects adipocyte glucose and fatty acid uptake and adipocyte lipoprotein lipase enzyme activity (151). It is remarkable that although GIP was regarded as an obesogenic hormone, mice overexpressing GIP showed improved β-cell function and improved glycemic control and were resistant to DIO (152). Additionally, in studies with mice, it was shown that the chronic GIP agonist administration improves glucose metabolism without body weight changes (153). In 2013, two single-molecule multi-agonists GLP1/GIP were introduced, whose action was based on the insulinotropic action of both components (153). GIP agonist enhanced GLP1 action upon glucose metabolism and GLP1 could mitigate obesogenic effect of GIP via its anorectic effect. The biochemical structure of multi-peptide was similar to GLP1/glucagon multi-agonist i.e. a single peptide with potency at both receptors (GIP residues were introduced in the median and the C-terminal part of peptide; certain modifications that increased activity on the glucagon receptor were removed; the C-terminus of the peptide ended with the nine amino acid extension found in exendin-4 and an Aib was added at position 2 to protect against DPP-IV inactivation) (154). Several clinical trials in mice, rodent models, non-human primates and humans were performed, concluding that the GLP1/GIP multi-agonist therapy reduced food intake, and consequently body weight, improved glycemic control, lipid profile and lipolysis but without any improvement in energy expenditure.

 

GLUCAGON LIKE PEPTIDE 1/GLUCAGON/GLUCOSE-DEPENDENT INSULINOTROPIC POLYPEPTIDE

 

The creation of this single-molecule multi-agonist was based on the biochemical structure of GLP1/GIP and GLP1/glucagon multi-peptides. An Aib at position 2 both protected the molecule from DPP-IV inactivation and decreased its potency at the glucagon receptor; an amino acid lysine at position 10 was fatty-acylated via a γ-glutamic acid linker to palmitic acid; amino acids at positions 16,17, 20, 27, 28 replaced balanced glucagon bioactivity; a C-terminal exendin-4 extension sequence (CEX) succeeds agonism at all three receptors 10-fold greater than native hormones (155). The main mechanism of action is based on the combination of the anorectic effect of GLP-1, the lipolytic and thermogenic characteristics of glucagon, and the action of GIP on β-cell function and glycemic control. Contrary to GLP-1/GIP multi-agonist, which doesn’t affect energy expenditure, this triple agonist increases energy expenditure. (see Table 18)

 

Table 18. Single Molecule Multi-Agonists
Drug name	Clinical benefits	Adverse events
Glucagon-like peptide 1/glucagon oxyntomodulin, MED10382, G530S (Glucagon analogue/Semaglutide), GC-co-agonist 1177	↓ food intake, obesity, hepatic steatosis, HbA1c, lipid profile ↑energy expenditure
Glucagon-like peptide1/amylin co-agonism	↓ blood glucose and body weight dose-dependently
Glucagon-like peptide 1/glucose-dependent insulinotropic polypeptide	↓ blood glucose, lipid profile, food intake, body weight, ↑ lipolysis	No improvement in energy expenditure
Glucagon-like peptide 1/glucagon/glucose-dependent insulinotropic polypeptide	↓body weight, HbA1c, hepatosteatosis, cholesterol, ↑energy expenditure, lipolysis

 

Peptide-Mediated Delivery of Nuclear Hormones

 

The use of nuclear hormones as an agent of GLP-1 and Glucagon is a novel promising therapy in the treatment of obesity. Nuclear hormones are characterized by high potency and pleiotropic action as well as unwanted adverse effects. The basic idea involves a linkage of a nuclear hormone to a peptide, usually through a linker that would allow metabolism of the nuclear hormone only within the targeted cell reducing the undesirable effects in other tissues. However, in the cell types that possess the specific peptide receptor, its activation should lead to internalization of the ligand-nuclear hormone receptor complex. In this case, the peptide receptor plays the role of a gateway into the cell. Upon internalization, biological processing of a suitably designed linker would release the nuclear hormone and allow activation of its intracellular receptor. Although a promising option, not all nuclear hormones can be used as peptide-mediated agents. They should have high tissue selectivity, ability to be internalized and compatibility to peptide wanted. Estrogens, tri-iodothyronine, and dexamethasone are the nuclear hormones that have been tested.

 

GLUCAGON-LIKE PEPTIDE 1-MEDIATED DELIVERY OF ESTROGEN

 

Glucagon-Like Peptide 1-mediated delivery of estrogen was first introduced in 2012. The use of estrogens was indicated by the fact that estrogen replacement therapy in postmenopausal women improved multiple cardio metabolic parameters (156). Furthermore, estrogens have anabolic, insulinotropic, and anorectic effects (157). The combination of estrogen and GLP-1 was found to improve body weight and glycemic control in rodent models with the metabolic syndrome (158). The weight-lowering effect was due to appetite suppression, while the GLP-1/E2 combination showed greater potency comparing to GLP-1 analog or E2 alone. Further clinical trials enhanced this finding showing an influence on feeding behavior. Additive contribution of GLP-1/E2 on pancreatic islet function, cytoarchitecture and protection from deleterious insults such as lipotoxicity was found in 2015 (159). Despite the powerful metabolic benefits associated with estrogen action, effects on the reproductive endocrine system and oncogenic potential have restricted their clinical use in postmenopausal women. Furthermore, many aspects of molecular pharmacology and mechanism of action remain unresolved. Specifically, neither the precise intracellular processing of the GLP-1/E2 conjugate, which results in active estrogen cargo release, nor the molecular identity that delivers estrogen activity, have been determined. It is possible that estrogens enhance brain penetration and alter the bio-distribution of the conjugate to more privileged sites for central nervous action.

 

GLUCAGON-MEDIATED DELIVERY OF TRI-IODOTHYRONINE

 

Glucagon and thyroid hormone can separately lower body weight and LDL cholesterol in humans. Thyroid hormones act both on liver, regulating hepatic lipid metabolism and hepatosteatosis, and in adipose cells, increasing energy expenditure and enhancing lipolysis (160, 161). On the other hand, they can cause cardiac hypertrophy, tachycardia, muscle catabolism, and bone deterioration. Glucagon receptors are highly concentrated not only in the liver, which is the preferred site for T3 action, but also in adipose tissues, kidney, and the cardiovascular system resulting in metabolic enhancement along with toxicity risk. Considering all of the above, a glucagon/T3 conjugate was created. A native T3 combined with a DPP4-protected C-terminally extended glucagon analog via a peptide spacer (162). Several control compounds were also generated to permit appropriate pharmacological comparisons. These additional peptides included a conjugate with selective chemical substitution in the peptide to suppress glucagon activity, a compound with a linker that proved metabolically stable and was incapable of intracellular T3 release, and a third control conjugate that carried a metabolically-inert thyroid hormone. Finan found that the conjugate glucagon/T3 corrected lipid metabolism in rodent models with dietary-induced metabolic syndrome. The above findings showed that the body-weight effect of the conjugate can partially be governed by actions in adipose depots because glucagon receptors exist in rodent adipocytes, less than in liver. Moreover, the glucagon/T3 conjugate effect is supported by the uncoupling protein 1-mediated thermogenesis, enhanced FGF21 secretion and biased by PGC-1 cofactor signaling. Interestingly, the combination of glucagon/T3 seems to decrease arterial plaque area in LDL receptor -/- mice and fibrosis in mice with advanced fatty liver disease.  Although the above data demonstrate the cardiovascular benefit of this conjugate, further chemical improvements should be made in order to be safe for chronic use in higher mammals and especially humans.

 

GLUCAGON-LIKE PEPTIDE 1-MEDIATED DELIVERY OF DEXAMETHASONE

 

It is widely known that dietary-induced obesity causes chronic peripheral and central inflammation (163). Glucocorticoids are widely known for their anti-inflammatory characteristics, but due to their ubiquitous action profile, their therapeutic use can lead to off-target effects. In 2017, DiMarchi and Tschop created a GLP1/dexamethasone conjugate which managed to improve body weight in DIO mice, in a superior way to GLP1 or dexamethasone alone.  This combination improved hypothalamic inflammation, astrocytosis, microgliosis, and insulin sensitivity. The targeted delivery of dexamethasone to GLP1R-positive cells prevented typical dexamethasone off–target effects on glucose metabolism, bone density, and the hypothalamus-pituitary-adrenal axis activity (164). (see Table 19)

 

Table 19. Peptide-Mediated Delivery of Nuclear Hormones
Drug name	Clinical benefits
Glucagon-like peptide 1/estrogen	↓ food intake, body weight, HbA1c
Glucagon/tri-iodothyronine	↓ lipid profile, arterial plaque and fibrosis in advanced fatty liver disease
Glucagon-like peptide 1/dexamethasone	↓ hypothalamic inflammation, astrocytosis, microgliosis, ↑insulin sensitivity

 

Peptide Y (PYY)

 

PYY is a 36-amino acid anorexigenic peptide with a hairpin-like U-shaped fold secreted from the entero-endocrine L-cells of the ileum and colon in response to feeding. PYY presents in two major forms, PYY1-36 and PYY3-36. More specifically, PYY is a member of the pancreatic polypeptide-fold (PP-fold) family which also includes NPY and PP and interacts with a family of receptors (mainly Y2R). It is produced postprandially, in response and proportionally to caloric load, by the distal-intestinal L cells along with oxyntomodulin (OXM) and GLP-1. Just like GLP-1 and OXM, PYY1-36 is rapidly proteolyzed by DPP4. However, unlike the other two neuropeptides, the cleaved product PYY3-36, is bioactive. Human studies have shown that PYY delays gastric emptying and promotes satiety (165), while short-term intravenous administration of PYY3-36 , at doses generating physiologic postprandial blood excursions, was shown to decrease calorie intake by approximately 30% in lean and obese subjects, without causing nausea, affecting food palatability, or altering fluid intake, nor was it followed by compensatory hyperphagia (166). Another study confirmed the above findings, reporting dose-dependent reductions of food intake (maximal inhibition, 35%; P<0.001 vs control) and calorie intake (32%; P<0.001) after intravenous infusions of several different concentrations of PYY3-36 (167). Sloth et al. first showed the significantly higher energy expenditure following PYY3-36 intravenous infusion compared with PYY1-36 or control. In a recent study, the effect of infused PYY3-36 on energy intake was compared to that of OXM or the combined PYY3-36/OXM treatment; the results demonstrated that energy intake was significantly less with the combined treatment compared to PYY3-36 or OXM monotherapy (168). Whether these findings pointed to a weight loss efficacy of PYY was evaluated in a 12-week trial of 133 obese patients who were randomly assigned to intranasal PYY3-36 (200 or 600 mcg three times a day before meals) or placebo, in conjunction with diet and exercise. At the 200 mcg dose, PYY3-36 failed to reduce body weight, while 60% of patients treated with the high PYY3-36 dose (600 mcg three times a day) dropped out due to nausea and vomiting, so that no meaningful inference could be drawn from the few patients who completed the study on 600 mcg. These findings contrast with those in rodents (169, 170) and nonhuman primates (171) where PYY3-36 preparations reduce body weight. One suggested explanation is that the PYY3-36 effect is critically modulated by the time of injection. As the main anorexigenic effect of PYY is by Y2R-mediated NPY inhibition, PYY is obviously more effective at times that the orexigenic NPY is increased. In accordance with this theory is the reported weight loss effect of PYY3-36 when injected in rodents in the fasting state or in the early dark cycle — times when NPY is naturally induced (172).

 

PYY3-36 is structurally similar to pancreatic polypeptide (PP); PYY3-36 acts mainly through Y2R, while PP acts through Y4R. Obinepitide (TM30338), a synthetic dual-analogue of PYY3-36 and PP that stimulates both Y2/Y4-receptors, has been developed. Pre-clinical studies have shown that obinepitide efficiently reduces weight in obese mice. Furthermore, initial studies in humans have shown that once-a-day subcutaneous administration of obinepitide in obese human subjects inhibited food intake, at a statistically significant level, up to at least nine hours after dosing (173). Various PYY analogues have been created including intravenous, oral or nasal formulations. Interestingly, the combined therapy of PYY3-36 and GLP-1 receptor agonist (exendin-4) was found to decrease food intake and body weight in an additive manner in animal models and humans. Specifically, this synergistic result was attributed to the enhancement of c-fos reactivity in special cerebral nuclei (174). (see Table 20)

 

Table 20. PYY
Mechanism of action	Anorexigenic peptide which decreases gastric motility, increases satiety, inhibits NPY receptors
Clinical Benefits	↓ appetite, decreases food intake, ghrelin levels
Adverse events	Short-time action

 

Ghrelin Vaccines and Ghrelin Inhibitors

 

Ghrelin is a 28-amino acid peptide produced primarily by the stomach and proximal small intestine (175). It is the only known circulating orexigenic hormone and signals both on vagal afferents and in the arcuate nucleus where it powerfully enhances NPY orexigenic signaling (176, 177). Its levels increase before meals and are suppressed by ingested nutrients, with carbohydrates being the most effective ones (compared to proteins and lipids). Ghrelin’s suppression results from neutrally transmitted (non-vagal) intestinal signals, augmented by insulin. An experimental ghrelin vaccine, CYT009-GhrQb, was discontinued in 2006 as it did not have the expected effects on weight loss. A novel one conjugated to the hapten, keyhole limpet hemocyanin (KLH), tested in rodent models, was shown to decrease feeding and induce weight loss (178). NOX-B11 is a ghrelin-neutralizing RNA spiegelmer that attaches to the active form of ghrelin and blocks its ability to bind to its receptor thus blocking the orexigenic activity of exogenously administrated ghrelin in rats (179). However, NOX-B11 did not affect basal food intake in nonfood-deprived rats, thus this treatment may only be efficacious when plasma ghrelin levels are high, such as before a meal or during times of food restriction (dieting).Since the discovery that the effects of ghrelin are primarily mediated by the GH secretagogue receptor (GHSR) 1a, there have been multiple potent, selective, and orally bioavailable ghrelin antagonists produced with good pharmacokinetic (PK) profiles that are currently in preclinical testing. An amide derivative 13d (Ca2+ flux IC50 = 188 nM, [brain]/[plasma] = 0.97 @ 8 h in rat), for example, showed a 10% decrease in 24-hour food intake in rats, and over 5% body weight reduction after 14-day oral treatment in diet-induced obese (DIO) mice (180).

 

Moreover, the discovery of ghrelin O-acyltransferase (GOAT) as the enzyme that catalyzes ghrelin octanoylation, revealed several therapeutic possibilities including the design of drugs that inhibit GOAT and block the attachment of the octanoyl group to the ghrelin third serine residue; such GOAT inhibitors could potentially prevent or treat obesity (181). Octanolyation of ghrelin by GOAT on its third amino acid (serine-3) is necessary for the hormone’s biological functions. Octanoylated ghrelin enhances hyperphagia and increases gastrointestinal motility. Furthermore, it reduces insulin secretion causing glucose dysfunction, enhances thermogenesis, adipogenesis and liver lipogenesis, limiting lipolysis at the same time (182). So, inhibiting GOAT could impede the production of acyl-ghrelin and increase desacyl-ghrelin, thus improving glucose homeostasis. In 2010, GO-CoA-Tat was created. A peptide-based bi-substrate analog which inhibited GOAT activity. The chronic treatment with GO-CoA-Tat, resulted in body weight stabilization in vehicle-treated mice fed MCT-rich HFD. Additionally, a decrease of fat mass was shown, but not of lean mass (183). Another study on Siberian hamsters also resulted in improvement in ingestive behavior. Remarkably, after 48h food deprivation, GO-CoA-Tat attenuated food foraging, food intake, and food hoarding post-refeeding relative to animals treated with saline. GO-CoA-Tat treated mice improved their blood glucose (184).

 

Another promising anti-obesity agent against ghrelin is a brain penetrant CAMKK2 inhibitor. Generally, CAMKK2 has been identified as the hypothalamic AMPK kinase that transduces Ca2+-mediated ghrelin signaling, inhibiting selectively hypothalamic AMPK and NPY’s downstream orexigenic effect. 4t, a 2,4-diaryl 7-azaindole, was created in order to inhibit AMPK phosphorylation in a hypothalamus-derived cell line. When this agent was tested in rodents, it managed to reduce ghrelin-induced food intake (185) (see Table 21).

 

Table 21. Ghrelin Vaccine (NOX-B11)
Mechanism of action	Ghrelin vaccine
Clinical Benefits	↓ food intake, hypothalamic orexigenic signals, ↑energy expenditure
Adverse events	No weight loss seen in human trials

 

Fat-Specific Satiation Peptides

 

ENTEROSTATIN AND APOLIPOPROTEIN A-IV

 

Enterostatin and apolipoprotein A-IV appear to be GI peptides that are specifically stimulated by fat ingestion and subsequently regulate intake and/or metabolism of lipids. Although peripheral and central enterostatin administration decreases dietary fat intake in animals (while enterostatin-receptor antagonists did the opposite) (186), its administration to humans has shown no effects on food intake, appetite, energy expenditure, or body weight (187). Similarly, apolipoprotein A-IV, which is synthesized and secreted exclusively by the small intestine (primarily by the jejunum, but also by the duodenum and ileum), acts as a satiety factor that is downregulated by leptin (188) and upregulated by insulin and PYY in both rodents and humans (189). Although exogenous administration of apolipoprotein A-IV was quite effective concerning meal size, food intake, and weight gain reduction in rats (190), data is lacking regarding apo A-IV therapeutic administration in humans and its effects on body weight.

 

Pancreatic Satiation Peptides

 

PANCREATIC POLYPEPTIDE (PP)

 

Pancreatic polypeptide (PP) is a 36-amino acid peptide that is structurally similar to PYY. It is primarily produced in the pancreas in response to ingestion of food and in proportion to caloric load (191). Animal studies have shown that peripheral administration of PP decreases feeding (through Y4R in the area postrema), whereas centrally administrated PP increases it (through Y5R deeper in the brain) (192). In humans, intravenous infusion of PP (10 pmol/kg/min) (supra-physiological levels of PP) in ten healthy volunteers (men and women of normal body weight) caused a sustained decrease in both appetite and cumulative 24-hour energy intake by 25.3 +/- 5.8% (193). The findings of another study studying the anorexigenic effect of a lower infusion rate of PP (5 pmol/kg/min) in lean fasted volunteers were similar, holding promise for potential use as an anti-obesity agent (194). Another trial studying whether combined treatment with PP/PYY3-36 is superior regarding weight loss compared to either agent alone concluded that PP and PYY3-36 do not inhibit feeding additively in humans (195). Again, this study was conducted on lean subjects. Conversely, as previously mentioned, a synthetic analogue (TM30338) of both PYY3-36 and PP, which acts as an agonist of both the Y2 and Y4 receptors, yielded very promising results as concerns early meal termination when administered once-a-day subcutaneously in obese human subjects. Similarly, initial reports of a selective Y4-receptor agonist (TM30339) currently under development were also quite promising inducing reduction of food intake and promoting weight loss.

 

AMYLIN AND AMYLIN ANALOGUES

 

Amylin is a 37-amino acid neuroendocrine peptide hormone co-secreted postprandially with insulin by pancreatic β-cells. Among other properties, amylin is characterized by centrally mediated glucoregulatory and anorexigenic actions (196). It inhibits gastric emptying and glucagon secretion as well as decreases meal size and calorie intake (fat specific) (197) in a dose-dependent manner. These are vagus-independent actions and are exerted via binding to specific amylin receptors in the hindbrain area postrema (198), which is in contrast with the peripheral neural mechanisms engaged by most other gut peptides involved in energy homeostasis system regulation. The anorectic efficacy of amylin along with its glucoregulatory actions were investigated in human studies with the usage of pramlintide, a subcutaneous injectable amylin analogue which differs from amylin by only three amino acids. Studies in patients with type 1 and type 2 diabetes have shown great improvement in glycemic control plus sustained reductions in food intake and meal size, as well as mild progressive weight loss, following acute and long-term adjunctive pramlintide treatment (120 μg) (199). The most common adverse event associated with pramlintide usage was transient, mild-to-moderate nausea. This weight loss is noteworthy because it occurred in subjects with type 2 diabetes, on concomitant insulin therapy, and in the face of a significant A1C reduction, factors that all favor weight gain. Similar to the GLP-1 analogues discussed previously, pramlintide is currently approved for the treatment of type 1 and type 2 diabetes.

 

Whether pramlintide could constitute a potent anti-obesity agent was investigated in well-designed trials addressing this issue. In such a study (16-week randomized, double-blind, placebo-controlled), 204 individuals with obesity but not diabetes were treated with self-administered subcutaneous injections of pramlintide (nonforced dose escalation ≤ 240 μg) or placebo three times a day, 15 minutes before meals without concomitant lifestyle intervention (200). Pramlintide was generally well-tolerated and approximately 90% of the pramlintide-treated subjects were able to escalate to the highest dose of 240 μg three times a day. In contrast to the placebo-treated subjects who experienced minimal changes in body weight over the 16-week treatment period, the pramlintide-treated subjects attained significant weight loss from baseline as early as week 2, which was progressive up to week 16, with no evidence of a plateau. At week 16, the placebo-corrected reduction in body weight after pramlintide treatment was statistically significant compared with placebo (3.7 ± 0.5%, P < 0.001; 3.6 ± 0.6 kg, P < 0.001). Furthermore, the reduction in weight in pramlintide-treated subjects was accompanied by a significant reduction in waist circumference compared with placebo-treated subjects after 16 weeks of treatment (evaluable 4.3 ± 0.6 vs. 0.7 ± 0.9 cm, P < 0.01). At the end of the 16-week trial, 31% of the subjects treated with pramlintide achieved ≥ 5% weight loss compared to just 2% of the placebo group (P < 0.001). Interestingly, 8 weeks after treatment cessation, the pramlintide-treated subjects had on average regained one third of the overall weight loss observed by week 16. These findings constitute a proof of concept that pramlintide may have therapeutic use as an anti-obesity agent. Remarkably, at this higher dose (240 μg three times a day), the mean reduction in body weight with pramlintide treatment over 16 weeks was approximately twice that previously observed over a similar time-frame in insulin-treated subjects with type 2 diabetes who were treated with lower pramlintide doses (120 μg). This could suggest that higher doses of pramlintide might be necessary to achieve significant weight loss, although it is not yet clear whether concurrent insulin treatment was the main cause of that difference.

 

AMYLIN/PRAMLINTIDE COMBINATIONS

 

Previous animal studies have shown that amylin treatment significantly enhanced hypothalamic anorexigenic leptin signaling, while the combination treatment with amylin and leptin led to marked, synergistic reductions in food intake (up to 45%) and fat-specific weight loss (up to 15%). Recently, the weight-lowering effect of combined amylin/leptin agonism in human obesity was evaluated using the analogues pramlintide/metreleptin, respectively. As previously discussed, (see leptin), three trials addressing the weight loss efficacy of the combined treatment over 20, 28, and 52 weeks, respectively) reported sustained and robust weight loss by the combined treatment. Development was discontinued following commercial reassessment of the program. A Phase II study of davalintide, a second-generation analogue of amylin, for the treatment of obesity has also completed. In this study however, the weight loss efficacy and tolerability profile of davalintide was not superior to pramlintide, and was inferior to the pramlintide/metreleptin combination, thus resulting in deciding to halt further development of davalintide.

 

The anti-obesity effect of the combined treatment amylin/PYY3-36 was evaluated in an animal study, given that they both may have the potential for short-term signals of meal termination with anorexigenic and weight-reducing effects (201, 202). Statistical analyses revealed that food intake suppression with the combined treatment was synergistic, whereas body weight reduction was additive; this combination has not yet been studied in humans.  Additional preclinical studies looking at the safety and efficacy of the combined treatment with pramlintide/phentermine and pramlintide/sibutramine was evaluated in a randomized placebo-controlled study with 244 obese or overweight nondiabetic subjects (203). The results suggested that the weight loss achieved at week 24 with either combination treatment was greater than with pramlintide alone or placebo (P < 0.001; 11.1 +/- 1.1% with pramlintide + sibutramine, 11.3 +/- 0.9% with pramlintide + phentermine, -3.7 +/- 0.7% with pramlintide; -2.2 +/- 0.7% with placebo; mean +/- s.e.), without any major adverse events.

 

As mentioned above, the human amylin receptor subtypes consist of calcitonin receptor and receptor activity-modifying proteins. Because of their mechanism of action, amylin mimetics coupled with calcitonin receptor agonists, are known as dual action amylin and calcitonin receptor agonists (DACRA). DACRA KBP-088 showed greater efficacy relative to davalintide regarding in vitro receptor pharmacology and in vivo efficacy of food intake and body weight (204). DACRA KBP-088 and KBP-042 improved body weight, glycemic control and adipose hypertrophy in high-fat diet-fed rats (205). A long acting amylin analogue is also in phase I clinical trial as a once daily anti-obesity treatment (206). (Table 22)

 

Table 22. Amylin/Pramlintide Combinations
Drug name	FDA approved/Phase	Mechanism of action	Clinical Benefits	Adverse events
pramlintide	Approved for DM1, DM2	Amylin analogue	-in DM1, DM2: ↓ blood glucose, food intake, body weight, waist circumference	Nausea
Davalintide (AC2307)	Phase II	Amylin analogue	↓food intake, body weight, HbA1c	hypoglycemia
DACRA KBP-088, KBP-042		Dual amylin and calcitonin receptor agonist	↓body weight, glycemic control, adipose hypertrophy

 

PERIPHERAL MODULATORS OF THE EFFICIENCY OF DIGESTION, METABOLISM, AND LIPOGENESIS

 

Lipase Inhibitors

 

Apart from early termination of food intake augmented by the centrally acting appetite suppressants, another potential therapeutic anti-obesity approach is the induction of a negative energy balance through the inhibition of nutrient, particularly fat, absorption. Lipase inhibitors inhibit gastric and pancreatic lipases in the lumen of the gastrointestinal tract that decrease systemic absorption of dietary fat. Orlistat is currently the only marketed anti-obesity drug of this category licensed for the treatment of obesity (including weight loss and weight maintenance). Additionally, it has been proven to improve glucose metabolism and nonalcoholic fatty liver disease. The most common adverse events are gastrointestinal system and include oily spotting, flatus with discharge, diarrhea, fecal urgency, and vitamin malabsorption (207).

 

The only other pancreatic and gastrointestinal lipase inhibitor currently in clinical development is Cetilistat (ATL-962). A short-term (12-week) randomized, placebo-controlled study of weight reduction addressing the efficacy, safety, and tolerability of Cetilistat in obese patients reported that Cetilistat produced a clinically and statistically significant weight loss in obese patients to similar extents at all doses examined compared to placebo (60 mg t.i.d. 3.3 kg, P<0.03; 120 mg t.i.d. 3.5 kg, P=0.02; 240 mg t.i.d. 4.1 kg, P<0.001), plus it significantly improved other obesity-related parameters including waist circumference, serum cholesterol and low-density lipoprotein cholesterol levels. Cetilistat treatment was also well-tolerated and the common orlistat-induced GI adverse events, such as flatus with discharge and oily spotting, occurred in only 1.8-2.8% of subjects in the Cetilistat-treated group (208). The combined results from three Phase I clinical studies designed to investigate the efficacy, pharmacodynamics, and tolerability of a range of Cetilistat doses [50 mg t.i.d. (n = 7), 60 mg t.i.d. (n = 9), 100 mg t.i.d. (n = 7), 120 mg t.i.d. (n = 9), 150 mg t.i.d. (n = 16), 240 mg t.i.d. (n = 9) and 300 mg t.i.d. (n = 9)] compared with placebo or orlistat [120 mg t.i.d. (n = 9)] in healthy volunteers were published (209). They reported that Cetilistat is equipotent with orlistat regarding fecal fat excretion; it however achieves a much better tolerance profile, as the number of episodes of steatorrhea per subject in the orlistat group (4.11) was 2.5-fold greater than that in the Cetilistat-treated group. The different tolerance profile between the two lipase inhibitors, seems to be related to the physical form of the fat in the intestine (rather than the amount of fat) resulting from each medication. Thus, Cetilistat acts more like a detergent, whereas orlistat may promote the coalescence of micelles, leading to oil-drops and increased gastrointestinal adverse events. Finally, a 12-week trial compared the efficacy and safety of Cetilistat (40, 80 or 120 mg three times daily) and orlistat (120 mg t.i.d.) relative to placebo in obese patients with type 2 diabetes on metformin (210). In this study similar reductions in body weight were observed in patients receiving Cetilistat (80 or 120 mg t.i.d.) or orlistat; these reductions were significant compared to placebo (3.85 kg, P = 0.01; 4.32 kg, P = 0.0002; 3.78 kg, P = 0.008). Furthermore, treatment with Cetilistat (80 or 120 mg t.i.d.) or with orlistat significantly improved glycemic control relative to placebo; again, Cetilistat was well-tolerated and showed fewer discontinuations due to adverse events than in the placebo and orlistat groups. Based on the above findings, this novel lipase inhibitor is currently at the furthest stage in the clinical development of new drugs of this class (see Table 23).

 

Table 23. Lipase Inhibitors
Drug name	FDA approved	Mechanism of action	Weight loss vs placebo	Clinical Benefits	Adverse events
Orlistat (Xenical)	1999	Lipase inhibitor	2.6%	↓ HbA1c, nonalcoholic fatty liver disease	Gastrointestinal side effects, vitamin malabsorption Contraindicated in:Chronic malabsorption syndrome, cholestasis
Cetilistat (ATL-962)		Pancreatic and gastric lipase inhibitor		↓body weight, lipid profile, waist circumference	Gastrointestinal (less than orlistat)

 

Growth Hormone (GH) and GH Lipolytic Domain Synthetic Analogues

 

Besides its growth effects, GH also possesses significant metabolic properties, including lipolysis induction. On the other hand, GH dynamics change with increasing adiposity and GH circulating levels and response to stimuli are repressed in obesity (211, 212). Taken together, it could be hypothesized that GH administration is an effective therapeutic option for weight loss and fat mass reduction in obese individuals. However, the majority of the 16 clinical trials of GH administration in obesity indicated little or no beneficial effects of GH treatment on body weight (213). There is a report from an Australia-based biotechnology company of the development of a modified fragment of amino acids 177-191 of GH (hGH177-191) (AOD-9604) that mimics the lipolytic effects of GH without producing growth effects. AOD-9604 however failed to induce significant weight loss in a 24-week trial of 536 subjects and its development as an anti-obesity agent was terminated (214). In 2018, it was announced that GH not only promotes lipolysis, but also enhances the creation of beige adipose tissue through activation of STAT5 and induction of ADRB3. Consequently, it promotes the adrenergic action of WAT.

 

β3-Adrenoreceptor Agonists

 

The β3-adrenergic receptor is expressed in adipocytes; its activation by cognate β-agonists cause lipolysis and increase thermogenesis. Thyroid hormones increase thermogenesis via the thyroid hormone receptor β subtype; however, to date, every attempt to develop selective thyroid hormone receptor agonists which are effective in adipose tissue without systemic side-effects has failed. In 2000, a selective human β3-agonist, L-796568, was developed (215). Although its acute (4-hour period) administration in overweight human subjects was associated with significant increase in energy expenditure (by ~8%) (216), a 28-day clinical trial investigating the efficacy of chronic use of L-796568 in overweight and obese non-diabetic men receiving the drug (350 mg/d) failed to display any significant changes in body composition or 24-hour energy expenditure (217). The ineffectiveness of β3-adrenreceptor activation to induce significant and sustained lipolysis in humans may be explained by the fact that human WAT expresses minimal levels of β3-adrenoreceptors; similarly, their expression is also low within human brown adipose tissue.

 

11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors

 

Previous studies have shown enhanced conversion of inactive cortisone to active cortisol through the expression of 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) in cultured omental adipose stromal cells (218); the autocrine action of cortisol may be crucial in the pathogenesis of central obesity and features of the metabolic syndrome, such as insulin resistance. The reports relating to effectiveness of carbenoxolone (nonselective 11β-HSD inhibitor) in reducing central obesity are conflicting (219). Currently, several pharmaceutical companies are developing selective 11β-HSD1 inhibitors that are effective in adipose tissue and may be more effective in improving insulin sensitivity and reducing body weight. Preliminary data from animal studies evaluating the weight-loss benefit of T-BVT, a new 11β-HSD1 pharmacological inhibitor with specificity for WAT, are very promising regarding its anti-obesity effectiveness and amelioration of multiple metabolic syndrome parameters (220). CNX-010-49, is another selective tissue-acting 11β-HSD1 inhibitor under investigation. Animal studies showed that this inhibitor acts on glucocorticoids and isoproterenol resulting in lipolysis in mature 3T3-L1 adipocytes. It not only enhances muscle glucose oxidation and mitochondrial biogenesis, but also reduces proteolysis and gluconeogenesis in primary mouse hepatocytes. As a result, it improves glucose control, lipid metabolism, and inhibits body weight gain without affecting feed consumption. A potential cardiovascular benefit was found because of the action of CNX-010-49 on plasminogen activator inhibitor-1 (PAI-1), interleukin-6 (IL-6), and fetuin-A (221). (see Table 24)

 

Table 24. 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors
Drug name	Mechanism of action	Clinical Benefits
T-BVT	Selective to white adipose tissue 11β-HSD1
CNX-010-49	Selective to white adipose tissue 11β-HSD1	↑lipolysis, ↓ HbA1c, lipid metabolism, inhibits body weight gain without affecting feed consumption

 

Angiogenesis Inhibitors

 

Increasing adiposity is associated with expansion of the adipose capillary bed. Several vascular growth factors are produced by enlarged adipocytes, for example, vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), and angiogenin, which may in turn facilitate the expansion of adipose tissue. Thus, anti-angiogenesis may eventually participate in the treatment of obesity. This hypothesis is strengthened by studies where the experimental administration of anti-angiogenic agents in mice from different obesity models resulted in significant weight reduction and adipose tissue loss (222). Remarkably, there were benefits on food intake, metabolic rate, and preferred energy substrate. These findings appeared to modulate fat tissue by altering vasculature. Although there are many foods and beverages containing naturally occurring inhibitors of angiogenesis (e.g. green tea, oranges, strawberries, lemons, red wine, ginseng, garlic, tomato, olive oil, etc.), no convincing clinical trials have been conducted investigating their anti-obesity effect so far. Currently, a Phase II trial using the anti-angiogenic/anti-MMP drug ALS-L1023 for the treatment of obesity is underway (223). Similarly, endostatin was found to have both anti-adipogenic and anti-angiogenic action protecting mice against dietary-induced obesity (224).

 

Sirtuin 1 (SIRT1) Activators

 

Sirtuin 1 (SIRT1) is a member of the Sirtuin family of proteins that comprises seven members in mammals (SirT1-T7). Sirtuin proteins have gained considerable attention due to their importance as physiological targets for treating diseases associated with aging. They contribute to cellular regulation interacting with metabolic pathways and may serve as entry points for drugs. SIRT1 has gained popularity as it has been linked with the French Paradox and the calorie restriction-mediated longevity and delayed incidence of several diseases associated with aging, such as cancer, atherosclerosis, and diabetes. The calorie restriction-induced modulations have been demonstrated in organisms ranging from yeast to mammals. White adipose tissue seems to be a primary factor in the longevity brought about through calorie restriction, as mice engineered to have reduced levels of WAT live longer (224). Corroborating this, it was found that food withdrawal is followed by SIRT1 binding and repression of genes controlled by the fat regulator PPAR-γ (peroxisome proliferator-activated receptor-γ), including genes mediating fat storage. This, in turn, activates fat mobilization and lipolysis and reduces WAT mass (225). In addition to PPAR-γ, SIRT1 also interacts with PGC-1α, inducing the expression of mitochondrial genes involved in oxidative metabolism and fatty acid oxidation, while it also enhances leptin sensitivity by repressing PTP1B. The weight restricting effects of SIRT1 were further supported by experiments with resveratrol (RSV), a potent allosteric SIRT1 activator, which was shown to protect mice from diet-induced obesity (226). Furthermore, mice treated with SRT1720, a potent, selective synthetic activator of SIRT1, were resistant to diet-induced obesity due to enhanced oxidative metabolism in skeletal muscle, liver, and brown adipose tissue, indicating the positive metabolic consequences of specific SIRT1 activation (227). Currently, several pharmaceutical companies are investigating specific SIRT1 activators in Phase I and Phase II trials for the treatment of type II diabetes and obesity (228) to define their utility in the treatment of obesity and metabolic diseases.

 

Cyclic-GMP Signaling in Anti-Obesity Pharmacotherapy

 

Cyclic nucleotides, including 3-5-cyclic guanosine monophosphate (cGMP) and 3-5-cyclic adenosine monophosphate (cAMP), are second messengers important in many biological processes. Knowledge of the role of cAMP in the regulation of energy homeostasis has been extended, thanks to its intimate relationship with AMPK (AMP-activated protein kinase) signaling; intracellular cAMP activates the AMPK signaling pathway. AMPK regulates energy balance at both cellular and whole-body levels (229). Activation of AMPK facilitates fatty acid oxidation and mitochondria biogenesis, which promotes energy expenditure (230). Interestingly, activation of AMPK in the hypothalamus promotes food intake behavior (231). e.g. physiologic processes in the same direction and induces weight loss by mutual reinforcement. Moreover, off-the-shelf approaches might be possible, given the existence of an established market for medications targeting cGMP pathways, with FDA- and EMA-approved drugs such as sildenafil and linaclotide. Sildenafil acts on adipocytes, possibly through cGMP-dependent protein kinase I and mechanistic/mammalian target of rapamycin (mTOR) signaling pathways, browning subcutaneous white fat, thus increasing energy expenditure (232).

 

Beloranib

 

Beloranib is an analogue of the natural chemical compound fumagillin and is a methionine aminopeptidase 2 (MetAP2) inhibitor acting to reduce production of new fatty acid molecules by the liver and converting stored fats into useful energy (233). It was first tested in 31 obese women, who were divided into four groups (0.1mg, 0.3mg, 0.9mg, or placebo twice weekly). A dose-dependent weight loss was shown after four weeks of 0.9mg Beloranib administration with mean 3.8kg loss vs 0.6kg in the placebo group. It also improved lipid metabolism and lowered C-reactive protein and adiponectin. A phase II double-blinded, randomized clinical trial examined the efficacy and safety of Beloranib administration (234).147 obese patients were divided into four groups: 0.6, 1.2, 2.4 mg subcutaneous injection or placebo. After twelve weeks of administration, a dose-dependent weight loss of -5.5, -6.9, -10kg, respectively, was reported, vs -0.4kg in the placebo group. The main adverse events were sleep disturbance and gastrointestinal abnormalities. Beloranib may also cause robust weight loss and hypophagia in rats with hypothalamic and genetic obesity (235). In 2015, however, a phase III clinical trial for Prader-Willi was stopped after a second patient death (236). (see Table 25)

 

Table 25. Beloranib
FDA approved/Phase	Phase III aborted in 2015 after second patient death in Prader-Willi trial
Mechanism of action	Fumagillin analogue with methionine aminopeptidase 2 inhibition that reduced fatty acid synthesis in the liver and converted stored fat into useful energy; originally designed as an angiogenesis inhibitor
Clinical Benefits	↑ weight loss, hypophagia, ↓ lipid metabolism, CRP, adiponectin, cardiovascular factors
Adverse events	Sleep disturbance, gastrointestinal abnormalities

 

Fibroblast Growth Factor (FGF21)

 

Fibroblast growth factor (FGF) 21, expressed primarily in the liver, but also found in adipose tissue, skeletal muscle, and pancreas, is a member of the FGF family and acts as a metabolic regulator of body weight, glucose metabolism, and lipid metabolism (237). In WAT, FGF21 induces glucose uptake and adiponectin secretion with browning of white adipose tissue. In brown adipose tissue, it stimulates glucose uptake and thermogenesis, thus increasing energy expenditure. In the liver, it blocks GH signaling, regulates fatty acid oxidation both in the fasted state and in mice consuming high-fat, low-carbohydrate ketogenic diet and it maintains lipid homeostasis (238). FGF21 is characterized by anti-inflammatory, anti-oxidative stress properties with its circulating concentration increasing during periods of muscle activity or critical stress (239). Although, it is an attractive anti-obesity and anti-diabetes target, FGF21 levels are increased in obese ob/ob and db/db mice and correlate positively with BMI in humans. Exogenous administration of FGF21 in DIO in mice show virtually no beneficial effects on glucose tolerance and lipid metabolism, suggesting that the obesity state is FGF21-resistant (240).

 

ALTERNATIVE AND COMPLEMENTARY TYPES OF TREATMENT OF OBESITY

 

Gut Microbiota

 

Recently, a major shift in research has occurred towards the investigation of gut microbiota effects on energy expenditure and metabolism. Gut microbiota are responsible for a significant amount of the interaction between the host and the nutritional environment. Soluble fiber such as galacto-oligosaccharides and fructo-oligosaccharides (FOS), are fermented by the gut microbiota into short-chain fatty acids (SCFAs) acetate, propionate and butyrate (241). This mechanism provides to host 10% of its daily energy requirement (242). These SCFAs are an energy source for colonic epithelium, liver, and peripheral tissues (243). By fermenting nondigestible dietary fibers, host metabolism is enhanced. In mice with DIO, SCFAs improved glucose metabolism, insulin resistance, and obesity. In other animal studies, butyrate-producing bacteria (F. prausnitzii) induced secretion of glucagon-like peptide 1 (GLP1) from colonic L cells through the fatty acid receptor FFAR2(244). Furthermore, butyrate and propionate activate intestinal gluconeogenesis. Butyrate, through a cAMP-dependent mechanism, promotes the gene expression involved in intestinal gluconeogenesis. Propionate, itself a substrate for intestinal gluconeogenesis, activates its expression viaa gut-brain neural circuit involving the fatty acid receptor FFAR3 (245).

 

Given the key role played by microbiota in host nutrient processing and metabolism, it is not surprising that data points to a strong relation between gut microbiota and obesity and diabetes in humans. A reduced gut microbial diversity and altered microbiota composition is observed in obese individuals. There is also a low rate of gut microbial richness and specific bacterial groups are enriched or decreased in obese patients in comparison with lean people (246). Moreover, chronic diseases, such as obesity, diabetes, and HIV are associated with chronic low-grade inflammation. Gut microbiota regulates this inflammation through several mechanisms. Lipopolysaccharides (LPSs) from the outer membrane of Gram-negative bacteria may translocate through the intestinal border and cause subsequent systemic inflammation (247). Indeed, the intestinal barrier of obese patients is more permeable compared with that of lean individuals. Bile acids are characterized by a strong relation with gut microbiota affecting host’s body-weight homeostasis. Bile acids are microbially altered metabolites that are first endogenously produced by the liver and further metabolized by the gut microbiota (248). FXR signaling is an important pathway connecting gut microbiota and bile acids.

 

Based on the above knowledge, several interventions involving manipulation of the microbiome have been proposed as anti-obesity treatment. A diet which contains soluble fiber, prebiotics and/or probiotics could enhance the growth of beneficial gut microbiota and boost host metabolism. Lately, there has been interest in berberine administration in T1D, T2D, gestational diabetes, and prediabetes. The early reports of interventions using probiotics appear successful (249). Fecal microbiota transplant (FMT), the transfer of fecal suspension from a healthy (lean) donor into the gastrointestinal tract of an individual with disease (obesity) in order to restore a healthy gut is a potentially novel option to treat obesity.  However, there is not enough data about the safety of this method, that is why it is only FDA approved for recurrent Clostridium difficile infection.

 

Anti-Obesity Vaccines (Ghrelin, Somatostatin, Ad36)

 

The idea of a vaccination against obesity is also intriguing. The main action of these vaccines would be based on suppressing appetite-stimulating hormones or blocking food absorption. Three vaccines have been tested so far:

 

1. An anti-ghrelin vaccine was found not only to reduce appetite by decreasing hypothalamic orexigenic signals but also to increase energy expenditure in rodent and pigs (250). Despite the promising results in rodents, clinical trials in humans showed no weight loss despite the development of ghrelin autoantibodies after four injections of anti-ghrelin vaccine (251). Another study, however, showed that IgG anti-ghrelin autoantibodies could protect ghrelin from degradation, suggesting that an autoimmune response may be involved in the orexigenic effects of ghrelin (252).

 

2. An anti-somatostatin vaccine. Somatostatin is a peptide hormone which is produced, mainly, in the hypothalamus as well as other tissues, such as the gastrointestinal system. Somatostatin has the ability to suppress GH and insulin-like growth factor 1 (IGF-1) secretion. Reduced GH is associated with obesity and increased adiposity. So, the somatostatin vaccine could increase the secretion of GH and IGF-1(253). However, clinical trials in mice failed to reduce food intake, though a 10% improvement of body weight was observed (254).

 

3. A live adenovirus 36 (Ad36) vaccine. Adenovirus 36 increases the risk of obesity in humans, characterized by increased inflammation and adiposity (255). Mice were injected with live Ad36 vaccine and compared to the control group (unvaccinated) after 14 weeks. The control group had 17% greater body weight and 20% more epididymal fats versus the vaccinated group, which also had decreased inflammatory cytokines and macrophages in fat tissue (256). (see Table 26)

 

Table 26. Anti-Obesity Vaccines
Drug name	Mechanism of action	Weight loss vs placebo	Clinical Benefits
Anti-obesity vaccine: somatostatin vaccine	Increases the secretion of GH, IGF-1	10%
Adenovirus 36	Live adenovirus36		Decreases body weight, epididymal fat in mice, inflammatory cytokines and macrophages

 

Nanomedicine

 

The introduction of nanomedicine in the field of obesity treatment is highly novel (257). Nanoparticles can achieve targeted drug delivery along with minimized side effects. The poor water-solubility of anti-obesity drugs can be overcome via nano-encapsulation. More specifically, nanoemulsion of orlistat has been tried in order to overcome its high lipophilicity, to improve its dissolution and to avoid the pancreatic lipase inhibition caused by this pharmaceutical agent in vivo (258). Additionally, a conjugated polymer-nanocarrier was created in order to reduce the side effects of orlistat (259). In 2014, the ability of mesoporous silica particles to reduce body weight was investigated (260). They found that the silica particles embedded in food could sequestrate lipase in their small pores through a lipase-specific interaction, leading to decreased absorption of fat.

 

Appetite suppression is an alternative method to decrease food intake and impact energy homeostasis (261). As mentioned above, however, anti-ghrelin vaccine was formed using virus-like particles for obesity treatment. The passive delivery of anti-ghrelin antibodies did not lead to long-term inhibition of food intake. So, to solve this problem, investigators immunoconjugated ghrelin with virus proteins to create a vaccine that was able to trigger an immune response leading to generation of specific anti-ghrelin antibodies. This anti-ghrelin vaccine played an important role in maintaining energy homeostasis in a DIO murine model.

 

In other examples, nanomedicine has enhanced the action of antiangiogenic agents in the treatment of obesity. Detailed above, antiangiogenic therapy inhibits the progression of adipocyte hyperplasia and reduces weight gain. A targeting nanoparticle was created in order to enhance the accumulation of the antiangiogenic drug in WATs by delivering it to vascular endothelial cells. Unlike WAT, brown adipose tissue (BAT) is full of mitochondria and a robust vascular structure helps to induce thermogenesis, increasing energy expenditure, and decreasing body weight. Thus, two nanoparticle platforms delivering browning agents to adipose tissue vasculature were formed (262). PPARγ nuclear receptor agonists (including rosiglitazone) have been shown to be characterized by anti-inflammatory properties against obesity and atherosclerosis. However, they are associated with severe side effects that limit their therapeutic use (263). In another, a mitochondria-targeted nanoparticle delivers the proposed anti-obesity compound PLGA-bPEG-triphenylphosphonium (TPP) polymer (264). The PEG shell extends the circulation time of nanoparticles, and TPP could facilitate the internalization into the matrix space of mitochondria to achieve targeted drug delivery.

 

Instead of targeted delivery, a localized and sustained release of a browning agent is a promising alternative for facilitation of WAT browning. Two nanoparticles, one injectable (265) and one in a painless microneedle array patch (266) were introduced. In vivo studies revealed successful delivery of the model drug into the human adipose tissue followed by ~15% decrease of weight gain after a four-week treatment.

 

CONCLUSION

 

The field of anti-obesity molecular pharmacotherapy is expanding. The homeostasis of body weight and metabolism are tightly linked to the central nervous system. The latter is characterized by centers that send orexigenic and anorexigenic signals regulating starvation and satiety, reducing and increasing energy expenditure, respectively. Pharmaceutical multi-agents in single compounds containing active portions of two or more drugs may allow for simultaneous effects on several synergistic pathways affecting appetite control and energy expenditure. Such medications could achieve increased weight loss with fewer side effects. Furthermore, the possibility of improved formulations (e.g., injectable forms of anti-obesity drugs and or once weekly verses daily administration) serve to enhance compliance. Considering that obesity is a multifactorial disease, it needs multimodal treatment. In an era where a variety of different therapeutic options is the norm for the management of chronic diseases such as type 2 diabetes and hypertension, the hope is that this process will led to better personalized anti-obesity treatments, focusing on the special characteristics, needs, and comorbidities of each patient and the effectiveness and safety of the recommended therapy. Thus, before starting any therapy, it will be important to record the detailed medical profile of the patient. Hereditary or acquired diseases, lifestyle parameters, and psychiatric history have to be taken into account when anti-obesity treatment is tailored for each patient. Further on the therapeutic horizon and still in much need of research are the place for altering gut microbiota balance and development of anti-obesity vaccines, novel peptide-mediated delivery of nuclear hormones, single molecular multi-agonists, and nanotechnologies that improve drug delivery and hold promise in the future of molecular pharmacotherapy of obesity.

 

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ABSTRACT

 

Subcutaneous adipose tissue diseases involving adipose tissue and its fascia, also known as adipofascial disorders, represent variations in the spectrum of obesity. The adipofascia diseases discussed in this chapter can be localized or generalized and include a common disorder primarily affecting women, lipedema, and four rare diseases, familial multiple lipomatosis, angiolipomatosis, Dercum disease, and multiple symmetric lipomatosis. The fat in adipofascial disorders is difficult to lose by standard weight loss approaches, including lifestyle (diet, exercise), pharmacologic therapy, and even bariatric surgery, due in part to tissue fibrosis. In the management of obesity, healthcare providers should be aware of this difficulty and be able to provide appropriate counseling and care of these conditions. Endocrinologists and primary care providers alike will encounter these conditions and should consider their occurrence during workup for bariatric surgery or hypothyroidism (lipedema) and in those that manifest, or are referred for, dyslipidemia or diabetes (Dercum disease). People with angiolipomas should be worked up for Cowden’s disease where a mutation in the gene PTEN increases their risk for thyroid and breast cancer. This chapter provides details on the pathophysiology, prevalence, genetics and treatments for these adipofascial disorders along with recommendations for the care of people with these diseases. 

 

INTRODUCTION

 

People with subcutaneous adipose tissue (SAT) diseases have fat within this compartment that grows abnormally in amount or structure, often causing pain and other discomfort.  Subcutaneous adipose tissue is loose connective tissue, or adipofascia, which is the most common type of connective tissue in vertebrates. The focus of this chapter is on abnormal SAT that has within it changes in blood vessels, lymphatic vessels, immune cells, mesenchymal stem cells, fascia, interstitial matrix organ, or other components that make up loose connective tissue. 

 

The SAT diseases discussed here include lipedema, which commonly occurs in women, and four rare adipose tissue diseases (RAD): familial multiple lipomatosis, angiolipomatosis, Dercum disease, and Madelung disease (1). Adipose tissue in SAT diseases is resistant to loss by usual measures including extreme dietary changes (both hypocaloric and in macronutrient content) and exercise. Because of this, it is often referred to persistent fat tissue. People with diabetes and/or obesity may have a mixture of normal and persistent fat, making the understanding of SAT diseases by clinicians important in the care of these patients. Persistent fat may also be found in conditions where adipose tissue proliferation occurs, such as during infection, in autoimmune diseases, in those with hypermobile joint disorders, or with exposure to environmental toxins. Information on subcutaneous adipose tissue diseases not discussed here can be found in recent reviews and other Endotext chapters, including those covering lipodystrophies (2-4), cellulite (5), obesity (6,7), and other fat depots such visceral fat (abdominal, perirenal, pericardial), and perivascular fat (8).

 

Along with the gut (9), subcutaneous adipose tissue is thought to be one of the largest endocrine organs in the body (10). Subcutaneous adipose tissue houses immune cells including monocytes/macrophages, mast cells, and lymphocytes, which produce some of the hormones secreted by fat tissue (11,12). Greater amounts of fat and immune cells result in an inflammatory process that can lead to insulin resistance and slow intrinsic pumping of lymphatic vessels, which, in turn, may prolong inflammation in this tissue (13).   

 

Patients, most often women with swelling, have slow blood flow in, and lymph flow out of, depots of increased fat on the abdomen (14,15) or the gynoid area (hips, thighs and buttocks) (16). Poor blood and lymph flow through fat tissue results in accumulation of fluid, cell waste material, proteins, cells and other metabolic products in the extracellular matrix (ECM) around adipocytes and other components of adipofascia, resulting in a hypoxic environment, especially in adipocytes furthest from their nutrient and oxygen sources. These adipocytes then send signals that recruit more immune cells, resulting in a state of sustained inflammation and tissue degradation. Connective tissue then replaces degraded tissue in a process called fibroplasia or fibrosis. When tissue ischemia occurs or ECM accumulation outpaces its degradation, fibrosis may become unchecked and lead to widespread pathological remodeling of the ECM culminating in permanent scar tissue that completely inhibits flow through the adipose tissue (17).

 

Obesity is a main cause of densification of fascia and fibrosis development in loose connective tissue (18). The result is a fibrotic mesh around adipocytes and fat lobules which has been well described (19). This sick fat, or adisopathy, increases the risk of metabolic disease (20). In addition, more fibrotic adipose tissue is less responsive to mobilization and reduction attempts through diet, exercise, use of weight loss medications, or bariatric surgery (19,21,22). All the SAT disorders in this chapter have a component of fibrosis in the tissue that prevents loss by usual measures. An important goal is to determine why the loose connective tissue in SAT diseases becomes fibrotic and adisopathic to prevent its occurrence and progression and treat when identified.

 

LIPEDEMA

 

Lipedema is a common SAT disease that was first described in 1940 at the Mayo clinic by Drs. Allen and Hines (23). A second seminal paper in 1951 provided a description of lipedema that is still commonly used for clinical diagnosis. Lipedema occurs almost exclusively in women but has been reported rarely in men (24-26).

 

Lipedema fat is located just under the skin on the limbs including upper arms, hips, buttocks, thighs, lower legs, generally sparing the trunk and feet. It feels nodular when palpated, may be painful to touch, and often has prominent superficial veins. Lipedema tissue can be found under the umbilicus and in some woman, a deeper nodular adipofascia is found in the lateral abdomen. This inner nodularity may reflect changes in the ECM that may be a precursor to lipedema fat if abdominal obesity develops. Disease defining key questions and physical examination characteristics can help to establish the diagnosis of lipedema (Figure 1).

Classification of Lipedema

 

Lipedema is classified by stages and types (27). In Stage 1 (Figure 2) the skin surface is normal over an enlarged hypodermis that already has palpable pea-sized nodules in the fat. These pea-sized nodules represent enlargement of and fibrosis in the ECM and in the connective tissue surrounding the fat lobule. Stage 2 skin is uneven with indentations (like cellulite) representing thickening and contraction of underlying connective tissue fibers over increased fat with small to larger hypodermal masses. Lobular extrusions of skin, fat and fascia tissue in Stage 3 represent significant loss of elasticity in the adipofascia drastically inhibiting mobility; blood flow in and lymph flow out of the lobules is reduced resulting in inflammation followed by fibrosis; it is in this stage that fibrosis in the tissue becomes prominent and clearly palpable; fibrosis may or may not affect the skin and the skin may develop thinning and a looser connection to the underlying hypodermis (Figure 1). Modifications of diagnostic criteria for lipedema have been suggested (28).

 

Lymphedema can occur at any stage, but is more often found in women with Stage 3 lipedema when it is often called lipo-lymphedema or Stage 4 (26). Rather than use this combined term, however, it is preferable to identify the lipemia stage and state whether lymphedema is also present or not. Lymphedema can be identified in women with lipedema by visible swelling of the hands or feet, pitting edema, asymmetry between the size of one limb versus the other, and/or a positive Stemmer sign. A positive Stemmer sign occurs when edema in the limb makes it difficult to pinch skin on the great toe, top of the foot, finger, or dorsal hand. A negative Stemmer sign occurs when only skin is pinched. Other differences between lipedema and lymphedema include symmetry (lipedema tissue occurs symmetrically versus lymphedema, which is usually unilateral), sparing of the hands and feet in lipedema, and report by patients of pain in lipedematous but not lymphedematous tissue.

The type of lipedema is defined by its anatomical location (29). Women with Type I lipedema have affected fat on the pelvis, buttocks and hips (saddle bag phenomenon). Women with Type II have affected fat from the buttocks to knees with formation of a tender deposits of fat around the inner side of and below the knee. Women with Type III lipedema have affected fat from the buttocks to ankles where a prominent “cuff,” or ledge, of fat tissue develops. Women with Type IV lipedema fat have affected arms and women with Type V lipedema, a rare type, have only affected lower legs. The most common phenotype of women with lipedema are combinations of II and IV or III and IV (Figure 3).

Prevalence of Lipedema

 

From one specialty lymphedema/obesity clinic in Germany, the prevalence of lipedema in women was estimated to be 11%. Estimates from similar clinics reported prevalence rates of lipedema ranging from 15 to 18.8% (30,31). The prevalence of lipedema in children in the United States in a vascular clinic was reported to be 6.5% (32). Examination of 62 women outside of clinics in Germany found a prevalence rate for all types of lipedema of 39% (33).  Using the lowest prevalence estimate in adults of 11%, over 16 million women in the US may be affected with lipedema.  

 

Genetics of Lipedema

 

The gene or genes underlying lipedema are not known, but another affected immediate family member has been reported in up to 60% of women (34-37). This is compatible with an autosomal dominant inheritance with incomplete penetrance (38) in which an affected parent has a 50% chance of passing lipedema to their child. Supportive of a genetic component, lipedema has been reported in children (32) and as early as infancy by some women. The phenotypic expression of lipedema may vary amongst affected females, especially if there is also obesity in the family. Males that carry the putative gene do not generally exhibit the phenotype, even the fathers of affected daughters. 

 

A mutation in the POU1F1/PIT-1 gene has been shown to cause multiple anterior pituitary deficiencies including thyroxine and growth hormone (GH) deficiency. A PIT-1 mutation was associated with the phenotypic presentation of lipedema in a short mother but not her short son who also carried the mutation, and not in her normal height daughter who did not carry the mutation (39). In mice with GH receptor (GHR) antagonism or lacking GH function, subcutaneous adipose tissue is increased more than other fat depots similar to lipedema in humans (40). No other cases of women with lipedema and a mutation in PIT-1 have been reported to date and women with lipedema are not known to be more likely to have short stature. Classic features of lipedema can be found in people with Williams syndrome caused by a chromosomal 7q11.23 microdeletion of ~1.6 million base pairs, which includes the elastin gene ELN (41). Loss of elasticity results in the reduction of the ability of tissue to contract back after being stretched. Changes in elasticity may therefore allow more fat to grow.  These reports suggest there may be more than one genetic mutation causing expression of the lipedema phenotype. Additional genes that may be important in the development of lipedema have been reviewed (42).

 

Pathophysiology of Lipedema

 

The cause of lipedema remains unknown. Given the predominance of occurrence in women, it is tempting to consider sex steroids, especially estrogen, as major triggers or contributors of this condition. That knee laxity in women peaks when estrogen levels decline between ovulation and post-ovulation is indictive of estrogen’s effect on connective tissue (43). Other observations that support this effect include reports that lipedema is often first noticed at the time of puberty in young girls and occasionally following pregnancy, when multiple hormone levels are high, including estrogen. Although data in men is sparse, those reported to have lipedema tend to have low testosterone or liver disease, both of which are associated with a relative increase in estrogen levels and therefore a higher estrogen to testosterone ratio (21). While higher levels of testosterone in women with polycystic ovarian syndrome are not protective against lipedema, the adipose tissue in women with this condition may be predisposed to lipedema due to abdominal obesity and inflammation associated with pre-diabetes or diabetes. A causative role for estrogen in the expression of lipedema remains speculative until well-controlled studies are conducted that quantify sex hormone levels, sex hormone receptors, tissue effects, metabolism or sex hormone driven pathways in men and women with lipedema. 

 

PROPOSED THEORIES TO EXPLAIN LIPEDEMA

 

Theory 1: Abnormal Blood Microvasculature

 

We and others (36,44,45) have advanced the theory that increased compliance from structural changes in connective tissue results in the ability to hold on to fluids, proteins and other constituents within the ECM and is causally important in the development of lipedema. As in lymphedema, changes in lipedema tissue may occur globally but are likely to also be found regionally in the same limb (46). Over 50% of women with lipedema are thought to have some kind of joint hypermobility consistent with a connective tissue disorder (25). Most women with lipedema and hypermobility fall into the Ehlers Danlos spectrum of disorders, the gene for which is not known (47,48). This hypothesis is consistent with loss of elasticity in tissue resulting in classic features of lipedema in Williams syndrome. Structures in loose connective tissue that contain elastin include blood vessels, lymph nodes, and connective tissue fascia that helps loose connective tissue hold its shape. Initial lymphatic vessels do not have elastic fibers, but elastic fibers support lymphatic vessels to open and close in response to pressure changes in the tissue; loss of elasticity could reduce the ability of lymphatic vessels to open with increased pressure in the ECM. Capillaries do not have elastic fibers but the loose connective tissue surrounding them does; as loose connective tissue enlarges due to growth of adipocytes, capillaries are at risk for dilation and distortion. Dilated and/or distorted capillaries may release their contents into tissues at a higher rate and/or amount in lipedema which initially, lymphatic vessels promptly pump out. Over time, due to compliance in fascia surrounding cells, malfunction of lymphatic vessels, and increased infiltrate leaving altered capillaries fill the ECM, with protein dense and salt-rich (49) deposits that accumulate in the interstitial space clogging flow through the tissue resulting in hypoxia. Hypoxia results in the secretion of hypoxia inducible factor (HIF)-1 by local adipocytes, which stimulates hypoxia response elements on a number of genes including the vascular endothelial growth factor (VEGF) gene and inducing proliferation of stem cells in the adipose tissue (50). Levels of VEGF have been shown to be elevated in women with lipedema (n=9) compared to women without lipedema (n=5) (51), supporting an underlying role for hypoxia in the pathogenesis of lipedema. 

 

Lymph fluid induces adipogenesis when added to adipocytes (52). Therefore, accumulation of pre-lymph fluid in the ECM may be a stimulating factor in adipogenesis. Mesenchymal stem cells isolated from lipedema stromal vascular fraction (SVF), a  heterogeneous collection of cells surrounding adipocytes within adipose tissue, contained the connective tissue cell marker CD90+ and endothelial/pericytic marker CD146+ (53). With ~50% of cells in the SVF expressing +CD146+, perivascular cells (pericytes) play a physiological role in vascular development and homeostasis (52). The presence of such high numbers of pericytes is consistent with a chronic capillary injury in lipedema leading to increased need for repair and increased protection of vessels.

 

As overworked lymphatic vessels eventually lose function, microaneurysms form in the lymphatic vessels in lipedemadous tissue, becoming high risk for breakage and leakage analogous to what happens in lymphedema (54,55). Adipokines, especially large adipokines such as leptin and monocyte chemoattractant protein (MCP)-1, become secreted primarily into the lymphatic system rather than blood capillaries (56). It would then follow that adipokine flow out of lipedema loose connective tissue would be diminished and systemic levels lower (e.g., leptin levels), leading to larger quantities of adipose tissue necessary to achieve weight homeostasis. 

 

Other potential contributors to expression of lipedema include release of lipids from leaky lymphatic vessels in the gut and tissue level (57), which could mediate induction of adipogenesis and have an important role in the development of the loose connective tissue in lipedema (58). Finally, inflammation in response to hypoxia or injuries could facilitate the development of fibrosis within loose connective tissue, not only reducing flow through the tissue further, but also impeding fat loss during weight reduction (19,21,22).

 

Theory 2: Abnormal Lymphatic Vasculature

 

Another theory posits that fluid accumulation in the ECM results from a primary defect in lymphatic vessels. Such accumulation enhances permeability issues in surrounding blood microvessels (59). In support, of this hypothesis, one study of women with lipedema and obesity noted a mismatch in the number of lymphatic vessels and the increased numbers of blood vessels in affected tissue (60). Instead there was an increase in the size (area) and area/perimeter ratio of the lymphatic vessels. Increased angiogenesis but fewer numbers and dilated lymphatic vessels has also been reported in a diet-induced obesity model in mice (61).  In another supportive study of lipedemadous tissue free of lymphedema, an expansion in the size of lymphatic vessels but no significant changes in transport in of lymphatic fluid was reported (62). However, against this hypothesis of a primary defect in lymphatic tissue as the proximal cause of lipedema is that lymphatic vessel function as determined by lymphangioscintigraphy appears normal in many women with early stages of lipedema and only later can reductions in lymphatic flow rate or function be detected in many women with late stage lipedema (54,63,64).  

 

Markers of Obesity, Cardiometabolic Health, and Aortic Disease in Women with Lipedema

 

Hypertrophic adipocytes, a marker of an inflammatory environment at risk for insulin resistance and other metabolic dysfunction, are reported in loose connective tissue in lipedema from women regardless of whether they were obese or not (58,65). Adipogenesis has also been identified in lipedema loose connective tissue (58) as has hypertrophy and hyperplasia of adipocytes in people who developed obesity after lifestyle changes. Unhealthy hypertrophic adipocytes undergo necrosis and become surrounded by macrophages that phagocytize the dead adipocytes forming crown like structures on histological exams of tissue. Crown-like structures have also been found in the loose connective tissue of women with lipedema (53,58). 

 

Adipose tissue stem cells collected from subcutaneous adipose tissue from people with obesity have reduced adipogenic potential and proliferative ability (66). The same reduction in adipogenic potential including a reduced capacity to produce leptin by cells in culture was found for adipose tissue removed by tumescent liposuction from women with lipedema compared to women without lipedema (67). These data support the possibility that even in early stages of lipedema when BMI is in the non-obese range, lipedema fat tissue shares characteristics of adipose tissue taken from people with obesity. Thus, even though femoral adipose tissue is known to be cardioprotective (68), this association weakens in later stages of lipedema. The later the stage, the greater the obesity and metabolic risk, including lower high density lipoprotein (HDL) cholesterol levels, higher diastolic and systolic blood pressures, higher reported history of hypertension, and higher percentages of pre-diabetes (69).  As such women with advanced lipedema should be closely monitored for these conditions as part of their ongoing care.

 

Women with lipedema are thought to have a connective tissue disease along the spectrum of hypermobile Ehlers Danlos. Transthoracic 2D echocardiography (2DE) and Doppler imaging revealed that women with Stage 2 lipedema in their early 40s with BMI ~30 kg/m² had impaired left ventricular apical rotation and left ventricular twist compared to people with lymphedema and those without either disease (70). Another paper by the same group used 2DE and Doppler imaging demonstrated enlarged ascending aortic systolic and diastolic diameters resulting in aortic stiffness in women with lipedema compared to controls (44). Individuals with Williams syndrome with loss of elasticity and features of lipedema also have aortic stiffness (71). These cardiac changes may reflect an underlying connective tissue disorder in women with lipedema and the possible need for cardiovascular screening even if lipid levels and other markers of metabolic syndrome are normal.

 

Imaging of Lipedema

There are currently no imaging exams that can be used to definitively differentiate lipedema fat from non-lipedemadous adipose tissue.  However, some imaging studies may be useful.  Nuclear medicine lymphangioscintigraphy (NM LAS) may be helpful in differentiating the presence of lymphedema in patients with lipedema. Flow of Technetium-99m-sulfur colloid injected dermally and taken up by the lymphatic vessels starting at the toe or finger webbing can be normal in lipedema (72), or the lymphatics can be tortuous especially below the knee (73). Other authors found slower lymphatic flow and a marked asymmetry of the lymphatic system in women with lipedema as compared with women without lipedema (74,75).          

 

Dual energy X-ray absorptiometry scans (DEXA) can be used for assessing whole body composition including regional fat mass and lean body mass in addition to bone mineral density; some scanners also estimate visceral fat mass. One study suggested that DEXA can be used to strengthen the confirmation of a diagnosis of lipedema in women, differentiating them from women without lipedema by a cutoff value of 0.46 for fat mass in the legs (kg) adjusted for BMI (76). Even though many women with lipedema also have obesity, the authors assert this cutoff value allows for a separation of lipedema of the legs from women without lipedema regardless of obesity.

 

Ultrasound of lipedema tissue compared to control tissue or tissue from women with lymphedema demonstrates thinner skin in agreement with previous data (77), and increased thickness and hypoechogenicity of the subcutaneous fat throughout the lower limb suggesting a diffuse increase in aqueous material (78). The hypoechogenicity was most significant in the distal extremity (medial calf) and may provide support to a clinical diagnosis when found.  Another group found no difference between ultrasonographic features of women with and without lipedema including compressibility and echogenicity (79). The control women were reported to have obesity or lipohypertrophy, an enlargement of the legs that is phenotypically similar to lipedema but painless. The definition of lipohypertrophy is unclear in the literature where authors have stated that symptoms of lipohypertrophy resolve with elevation suggesting a fluid component associated with the fat tissue (80). In personal communication with the authors, they state the relief of symptoms is due to lowering of pressure on the venous system suggesting that venous disease is important in the diagnosis of lipohypertrophy. Other authors state that lipohypertrophy is a precursor to lipedema which may explain why the latter ultrasound data showed no differences. Clearly, better means of distinguishing lipedema from those with larger legs but no lipedema is needed.

 

Finally, widening of lymphatic vessels up to 2 mm has been found by magnetic resonance imaging (MRI) of the legs of women with lipedema; women with lipedema and lymphedema had lymphatic vessel enlargement >3 mm (81). If this dilation of lymphatic vessels is consistent with lymphostatic decompensation (failure of lymphatic vessel function) in lipedema as the authors suggest, then salt should be found in the skin of women with lipedema as lymphatic vessels regulate Na+, Cl– and water in the skin, where reduced lymphatic vessel numbers are paralleled by increased blood pressure (82). Indeed Crescenzi et al. found increased salt in the skin and loose connective tissue of women with lipedema compared to women without lipedema, even in earlier Stage 1 lipedema where women tend to not have obesity (49).

 

Conditions Associated with Lipedema

 

OBESITY

 

Women with lipedema are often are often thought of as having common obesity whether or not they meet BMI criteria for this condition. The two striking differences between women with lipedema and women with obesity are that women with lipedema often have tenderness of the affected tissue and/or easy bruising of the skin overlying the lipedema fat, which is not found in women with common obesity (Table 1). However, some women with lipedema do not have pain in their tissues.  It is unclear if women with lipedema with pain have the same disease as women without pain. Of note, women with lipedema may have no pain in their lipedema fat tissue when they are well-controlled under treatment regimens, however, they should still be considered to have lipedema. For example, women with lipedema who eat low inflammatory foods, avoiding processed starch and sugar, who exercise most days of the week and wear compression garments on their legs can have minimal to no pain. Therefore, a good history is important to identify a history of pain in the tissue that would be indicate the presence of lipedema. As described above, helpful measures to differentiate women with lipedema from women with common obesity include the disproportionate distribution of their adipose tissue between the trunk and legs, any family history of lipedema, as well as a historical inability to lose much fat from the lipedema-affected areas. On the other hand, when women with obesity and lipedema lose more substantial weight through medical or surgical interventions, they can lose some fat from the areas with lipedema, which can then leave them with rolls of excess skin along in the areas of remaining lipedema fat tissue (Figure 4). 

 

Table 1. Clinical Similarities and Differences Between Lipedema and Obesity
Sign/Symptom	Lipedema	Obesity
Sex affected	Females	Females and Males
Onset	Puberty	Any age
Increased fat	Common	Common
Gynoid disproportion	Common	Possible
Influenced by lifestyle	No	Yes
Tenderness of the tissue	Common	Absent
Easy bruising	Common	Absent
Pitting edema	Uncommon	Uncommon
Stemmer sign	Negative	Negative
Able to lose fat from the legs/hips	Minimal	Common

 

Obesity (especially abdominal/visceral obesity) and/or polycystic ovary syndrome can worsen lipedema severity. This is thought to be mediated by increases in adipokines, tumor necrosis factor alpha (TNFa) and leptin that often accompany these conditions, which are associated with venous disease (83). Venous dysfunction that can lead to leakage of fluid back into tissue due to reflux may also be an important contributor to worsening of both lipedema and lymphedema, when present (84,85). 

LYMPHEDEMA

 

Women with lipedema are at risk for developing lymphedema, which may happens in lipedema Stage 3 > Stage 2 > Stage 1 (26). The presence of lymphatic disease or lymphedema increases the risk of cellulitis and wounds, which can be difficult to manage and disfiguring. Women with heavy limbs and swelling should be considered for manual lymphatic drainage and deeper tissue therapies such as instrument assisted soft tissue therapies (e.g., Astym therapy, Graston technique) or manual therapies (e.g., myofascial therapies or other deep tissue therapies (86)), followed by compression plus reduction of obese adipofascia to reduce the risk of developing lymphedema.

 

PSYCHOSOCIAL

 

Psychosocial issues are prominent in women with lipedema including appearance-related distress and depression (87), which can result in eating disorders (88). This is not surprising in the United States where very thin women or photos of women that have been photoshopped to accentuate the appearance of leanness are posted on the internet and on television. Imagine how a woman in today’s society might feel who developed lipedema at puberty and is told to diet and exercise by friends, family and healthcare providers to lose weight, something that she has done for years to no avail. One author polled women in Germany and found a high rate of suicide attempts in women with lipedema (89). Lower mobility associated with lipedema and obesity were also found to affect quality of life in women living with lipedema (87) and may contribute to social isolation. Prevention and management of obesity in women with lipedema becomes paramount to maintain their quality of life. High anxiety is associated with hypermobile joint disorders (90), and because hypermobile joint disorders are associated with lipedema (25), anxiety should be assessed and treated to help women living with lipedema.

 

DERCUM DISEASE (PAINFUL LIPOMAS)

 

Lipedema can be present in the same individual who also has Dercum disease (see below), and in this instance, would be considered a mixed disorder. Authors have tried to differentiate women with lipedema from those with Dercum disease by examining populations and finding that people with Dercum disease tend to have other pain disorders including higher pain scores, fibromyalgia, abdominal pain, and migraines, and more often have lipomas, cognitive dysfunction and shortness of breath; whereas women with lipedema have more often fibrotic tissue, easy bruising, hypermobile joints, venous disease and edema of the feet (25).

 

Numerous other conditions apart from those described above have been associated with lipedema (Table 2). Of note, hypothyroidism is found in 27% of women with lipedema (25,26).  In one case, a woman with lipedema was described as having lymphedema and multiple symmetric lipomatosis (91).

Table 2. Co-Morbidities and Complications Associated with Lipedema (60, 92-94)
Musculoskeletal	Soft Tissue	Vascular	Other
Gait disturbance	Obesity; fat deposits	Lymphedema/Idiopathic Edema	Pain
Change in posture (e.g., lordosis)	Loss of skin elasticity	Dilated Capillaries Microangiopathy	Psychological distress/anxiety
Genu valgum and arthritis of the knees	Thinning of the skin	Bruising	Shortness of breath
Ankle pronation	Lipomas	Varicose veins Venous insufficiency	Cellulitis
Hypermobile joints (Hypermobile Ehlers Danlos?)	Cellulite; fibrosis	Cherry angiomas	Slow metabolic rate

 

Clinical Care of Women with Lipedema

 

Depending on whether the astute clinician makes the diagnosis of lipedema during the course of taking a history and physical, affected patients may more typically seek care for an associated co-morbidity. For example, women with lipedemia who have thyroid disease and/or obesity may regularly be referred by their primary care provider to an Endocrinologist. Endocrinologists should be clued in to a possible diagnosis of lipedema in women who present with difficulty losing weight from their hips, buttocks and legs, and who are convinced they have a thyroid issue, but thyroid labs are normal. In desperation, patients with lipedema may ask for a “complete set of thyroid labs” including thyroid stimulating hormone (TSH), free T4, free T3, reverse T3 and thyroid peroxidase (TPO) antibodies to ensure that there is no thyroid issue, which may cause tension during a clinical visit when a provider chooses not to order all these laboratories. Other times, women with joint hypermobility are often cared for by rheumatologists and orthopedic surgeons, and those with lipedema and venous disease are often followed by vascular surgeons, physical therapists and lymphedema specialists.

 

DIAGNOSIS

 

Once the possibility of lipedema is considered, a good medical history will include an assessment of the food eaten, patterns of exercise, and a timeline of development of lipedema signs and symptoms with special attention to hormonal transitions in women including puberty, pregnancy, or menopause. Additionally, helpful findings on history include pain and easy bruising in affected areas and a family history of similar traits in other female members. The upper arms and legs should then be examined for physical manifestations of lipedema as described in more detail below. In the author’s experience, diagnosing lipedema in a woman who presents thinking they have another condition, such as thyroid disease but with normal thyroid function tests, and providing education and treatment recommendations can be transformative for the patient’s life and greatly enhance the patient-physician relationship. 

 

The physical exam to diagnose lipedema can be performed quickly if a woman can be seen in her underwear after donning a gown.  Visual inspection to establish disproportionality between the upper and lower body fat should be done initially and include a measure of the waist and hip ratio, which is also helpful in diagnosing central obesity.  Following this, examination (both visually and by palpation of fat tissues) should be performed with special attention to characteristics described in Table 3.

 

Table 3. Examination of Subcutaneous Fat for Lipedema, With or Without Obesity
No Obesity
Head	Normal
Neck	Normal
Arms	Normal (nodular fat tissue may be found around cubital nodes)
Wrist	Normal
Hands	Normal; Stemmer sign negative (no edema)
Abdomen	Normal (nodules may be found deep laterally or under the umbilicus)
Buttocks	Increased loose connective tissue; may be nodular and heavy
Hips	Increased loose connective tissue; may be nodular and heavy
Thighs	Increased loose connective tissue; may be nodular and heavy
Medial knee	Nodular or enlarged fat pad; usually tender
Under knee	Fat pad; may be nodular
Shin	May be covered in fat making the shin hard to palpate
Lateral malleolus	May have fat pad underneath
Ankle	Cuff may be very small but present in Type III lipedema
Feet	Normal; stemmer sign negative
Skin	Bruising; livedo reticularis; may see peau d’orange with long-standing disease
With Obesity
Head	May have hair loss and increased fat
Neck	May have filling of the supraclavicular fossae
Arms	Nodular fat tissue on upper and/or lower arms and around cubital nodes; hanging fat on upper arm that may be heavy
Wrist	A cuff of fat may be present; bend the hand back to easily see the cuff
Hands	Fat may be found at the base of the thumb, between the MCP joints or over the hand
Abdomen	Increased deposit of fat above and/or below umbilicus
Buttocks	Increased loose connective tissue; may be nodular and usually heavy
Hips	Increased loose connective tissue; may be nodular and heavy
Thighs	Increased loose connective tissue; may be nodular and usually heavy
Medial knee	Nodular fat pad; usually tender
Under knee	Fat pad; may be nodular
Shin	Usually covered in fat making the shin hard to palpate
Lateral malleolus	May have fat pad underneath
Ankle	Cuff present in Type III lipedema
Feet	May have increased fat; Stemmer sign negative (no edema) when no lymphedema
Skin	Bruising; livedo reticularis; may see peau d’orange with long-standing disease
There is a wide variation in the phenotype of lipedema (see Figure 2 Types) therefore lack of one or more physical exam finding does not negative the presence of lipedema.

 

At present, lipedema does not have an International Classification of Disease (ICD)-10 code but an ICD-11 code of EF02.2 has been proposed.  In the meantime, other ICD-10 codes useful when caring for patients with lipedema are listed in Table 4.

.

Table 4. ICD-10 Codes for Clinical Visits for Patients with Lipedema
Sign/Symptom	ICD-10 Code
Lymphedema/Swelling (may be non-pitting)	I89.0
Edema unspecified	R60.9
Lipomatosis not elsewhere classified	E88.2
Chronic pain	G89.4
Venous insufficiency	I87.2
Varicose veins	I83.10
Overweight	E66.3
Other Obesity	E66.8
Obesity (ICD-10 code varies by BMI)	Z68

 

Treatments for Lipedema

 

FOOD PLANS

 

Many women with lipedema bring along family members that can attest to their healthy or minimal eating and beneficial exercise patterns as they tend not to be initially believed by healthcare providers. There is very little data on the use of diets to reduce lipedema fat.  Although poorly studied, it is generally accepted that lipedema fat is resistant to weight loss mediated through lifestyle, which compounds patients’ frustrations when weight loss expectations are not met. In the absence of specific recommendations, dietary counseling can focus on establishing healthy eating patterns for overall health improvement and weight management.

 

Food plans are important in helping manage obesity that accompanies lipedema with a minimal goal of stabilizing weight and a maximal goal of losing obesity weight. The most successful food plans are those with low processed carbohydrates including added sugars that reduce insulin levels and inflammation and, therefore, reduce adipogenesis (95); fasting between meals (no snacking) has been suggested (96). One group used a 1200 calorie diet along with complete decongestive therapy to reduce volume in the legs of women with lipedema (97), but evidence for long-term weight loss maintenance by this approach is lacking.

 

EXERCISE

 

Exercise is important for women living with lipedema as the muscle action helps pump blood and lymph fluid through the limbs. However, women with lipedema have ~67% of the normative value for quadriceps muscle strength compared to women without this condition matched for age and BMI (98). One theory is that fibrosis from the fat tissue extends into and reduces muscle function. The Dutch guidelines for lipedema recommend graded exercise programs aimed at strength training and conditioning for women with unhealthy lifestyles or physical limitations, although they recognize that the body parts affected by lipedema tend to increase in tissue volume despite activity (80). These authors also state that exercise and heat can increase swelling and pain in the lipedematous areas. Anecdotally, women with lipedema appear to benefit greatly from water exercises, which may be in part due to the compressive effect of water on the body that helps mobilize fluid and soften fibrotic tissues, as well as from water jets that may also help reduce fluid in the adipofascia. Some women with lipedema have a concern about showing their bodies in public due to the commonality of public body shaming (99). Cropped pant, swim tights and other swimwear coverings have enabled more women with lipedema to feel comfortable during public swimming.  Garments with compression are generally recommended for women with lipedema to wear during land-based exercises especially, when using Nordic poles that improve the adipofasica of the arms and legs.

 

COMPRESSION GARMENTS

 

Compression garments are usually worn on the legs with a high waist (to treat fat on the abdomen) and on the arms as needed. Compression can be lower in millimeters of mercury (mm Hg) for lipedema than for lymphedema. For example, 15-25 mm Hg or Class I 20-30 mm Hg, compared to Class II 30-40 mm Hg or Class III 40-50 mm Hg. The type of knit for a lower pressure garment can be circular knit, which means it is seamless and is knitted on a round cylinder. Circular knit garments have more stretch and are best suited for women with lipedema that have less lymphedema or swelling. They can also stretch to fit any shape and size. Flat knit garments have less stretch and therefore provide better edema control. Flat knit is recommended especially for women with lipedema who have an ankle cuff or unusual shape requiring a custom fit and usually have a seam. A durable medical equipment (DME) order can be provided to patients to take to a medical supply store if they are able to get insurance coverage for compression garments. Therapists treating patients with lipedema can provide guidance on compression wear.

 

VENOUS DISEASE

 

Venous insufficiency has been documented in 25% of women with lipedema (92,100). When pitting edema is present, venous insufficiency should be investigated in women with lipedema by a venous duplex ultrasound of the legs. These studies are performed in a vascular lab and should specify to look at the greater and lesser veins of the legs to evaluate for venous insufficiency and not just thrombus. Care should be taken to treat venous disease conservatively first as there is no data showing correction of venous insufficiency by surgical means will improve lipedema. Anecdotally in reports from women with or without lipedema, lymphedema can occur after surgical treatment of venous insufficiency of the greater saphenous vein (101).

 

BARIATRIC SURGERY

 

Women with lipedema without some upper body obesity may respond poorly to bariatric surgery with regard to weight loss (102) and often feel like failures or are mistakenly told (directly or indirectly) by their providers that it was their fault, with devastating psychological impact.  Indeed, women that lose minimal weight from their lower abdomen, hips, and legs after bariatric surgery should be examined for the presence of lipedema. Even with less-than-expected weight loss, patients with lipedema should still be considered candidates for bariatric surgery as several procedures (e.g., laparoscopic gastric bypass and sleeve gastrectomy) have shown weight-independent benefits on glucometabolic outcomes, especially prediabetes and diabetes, and cardiovascular risk. When women do lose weight and it includes a portion of their lipedema-affected regions, it often results in accentuation of the “saddle bag” look (See Figure 4) and may worsen their body image anxieties.  Optimally, women with lipedema should be identified prior to bariatric surgery, counseled on their condition and how it might influence their overall weight-loss response, and be offered complete decongestive therapy and compression garments to reduce the risk of developing lymphedema after bariatric surgery and to improve weight loss success.  In addition, pre-surgery is a good time to initiate consultation with a plastic surgeon regarding options of removal of excess skin removal once weight stability is established post-operatively (usually between 1 and 3 years).

 

LIPOSUCTION

 

Women with lipedema typically have several medically necessary reasons for undergoing liposuction to remove lipedema fat, including:

• Loss of mobility
• Reduced quality of life
• Joint damage or altered gait
• Chronic pain
• Failure to improve signs and symptoms associated with lipedema despite conservative therapy

 

Complete decongestive therapy including manual lymphatic drainage, compression garments, a healthy eating plan, and as much activity as allowed or possible are important before liposuction to improve outcomes. Due to the increased vascularity of the lipedematous tissue and blood loss with liposuction, post-procedure anemia is not uncommon. Therefore, labs prior to surgery should include a complete blood count (CBC) with platelet level as well as coagulation labs to include activated prothrombin time (aPTT), prothrombin time (PT), thrombin time (TT), andfibrinogen.  People with normal coagulation labs and easy bruising can have hereditary and acquired platelet defects, hereditary disorders of vascular and perivascular tissues including Ehlers Danlos Syndrome, and other disorders of blood clotting.  Any woman with lipedema and a personal or family history of bleeding or clotting should work with a healthcare provider to determine if additional testing is needed before liposuction surgery (103).

 

Removal of lipedema fat by liposuction that spares lymphatic vessels (wet, not dry, technique) has been performed primarily in Europe, especially in Germany, since the 1990s (104-107).  The fat is saturated with Klein solution which includes saline or lactated Ringers solution, an anesthetic such as lidocaine or prilocaine, epinephrine, sodium bicarbonate buffer(108), usually without steroid (109).  This tumescent technique provides turgor to the tissue allowing blunt microcannula to slide through the fat tissue avoiding creation of shearing forces and tissue damage. When power assisted, tiny, rapid vibrations of the microcannula break up fat which is then suctioned out of the tissue. Water jet assisted liposuction (WAL) uses jets of saline and Klein solution to release fat for suction with minimal damage to cells and vessels(106) without the waiting period required to tumesce the tissue. Laser assisted tumescent liposuction is another technique which some reserve for fibrotic areas such as the posterior thighs.

 

Most affected women undergo liposuction in stages, involving removal of an area of lipedema fat from the lower body and arms followed by a period of recovery and healing before returning to remove an adjacent region. The average number of surgeries for a women with Stage II lipedema ranged between two and three (110), but some had more than five (37). Patients are either awake during the liposuction procedure with or without conscious sedation (104,111,112), or general anesthesia, the former allowing for rapid recovery (111). Some medications used in general anesthesia reduce the pumping activity of lymphatic vessels (113-116). Prior to undergoing liposuction by a qualified surgeon, therefore, a patient should have a thorough understanding of the surgeon’s technique, whether the surgeon uses general anesthesia along with the type of analgesia, the number of surgeries performed by the surgeon and outcomes and their complication rate. After liposuction, the surgically treated areas may be quite tender and uncomfortable for days to weeks.

 

Most studies on liposuction are from surgeons performing the procedure, are not randomized or controlled, and do not include external oversight of data collection. Nevertheless, current data are compelling for benefit. Twenty-five women with lipedema had significant improvements in pain, tension in the legs, excessive warmth, muscle cramps, leg heaviness, tired legs, swelling, itching, general involvement of the skin, difficulty walking, quality of life, and appearance of the legs six months post-liposuction surgery (104). A larger study of 85 women from the same clinic demonstrated significant improvements six months after surgery for all complaints with the greatest improvement in quality of life (110). In a longer study from a different clinic, 21 women over an average of 3.7 years after their first liposuction procedure and 2.9 years after the second liposuction showed improvement in the parameters of body disproportion, swelling, edema and quality of life, except for bruising which improved in all but two of the women (105).  A retrospective study of women with Stage I or II lipedema from the same clinic, four, and eight years after liposuction, showed sustained improvements during follow-up for parameters including pain, sensitivity to pressure, edema, bruising, restriction of movement, cosmetic impairment, reduction of overall quality of life and overall impairment (117). The most interesting data was the reduced need for combined decongestive therapy four years after liposuction, which decreased further after eight years (37). 

 

Any surgery, including liposuction, requires that efficacy of the procedure and the medical necessity be demonstrated to the insurance company.  What are currently needed are well conducted randomized, controlled trials of sufficient numbers of patients with lipedema to determine which patients do and do not benefit from liposuction. In the meantime, documenting patient baseline characteristics and outcomes by surgeons in the United States will be important to understand the benefits of liposuction for lipedema in the US population compared to reports from other countries (e.g., Germany). It is notable that surgeons agree that quality of life is strongly and consistently improved by liposuction (104,110,117,118). 

 

COMPLETE DECONGESTIVE THERAPY

 

Complete decongestive therapy (CDT) is commonly recommended for the treatment of lymphedema and includes skin care, education on home exercise programs, manual lymphatic drainage (MLD) therapy, wrapping as needed to reduce fluid build-up, and skin care recommendations performed by physical and occupational therapists and licensed massage therapists that have undergone additional training. Many women with lipedema benefit from CDT with reduced pain, limb volume and capillary fragility (119-121). Near-infrared fluorescence lymphatic imaging (NIRFLI) has added additional techniques to MLD including the “Fill and Flush” method (122). Complete decongestive therapy also improves lymph flow in brain lymphatic vessels (123). Deeper tissue therapies to reduce fibrosis in the lipedema tissues may also be beneficial for patients with lipedema. 

 

PNEUMATIC COMPRESSION DEVICES

 

Studies have shown the benefit of advanced pneumatic compression devices (PCDs) in the treatment of lymphedema. There are also studies on the benefits of PCDs in the treatment of lipedema (119,124). Important for the distorted and dilated capillaries in lipedema (36,88), PCDs decrease capillary fragility (120), improving vessel quality. Along with manual therapy to improve flow of fluid through lipedema tissue, PCDs are also recommended in conjunction with liposuction surgery for lipedema (110). If a woman with lipedema responds well to manual therapy, or she tries a PCD and has a reduction in tissue volume, she should be offered PCD therapy to continue treatment at home when insurance will no longer cover CDT or when distance or commitments prevent regular professional visits. The PCD should ideally be an E0652 device with a segmented, multi-ported pump that allows for individual pressure calibration at each port. This allows the patient to alter pressure in areas of severe pain or for different shaped tissue. Pump garments should wrap around and treat the abdomen and pelvis when the legs are pumped, and the chest when the arms are pumped.  If basic compression pumps are prescribed (E0650; E0651), compression garments to protect the abdomen, pelvis, chest and/or head should be worn during pumping. Without these compression garments, fluid is pushed up the leg into the abdominal and pelvic area where it accumulates due to lymphatic dysfunction. As this fluid sits in the tissue with all its nutrients and protein, evidence suggests it may stimulate further adipogenesis (125). With an E0652 pump, the abdomen is treated along with the leg and the chest is treated along with the arm preventing pooling of lymph fluid. PCDs can be easily ordered by writing a prescription for durable medical equipment with multiple suppliers.

 

DEEP TISSUE THERAPY

 

Women with lipedema treated with deep tissue manual therapy have reduced pain, fat tissue on the legs, tissue volume, tissue fibrosis and leaky or fibrotic vessels (86,126). This deep tissue therapy is in the spectrum of meridian massage shown to reduce body weight (127) and is thought to  improve lymphatic flow through lipedema fat tissue. Massage also reduced fat in preterm infants (128). Instrument-assisted soft tissue (IAST) therapy has cc in lipedema fat tissue with noted reduction in palpable fibrosis after treatment. Instrument-assisted soft tissue  techniques include Astym therapy, which increased fibroblast activation and number, production of fibronectin, movement, and decreased pain in patients with fibrosis (129) and Graston technique which reduces pain and improves movement (130), and are performed by physical therapists who can be located on websites for these techniques. Traditional Chinese gua sha tools or bian stones have been used to improve pain and function (131) as has cupping (132).  Pressure required to occlude lymphatic function in the upper limb was found to be 86 mm Hg, suggesting that deeper treatment into the tissue is safe, for example at pressures ranging from 15 to 25 mm Hg used to reduce scars (133), and will not damage lymphatic vessels (122).

 

PSYCHOLOGICAL SUPPORT

 

Women with lipedema have often spent years looking for answers and help for their condition.  Healthcare providers often hold strong negative attitudes and stereotypes about people with obesity, which may reduce the quality of care they provide to women with lipedema (134). Poor quality of life associated with mobility and appearance-related stress associated with lipedema can result in depression (87). For many patients, they experience a huge sense of relief when they finally get a diagnosis of lipedema after trying a myriad of diets and exercise programs, even bariatric surgery to lose the lipedema fat. In addition to treatment recommendations in this chapter, there are a number of things a healthcare provider can do to help improve the lives of people living with lipedema: 1) Reduce focus on body weight in lipedema and provide education on improving metabolism, reducing inflammation and improving quality of the lipedema fat tissue (reducing fibrosis); 2) Use motivational interviewing focusing on strides made to improve markers of health including healthy eating, activity, metabolic lab markers, and social interactions; 3) Ensure that the clinic environment is welcoming with tables and chairs that allow women with larger lower bodies to be comfortable; 4) Ensure that patients with lipedema have identity safety in clinic situations and encourage healthy social interactions at home and in on-line social groups that also provide safe affiliations known to improve satisfaction of life for women with lipedema (135); and 5) Ensure that the continuum of care includes adequate referral resources for counselling, physical therapy and message, and when indicated pain management specialists. Including providers that understand lipedema and the physical and the psychological burden this diagnosis carries for patients is especially important (134).

 

MEDICATIONS AND SUPPLEMENTS

 

There are no medications and supplements specifically for lipedema.  Instead, recommendations regarding use of medications and supplements for the treatment of lipedema should focus on reducing tissue inflammation, fibrosis, swelling, pain, and pharmacologic weight loss management for those who are overweight or have obesity.  Supplements used for lipedema are, in part, based on literature for lymphedema and venous disease, both complications of lipedema.  Some medications exacerbate symptoms in lipedema and should be avoided (Table 5). 

 

Sympathomimetic Amines

 

Sympathomimetic amines (SA) such as phentermine and amphetamine are approved by the food and drug administration (FDA) for the treatment of obesity. Sympathomimetic amines bind to adrenergic receptors (AR) located on adipocytes to induce lipolysis, reducing the storage of fat.  Adrenergic receptors are also located on blood vessels and lymphatic vessels. Activating AR on blood vessels induces vasoconstriction. Activating AR on lymphatic vessels improves the efficiency of lymphatic pumping by increasing the force of contraction (136); medications or supplements that improve lymphatic pumping are lymphagogues. Amphetamine and dextroamphetamine alone or in combination are also FDA-approved for the treatment of attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), and narcolepsy.  The use of SA for treatment of lipedema may be beneficial in reducing fat and improving lymphatic pumping. A retrospective questionnaire study found that low dose sympathomimetic amines improved quality of life, reduced weight, clothing size, pain and leg heaviness in women with lipedema (137). Contraindications of sympathomimetic amines include advanced arteriosclerosis, symptomatic cardiovascular disease, moderate to severe hypertension, hyperthyroidism, known hypersensitivity or idiosyncrasy to the sympathomimetic amines, and glaucoma.

 

Diosmin

 

Diosmin is a bioflavonoid found in the rind of citrus fruit and is traditionally prescribed for the treatment of inflammation associated with chronic venous insufficiency. Diosmin was shown to reduce oxidative stress markers in people with chronic venous insufficiency (138). Diosmin also functions as a lymphagogue, and in combination with its anti-inflammatory activity, reduces edema (138). Women with lipedema who have a feeling of heaviness in their legs, obvious edema, chronic venous insufficiency or Stage II and III lipedema report feeling less pain and improved swelling on diosmin based on the author’s experience. Diosmin can be found over the counter or ordered by prescription as a medical food.  Placing lemons, limes or other citrus in water to soak before drinking is a way to intake diosmin throughout the day.

 

Metformin

 

There are no current medications that can be used to reduce fibrosis already present in lipedema fat tissue, for which liposuction and deep tissue therapy are better modalities.  Metformin and resveratrol have been shown to reduce the development of hypoxia-inducible factor (HIF)-1 inflammation and fibrosis in mice fed a high fat diet (139). Metformin also prevented fibrosis and restored glucose uptake in fat after insulin stimulation, although it did not prevent side effects of doxorubicin that included tissue loss and inflammatory response (140).  Metformin should be considered early in women with obesity and lipedema Stages II and III where fibrosis in the fat tissue is prominent, as well as in women who have signs of metabolic syndrome (69).

 

Selenium

 

Selenium is a mineral found in the soil and in high concentration in Brazil nuts (Bertholletia excelsa). Selenium has been demonstrated to have anti-inflammatory effects on multiple levels of the inflammatory cascade (141-144).  Edema was significantly decreased after selenium intake in two placebo-controlled trials for people with lymphedema (145,146) and improved complete decongestive therapy while reducing the incidence of erysipelas infections in patients with chronic lymphedema (145). Each Brazil nut contains approximately 200 mcg of selenium with a no observed adverse effects for dietary intake of selenium up to 800 mcg daily (147).  Care must be taken to follow blood selenium levels as selenium deficiency and excess can both adversely affect glucose and lipid metabolism and potentiate the risk of development of type 2 diabetes in several animal studies, with less clear associations in human studies (148). One case report of a woman with lipedema showed reduced leg volume with a combination of selenium and Butcher’s broom (149).

 

Table 5: Medications and Supplements to Avoid When Treating People with Lipedema
Medication	Used for	Reason to avoid
Thiazolidinediones	Diabetes	Increases subcutaneous fat tissue; fluid retention
Calcium channel blockers	Hypertension	Fluid retention
Oral Corticosteroids*	Reduce inflammation	Weaken tissue; fluid retention; rebound inflammation
NSAIDs	Pain	Fluid retention
Sex hormones	Hormone replacement	Fluid retention; implicated to effect development of lipedema
Beta blockers	Cardiac health	Fluid retention
Clonidine	Hypertension	Fluid retention
Gabapentin	Pain	Fluid retention
Furosemide**	Edema	Concentrates protein in the interstitial organ eventually halting fluid flux

*Nasal or inhaled corticosteroids have less effect; oral corticosteroids should be used when medically necessary

**Aldactone and hydrochlorothiazide have less adverse effects in women with lipedema

NSAIDs: Non-steroidal anti-inflammatory drugs

 

Concluding Remarks on Lipedema

 

Lipedema is a common disease mostly in women resulting in an enlargement of the adipofascia on the limbs due to excess fibrosis in the tissue that typically defies expectations for loss by lifestyle, weight-loss medications, and bariatric/metabolic surgical interventions. The presence of fibrosis, especially in the interstitial spaces where it may serve to restrict blood and lymph out flow, is thought to contribute to the resistance of this tissue to weight loss. Women with lipedema should be recognized prior to weight loss efforts so that expectations can be discussed, and manual therapies and other treatments can be considered to improve outcomes.  Medications and supplements can be tried, but liposuction should be considered for women with lipedema who fail conservative measures and following weight loss with medications and/or bariatric surgery. There is a wide variety of presentations of lipedema in women due to co-morbidities and other genetic and environmental influences. Therefore, every affected woman should be considered on a spectrum and treatments personalized.

 

FAMILIAL MULTIPLE LIPOMATOSIS

 

Familial multiple lipomatosis (FML) is a rare adipose disorder (RAD) of multiple lipomas in subcutaneous fat (OMIM 151900).  Some members in an FML family may have only a few lipomas whereas others may have hundreds to thousands; it is not understood why there is unequal penetrance in families. Lipomas usually are not painful or tender to the touch except while growing; they may also cause a slight feeling of itching or burning when forming. Some lipomas can be tender if they develop in areas of pressure such as on the back of the legs, the lower back (pressure from a chair), or the lateral wrist due to repetitive stress such as comes from using a computer mouse (150,151). Another example of trauma-induced lipomatous growth includes movement of the xiphoid process (152).  

 

According to older FML literature (153), "pain may suddenly develop in one of the lipomas (called lipoma dolorosa), and will gradually extend to involve more and more of the discrete lipomas.” The authors state that lipoma dolorosa syndrome in families with FML is not the same as Dercum disease (see below) (154). This is confusing as individuals with painful lipomas in an FML family have been described as having Dercum disease. While painful lipomas in a person with FML may also be on the spectrum of Dercum disease, a more precise name is FML with painful lipomas, especially when a family history of FML is known.

 

It is interesting that by observation in some families with FML, the men will develop lipomas and the women often develop obesity in line with lipedema. This suggests an overlap between the development of one fat disorder (FML) and another (lipedema) and should prompt more detailed questions regarding other potentially affected family members.

 

Prevalence of FML

 

Familial multiple lipomatosis is considered to be a rare disease with an estimated prevalence of 1/50,000 (155).

 

Genetics of FML

 

Familial multiple lipomatosis is usually inherited in an autosomal dominant manner with males and females equally affected. The gene High Mobility Group AT-Hook 2 (HMGA2; 12q15) has been implicated in FML but is not thought to be causative. A mutation in partner and localizer of breast cancer (BRCA2, DNA-repair associated gene), called PALB2, was described in a family with FML (156). PALB2 is an intranuclear protein that anchors BRCA2 to nuclear structures.  PALB2 mutations are associated with a 2-fold increased risk of breast cancer, a Fanconi anemia subset, pancreatic cancer and ovarian cancer (156).

 

Conditions Associated with FML

 

In case reports, FML has been associated other rare or unusual disorders (Table 6).  Because multiple lipomas are often linked with mutations in tumor suppressor genes, FML can be considered clinically to be a marker for the presence of an underlying tumor suppression gene mutation and affected patients and their families should be appropriately screened.

 

For example, in MEN-1, lipomas have  been reported in association with a recessive mutation in a tumor suppressor gene (157).  In a family with retinoblastoma and multiple lipomas, the lipomas were present in people with a gene mutation in the RB1 gene who did not develop retinoblastomas (158). Multiple lipomas in Cowden's disease can be due to a germline inactivation of PTEN/MMAC1 that renders a person susceptible to thyroid and breast malignancies (159). Other genes including other tumor suppressor genes have been implicated in the growth of lipomas (160). For example, a mutation was found in the tumor suppression gene PALB2 in a family with multiple lipomas suggestive of a diagnosis of FML (156).  And finally, lipomatosis like that of FML has also been reported in two cases after chemotherapy (161,162), a treatment known to be associated with an increased risk of cancer development.  Because of these associations, people with multiple lipomas should be considered at increased risk for cancers and a referral to a geneticist considered.

 

Table 6. Disorders Found in Association with Multiple Lipomas

Atypical mole syndrome (163)

Gastroduodenal lipomatosis (no gastroduodenal lipomatosis in proband’s mother) (164)

Celiac disease (165)

Cowden’s disease (159)

Gastrointestinal stromal tumor (166)

Interhemispheric brain lipoma with corpus callosum hypoplasia and the malformation of cortical development in a young woman with refractory epilepsy (167)

Neurofibromatosis (NF1) (168)

Multiple endocrine neoplasia (MEN)-1 (169)

Retinoblastoma (Rb1) (158)

Legius Syndrome (SPRED 1); autosomal dominant; multiple café-au-lait macules and skin fold freckling, ± macrocephaly, a Noonan-like appearance, learning difficulties and/or attention deficit in children and lipomas in adults (170)

 

Pathophysiology of FML

 

The pathophysiology of lipoma growth in FML is not known. Single lipomas of subcutaneous fat tissue are the most common benign tumor growths in humans and may be induced by genetic changes, trauma, inflammation, or other causes.  As detailed above, multiple lipomas tend to be linked with tumor suppression genes. People with FML are known to be insulin sensitive, therefore an insulin-resistant metabolic cause of FML is unlikely (171). Additionally, the presence of the lipomas themselves do not confer insulin resistance.

 

Imaging of Lipomas in FML

 

Lipomas in FML are identified by palpation as connected to skin, surrounded by fat or connected to other structures such as muscle or solid fascial structures. Localized pain can assist in finding smaller lipomas. Silky or tight clothing can also assist in palpation. Sonographic evaluation is the best most inexpensive means to identify lipomas other than palpation, but the average sensitivity for three Radiologists when retrospectively reviewing sonographic exams of lipomas was only 48%, and average accuracy was 59% (172). Magnetic resonance imaging without contrast can be used to find lipomas (173), but small lipomas, lipomas without a capsule, and lipomas with minimal fibrosis or surrounding edema remain difficult to identify.  Radiologists were able to render the correct diagnosis for lipoma versus liposarcoma in 69% of cases (174). Computed tomography (CT) scans have been used to differentiate lipomas from liposarcomas (175) but should be used after sonography and MRI to avoid excess radiation exposure.

 

Evaluation of the Patient With FML

 

The initial workup for people with FML includes a family history of lipomas and cancer, and any associated conditions such as nevi or neuropathy. The exam incudes assessment for multiple lipomas usually located on the trunk, lower back, arms, and thighs; rarely on the upper back or calves. Skin should be examined for nevi and cherry angiomas, the latter seen commonly with multiple lipomatosis (176). Due to the associated cancer risk, the exam includes examination of the thyroid and breasts for nodules. Reflexes should be checked along with monofilament and/or vibration assessments for peripheral neuropathy. Cancer screening as appropriate for sex and age should be advised, and appropriate labs ordered (Table 7).  Although there is no definitive association of FML with dyslipidemia, statin therapy may be helpful in lowering lipoma size (177) and so a lipid panel is also appropriate.

 

Table 7. The FML Workup
Family history	Lipomas; cancer; nevi; celiac; neuropathy
Medical history	Lipomas; cancer; nevi; celiac; neuropathy
Physical Exam
Lipomas	Trunk, arms, low back, flanks, abdomen, thigh. Attached to skin, muscle, other.
Skin	Nevi; cherry angiomas
Thyroid	Nodules
Nervous system	Reflexes; skin sensory exam (monofilament)
Laboratory Studies
Thyroid	TSH
Blood fats	Lipid panel; other per family history
Fibrin clot (found in angiolipoma)	D-dimer
Food/gluten intolerance	Celiac panel

 

Treatment of FML

 

The current management of FML includes screening for associated conditions such as cancer (Table 7) and consideration of a referral to genetics for tumor suppressor gene workups as needed. A healthy diet and an exercise plan to avoid or reduce obesity is important as obesity in families with FML can be associated with pain (154) and, anecdotally, triathletes notice a reduction in lipoma size during high intensity training. A statin has been shown to reduce a lipoma in a case report (177). Painful lipomas or those that interfere with activities of daily living can be excised as needed but these procedures can cause numerous scars (Figure 5).  Massive amounts of lipomas can occur on the arms, hips/flanks, buttocks and thighs. Therefore, this condition can be psychologically devastating and people with severe FML do not consider it benign.

 

Liposuction is an option to excision of lipomas in people with FML as it provides good results in terms of skin appearance, and there is reported lack of recurrence or growth or development of other lipomas in the same area for at least 12 months (178). Injections of collagenase have been shown to shrink or destroy lipomas with minimal pain and good cosmetic result in a published abstract (179). Similar data were found for the detergent, deoxycholic acid (180), but anecdotally care should be taken not to inject too much detergent that can remain in the tissue requiring excision to remove. Additional treatments such as cryotherapy have been suggested and reviewed (181). More data is needed for the efficacy of injections and other therapies for the lipomas in FML as they are preferable to more invasive and scarring surgical techniques.

Concluding Remarks on FML

 

Familial multiple lipomatosis is a rare disease of multiple lipomas often associated with mutations in a tumor suppressor gene. Therefore, people identified with FML should be assessed for cancer. Liposuction should be considered to remove symptomatic lipomas and is preferable to surgical excision as multiple excisions leave many scars.

 

ANGIOLIPOMATOSIS

 

Angiolipomatosis also known as angiolipoma microthromboticum (OMIM 206550) is a rare disease of multiple angiolipomas and connective tissue that occurs commonly in men and usually begins after puberty; one case of a child with an angiolipoma in a family in which the father also had angiolipomatosis has been reported (182). Angiolipomas have been described as vascular malformations or vascular lipomas where blood vessels occupy between 10-90% of the angiolipoma. In families with familial angioliopomatosis, lipomas and angiolipomas can exist in the same person. Subcutaneous angiolipomas usually occur on the trunk and limbs, rarely on the head, hands, or feet (183). The angiolipomas can be the size of a rice grain, pea, a marble or much larger and are tender to the touch and can be associated with intense pain.  Angiolipomas may or may not be visible and may be palpable or non-palpable depending on their location and size. Numerous case reports describe epidural or extradural spinal angiolipomas, and rare cases report colonic (184), bronchial (185), joint (186), and testicular angiolipomas (187). Angiolipomas are known to be painful, although not always, and should be distinguished from other painful neoplasms (188). One case of angiolipomatosis was reported to occur after treatment with corticosteroids (189).

 

The loose connective tissue of angiolipomas contains adipose cells, fibrotic tissue, vessels with fibrin clots, and mast cells as salient features (Figure 6). Due to the large number of vessels, angiolipomas are bluish in color through the skin. Interestingly, the vessels in angiolipomas can grow from the dermis into the territory of the epidermis making the vessels palpable as small raised areas on the skin (Figure 7). A plethora of capillary “cherry” angiomas where a capillary grows and dilates through the epidermis may be found on the skin in areas of angiolipomas (Figure 8).

Prevalence of Angiolipomatosis

The prevalence of angiolipomatosis is unknown but it is considered to be a rare disease (190,191). 

 

Genetics of Angiolipomatosis

 

Angiolipomatosis most often occurs sporadically, but a family history can be identified in a minority of cases as autosomal dominant (192) or autosomal recessive (193,194). There are no known genes identified to date for angiolipomatosis.

Pathophysiology of Angiolipomatosis

Angiolipomas likely arise from fascia and therefore may also be painful because fascia is highly innervated, and when inflamed, is a likely source of pain (195). Inflamed fascia has robust angiogenesis (196) and may be important in the initial development of angiolipomas as resident mesenchymal cells in fascia can develop into adipocytes (197). It is thought that microthrombi in angiolipomas leads to necrosis of blood vessels, adipocytes and other components of adipofascia. Other hypotheses regarding pain include nerve damage from limited blood flow and tethering by fibrotic tissue. 

 

Subcutaneous angiolipomas are assumed to be congenital in origin where pubertal hormones may induce differentiation of adult adipose-derived stromal adipogenic precursors that reside in adipofascia; these precursors develop into adipocytes in intimate association with blood vessels (197). Vascular proliferation is thought to occur after repeated trauma to the fascia resulting in the development of an angiolipoma. However, there is a question of whether angiolipomas can become autonomous as a cancer. Two of three cases of angiolipomas in one publication suggest a neoplastic nature for these tumors due to deletion of parts of chromosome 13, a region containing the retinoblastoma gene, a tumor suppressor gene (198). The neoplastic nature of angiolipomas should be considered in individuals with significant numbers of angiolipomas and anti-neoplastic treatments considered when other conservative therapies fail.

Imaging of Angiolipomatosis

Identification of angiolipomas in tissue by Ga-PSMA PET/CT (199), magnetic resonance imaging (200), and ultrasound (201) allows surgeons to identify superficial and deeper angiolipomas targeted for removal. 

 

Treatment of Angiolipomatosis

 

SURGICAL

 

The only definitive treatment of angiolipomas to date is individual resection by excision or liposuction (202). Angiolipomas are typically removed if they are painful or restrict movement. A surgical emergency may occur to prevent hemorrhage of angiolipomas which can compress the spinal cord (203,204). Karyotypes of DNA from the angiolipomas should be assessed to determine the neoplastic nature of the angiolipomas so as to prepare the patient for the potential of multiple resections throughout life (198).

 

A concern with resection of lipomas is that inflammation is often a sequela of the removal process. As fascia plays an important role in the pathophysiology of angiolipomas, generation of inflammation in the fascia by surgical techniques has been anecdotally noted to incite a pain crisis. Removal of angiolipomas must therefore be considered carefully and manual or IAST therapies for the fascia should be considered after any surgery to speed recovery and reduce pain.

 

PAIN MANAGEMENT

 

The necrosis of tissue in angiolipomas and inflammation of fascia with all of its nerve endings can cause severe pain in individuals with angiolipomatosis.  In a case report from Germany, the systemic administration of acetylsalicylic acid, diclofenac, ketotifen, ranitidine, tramadol, or tilidine combined with naloxone did not provide adequate pain relief. In contrast, the antidepressant doxepin, which also has antihistaminergic effects to control the release of mast cell mediators, demonstrated good therapeutic efficiency for the pain from angiolipomas (205).  Depending on the mast cell burden in angiolipomas and their systemic effects including flushing, itching, nausea, diarrhea, angioedema, pain and a cadre of other signs and symptoms (206,207), individuals with angiolipomatosis may be considered to have mast cell disease or mast cell activation disease. Treatments to reduce the burden of mast cells in angiolipomas such as histamine 1 and/or histamine 2 receptor blockers, montelukast, non-steroidal anti-inflammatory drugs, antihistaminergic bioflavonoids such as quercetin or pycnogenol, amphetamines, and possibly stronger immunosuppressants that have been used for mastocytosis such as sunitinib (208) or mast cell activation syndrome such as tofacitinib (209) or imatinib (210) may provide benefit for pain and growth of angiolipomas. Non-neoplastic therapy for mast cell activation disease should be considered prior to the use of antineoplastic agents, which have been described extensively (211). Patients with angiolipomatosis can have a poor quality of life due to extreme pain and fatigue and consider suicide.  In these individuals, use of anti-neoplastic agents should be considered early. 

 

Many individuals with angiolipomatosis require opioid pain management and should be under the care of pain management specialists. Unfortunately, opioids can activate mast cells requiring concurrent treatment of mast cell signs and symptoms (212). Opioids should not be withheld during a pain crisis, and in fact may need to be escalated before weaning back down after the pain crisis has resolved.

 

Concluding Remarks on Angiolipomatosis

 

People with angiolipomas have severe pain that can be out of proportion to the outward appearance of the individual. Treatment with mast cell stabilizers, pain medications, and surgical treatments of angiolipomas are all important in management.  More research is needed for this rare disease to enable individuals with angiolipomas to live a full and active life.

 

DERCUM DISEASE

 

Dercum disease (DD; OMIM 103200) is a term used to describe extremely painful adipofascial tissue that is resistant to loss by diet and exercise and poorly responsive to analgesics. Other names include adiposis dolorosa (a term that is also used to describe women with lipedema) and Morbus Dercum. While Dercum disease is defined as painful fatty masses accompanied by other signs and symptoms of a chronic healing cycle disorder (25) (213), there remains a lot of confusion in the literature as to what exactly Dercum disease is. One review article stated that people with Dercum disease have obesity and chronic pain (214), which can easily be confused with people who have obesity and chronic pain for a variety of reasons including fibromyalgia. The old classification of Dercum disease and a new classification remain inadequate to differentiate the overlapping disorders that are bundled together as Dercum disease (65,215,216) because they describe only the phenotype and not the history (Table 8).

 

Table 8. Comparison of Outdated Classifications of Dercum Disease.
Older Classification	Previous Recent Classification
Type I: Diffuse Type. Widespread occurrence of painful lipomas in a diffuse manner	Diffuse Type. Diffusely painful adipose tissue that may present as painful folds of fats containing fat nodules that feel like pearls located around lymph node beds. Mostly resembles lipedema but extends or start in the trunk which differentiates it from lipedema
Type II: Generalized Nodular	Nodular type. Intense pain in and around grape-like clustered lipomas of variable size most commonly on the arms, legs, lower back or thorax; can include angiolipomas. Most resembles familial multiple lipomatosis
Type III. Localized Nodular	Nodular type. Intense pain in and around grape-like clustered lipomas of variable size in defined areas; can include angiolipomas
Type IV: Juxta-articular	NA
NA	Mixed Type: Combination of diffuse and nodular

 

A better classification of painful adipofascia considers the history of the disease (Table 9). For example, women with lipedema who become obese and/or develop lymphedema can metabolically become toxic or ill leading to the growth of painful masses in fat tissue. The etiology of these masses is likely due to the presence of inflammation known to slow lymphatic pumping leaving more pre-lymph fluid in the ECM, inducing adipogenesis, as lymph (even pre-lymph) makes fat grow. Women with lipedema, obesity, and painful fatty masses have dominated some studies on Dercum disease leading the authors to describe women with Dercum disease as having obesity and chronic pain (214). The masses that develop in women with lipedema and metabolic syndrome are similar to those that develop on the abdomens of people who have obesity and do not have lipedema. These tender masses resolve with weight loss and have been called Ander’s disease or adiposis tuberosa simplex (217). A good history taken from a woman with lipedema and the label Dercum disease, may reveal the development of lipedema earlier in life and additional weight gain later in life with development of tender masses, allowing treatment to be focused on lipedema and obesity rather than on Dercum disease.

 

Table 9. Conditions with Painful Adipofascia which Have Been Labeled as Dercum Disease
Types	Comments
Obesity-associated	Non-painful lipomas resolve with weight loss (Ander’s disease)
Lipedema with obesity and/or lymphedema	Painful lipomas resolve with weight loss; lipedema fat tissue remains
Familial multiple lipomatosis (FML) with obesity	Lipomas may get smaller and pain reduce with weight loss
Angiolipomas with or without obesity	Weight loss does not affect angiolipomas but is important to reduce inflammation
Localized due to trauma (218)	Multiple lipomas in an area of trauma and not just a single lipoma; likely due to injury of the fascia as with angiolipomas
Toxic/infectious; present around lymph node beds or diffuse with or without obesity	Likely due to a healing cycle disorder, infection, methylation deficiency, high oxalate or other toxin overload.

 

Signs and symptoms of Dercum disease include chronic pain, fatigue, brain fog, insomnia, cardiac arrhythmia most often tachycardia (palpitations), gastrointestinal distress often similar to irritable bowel syndrome, muscle weakness, tremor or jerking of muscles (myoclonus), joint pains, insulin resistance and diabetes, hypothyroidism, and other autoimmune disorders (219).  The signs and symptoms of Dercum disease have been suggested to be in the spectrum of fibromyalgia (220).

 

Dr. Dercum’s first patient was a woman with obesity with fat similar to a woman with Stage 3 lipedema (221). Dr. Dercum and his medical resident described rapid changes in fat tissue shape and size in real time suggestive of edema or fluid shifts. Therefore, involvement of the lymphatic system is likely in Dercum disease. Irregular and thickened lymphatic vessels have been described in Dercum disease suggesting that an altered lymphatic system can contribute to changes in the adipofascial tissue that found by palpation (222). Once people with Dercum disease are more accurately described by phenotype, there will be a better chance of finding a gene or biomarkers.

 

Prevalence of Dercum Disease

 

Many women with lipedema have been miscategorized as having Dercum disease when actually they have lipedema and metabolic syndrome, making the prevalence estimate of 1/1000 for Dercum disease in Sweden too high (223). There are no other prevalence studies of Dercum disease although the angiolipomatosis type is considered rare and the obesity- or lipedema-associated types are likely common, but these individuals are better described with what they have, angiolipomas, obesity, or lipedema respectively, with metabolic disease rather than lumping them all together as Dercum disease simply due to the presence of pain in the tissue.

 

Genetics of Dercum Disease

 

There is(are) currently no known gene(s) for Dercum disease.  Continuing to include people with angiolipomas, FML, and lipedema under the same moniker of Dercum disease will make it very difficult to discover genes important for these diseases when examining populations. The study of genes for specific families may be more helpful to find gene mutations that can then be assessed in individuals with painful adipofascia.

 

One family with familial multiple lipomatosis was found to have members that developed pain in the lipomas consistent with Dercum disease (adiposis dolorosa). While many of the family members with FML and pain also had obesity, not all were. Therefore the authors concluded that “adiposis dolorosa may in fact be an expression of familial multiple lipomas” (154). It remains unclear, however, why some individuals would develop pain and some not in a family with FML. Fascia can become inflamed for a variety of reasons including surgery, trauma, infection, toxin or drug exposure, and development of obesity. Lipomas in people with FML are often connected by a tail of connective tissue to solid fascial structures in the body, and fascia is a source of preadipocytes (Figure 9).  It may be that lipomas in FML are a marker of fascial disease and that pain in and around the lipomas depends on the amount and extent of inflammation present.  Other genes may modify susceptibility to prolonged inflammation including those yet to be identified in fibromyalgia (224).

Pathophysiology of Dercum Disease

 

The pathophysiology of Dercum disease needs to be determined by type, something that very few papers have done so accurately. In mostly women with lipedema type Dercum disease, substance P was lower in the spinal fluid compared to controls (225), confirming a strong pain component is present when women with lipedema develop obesity and metabolic syndrome. In another study, interleukin-6 levels were elevated in the fat from women with Dercum disease compared to women without lipedema supporting Dercum disease as an inflammatory disorder (226). Weight stabilization and when possible, weight loss in patients with obesity should be a focus for women who have developed metabolic disease, in addition to caring for their lipedema.

 

The juxta-articular type of Dercum disease where nodules in the adipofascial tissue are present around joints had been associated with rheumatoid arthritis (227). Lymph nodes are present around many joints including the elbow (cubit nodes), knees (popliteal nodes), and hips (femoral nodes), and in these locations adipofacial nodules have been found. Cases of juxta-articular Dercum disease suggest that inflammation in the adipofascia around joints may reduce lymphatic pumping in these areas resulting in a backup of fluid in the interstitial body leading to densification of fascia and eventually fibrosis around lobules of fat making them palpable as nodules. These nodules are tender due to inflammation of the fascia and nerves. As an example, a woman with rheumatoid arthritis was treated with tocilizumab, a humanized monoclonal antibody of class IgG1, targeting interleukin-6 receptors, and developed painful fatty masses of her knees documented by MRI (228). A similar pathophysiology would be likely for the trauma-induced Dercum disease. 

 

Familial multiple lipomatosis and angiolipomas have been previously discussed including why pain develops in angiolipomas. It is unclear why a person with FML would suddenly develop pain in and around lipomas qualifying for a diagnosis of Dercum disease (FML type with pain).  The presence of inflammation occurring in the body of a person with FML such as from obesity, trauma, hypermobile joint spectrum disorders, arthritis and any other inflammatory condition that includes the fascia in the inflammatory process likely accounts for the development of pain in FML. Resolving the inflammation in the fascia may reduce the pain and return the diagnosis back to FML alone.

 

One theory on the origin of Dercum Disease is based on the work of Robert Naviaux in which a failure of healing of inflammation occurs (213). According to Naviaux, a normal healing cycle includes normal wakefulness, restorative sleep, fitness and healthy aging. The cell “danger response” is an evolutionarily conserved cellular metabolic response activated when a cell encounters a threat that could injure or kill it, examples of which can be microbial, chemical, physical, or psychological in nature. Chronic disease occurs when cells fail to heal or contain inflammation, and a toxic repeating loop of incomplete recovery and re-injury occurs. Chronic pain disorders are included by Naviaux as a healing disorder and the author feels many people with Dercum disease fall into this category.

 

Imaging of Dercum Disease

 

The most inexpensive means to document lipomas in the adipofascia of people with Dercum disease is by ultrasound. Ultrasound findings include a hyperechogeneity (higher density) to the lipoma suggesting fibrotic tissue and no increased Doppler signal (minimal blood flow) (229).

 

Magnetic resonance imaging of the tissue of people with Dercum disease has found lymphedema in a woman and multiple lipomas in a man  (230). Nodular type lipomas have also been visualized by MRI in the tissue of people with Dercum disease (229). The lipomas were multiple, oblong, fatty lesions in the superficial subcutaneous adipose tissue, mostly < 2 cm in long axis diameter. A nodular ("blush-like") fluid signal was also found without the presence of contrast. According to Richard Semelka, MD, gadolinium contrast should not be used in people with Dercum disease unless absolutely necessary to avoid any risk for development of gadolinium deposition disease (231,232). MRI images demonstrate variability in the tissue of people with Dercum disease, from lymphedema to distinct lipomas, and exemplify the different phenotypes under the moniker of Dercum disease. To date there are no confirmed connections between multiple lipomas as in FML or trauma-induced Dercum disease and development of lymphedema.

 

Conditions Associated with Dercum Disease

 

Dercum disease has been associated with many conditions such as disrupted sleep cycle, headaches, cognitive difficulties, tachycardia, shortness of breath, and gastrointestinal symptoms (219). Many of these symptoms are consistent with mast cell activation disease (MCAD).  Therefore, MCAD is considered an associated condition in Dercum disease. Diabetes is common in Dercum disease (25,219) and cardiovascular disease should be evaluated for and treated in any person with Dercum disease especially if blood markers of inflammation are high, such as C-reactive protein. A woman with Dercum disease had a dysfunctional arteriolar venous reflex in her arm suggesting a blood vascular or nerve problem in Dercum disease (233).  Another case of a woman with the FML type of painful lipomas was described who had dizziness followed by left sided sensory-motor deficit suggestive of a vascular origin (234).  Anecdotally, some of the author’s patients with Dercum disease also have postural orthostatic tachycardia syndrome (POTS). Fibromyalgia is often an accompanying diagnosis in people with Dercum disease as are other pain syndromes such as migraines (25).

 

Many people with Dercum disease become concerned that the painful lipomas can spread throughout the body as with cancer.  Once case of a lipoma on the uterus of a woman with Dercum disease is known to the author, and two women with Dercum disease had invasive calcaneal lipomas that were resected.  Other lipomas in people with Dercum disease have been identified in the gastrointestinal system but these need to be verified. Lipomatous hypertrophy of the interatrial septum was found in one person with Dercum disease (235), but this type of fat can also be associated with obesity (236). Altered lymphatics were found in a few cases of Dercum disease (222). One family had Dercum disease with dysarthria, visual pursuit defect and progressive dystonia (237).

 

General swelling, a sensation of a “heaviness” in tissue, increased pain in one limb, or aching limbs all suggest that a lymphatic dysfunction may be present, which can be evaluated using lymphangioscintigraphy, which is performed in most nuclear medicine departments, or near infrared lymphatic imaging using indocyanine green, which is not yet to the point of being readily clinically available. Finding altered lymphatic function can change clinical management by steering practitioners towards prescribing manual lymphatic drainage therapy and compression garments to contain and support lymphatic flow.

 

Treatment of Dercum Disease

 

To maintain a healthy weight or lose excess adipofascial tissue, people with Dercum disease should be encouraged to eat a healthy diet such as Mediterranean, DASH, low processed sugar, plant-based low inflammatory foods, or foods that are low in histamine if mast cell activation disease is present or suspected; they should also undertake a graded exercise program.

 

PAIN MANAGEMENT OF DERCUM DISEASE

 

Signs and symptoms common in people with Dercum disease, including pain. should be treated symptomatically (Table 10). Opioids are often used for pain treatment for Dercum disease, but doses can escalate over time and care should be taken to try and find additional alternative treatments.

 

Table 10. Medications Used to Treat Pain and Other Symptoms in People with Dercum Disease
Medication	Comments
Deoxycholic acid (238)	Injection of deoxycholic acid reduced pain and size of lipomas in a man with FML type of Dercum disease
Doxepin (205)	Has antihistaminergic activity therefore useful for pain, depression and mast cell activation disease
Intravenous lidocaine (239)	Ketamine is often used in addition to or in place of lidocaine if not effective
Topical lidocaine (240)	Often combined with other medications in topical form such as EMLA (241)
Metformin (242)	Useful for metabolic disease and when inflammatory markers are high
Mexiletine and amitriptyline (243)	Mexilitine has been described as oral lidocaine and offers an alternative to opioids
Low dose naltrexone (244)	Effective for fibromyalgia pain, a condition often present in Dercum disease
Pregabalin (245)	Gabapentin has also been shown to reduce pain (246) but may increase edema
Sympathomimetic amines (137)	Phentermine, dextroamphetamine, amphetamine; sympathomimetic amines resolved lipomas and liver fat in two cases of Dercum disease.

 

NON-MEDICATION TREATMENT OF DERCUM DISEASE

 

People with Dercum disease should be offered manual or IAST therapies or pool/water therapy to reduce pain, improve mobility and impede progression of the disease. Manual lymphatic drainage combined with pregabalin improved weight and pain in a woman with Dercum disease  (245). It has also been reported that fascia improved, pain reduced, and fat was lost after women with lipedema and Dercum disease received deep tissue therapy (86,126).

 

Liposuction has been used as treatment for Dercum disease (247), reducing pain by one point on a visual analogue scale (248) and improving insulin sensitivity (249). Surgeons removing lipomas by liposuction must have experience in the removal of fibrotic tissue and manual or IAST therapies should be performed before and after any surgery to keep inflammation levels at a minimum.

 

Transcutaneous frequency rhythmic electrical modulation system (FREMS) reduced pain and the size of lipomas in one case of Dercum disease (250). Cycling hypobaric air around ten people with Dercum disease improved pain and mental quality of life after five days of therapy (251). Cycling air around the body by sequential pneumatic compression pump therapy is also useful for people with Dercum disease due to the presence of lymphatic dysfunction (222,229).

 

Concluding Remarks on Dercum Disease

 

People with Dercum disease have painful lipomas and other signs and symptoms of a healing disorder. The different types of Dercum disease need to be delineated before any gene or biomarker can be found. The pain and associated signs and symptoms of Dercum disease should be treated to improve quality of life. People with Dercum disease may be at high risk for cardiovascular disease and cardiovascular risk factors should be closely monitored and treated when appropriate.

 

MULTIPLE SYMMETRIC LIPOMATOSIS

 

Multiple symmetric lipomatosis (MSL; OMIM#151800) also known as Madelung disease, Launois-Bensaudesyndrome, cephalothoracic lipodystrophy, and benign symmetric lipomatosis is a rare disease first described by Brodie in 1846.This disorder is clearly not benign. Madelung reported data on 33 cases, but the classical description of the disease is attributed to Launois and Bensaude who published a detailed account of 65 cases in 1898. The literature on MSL was initially dominated by research on men with alcoholism; however, people who do not consume alcohol (252), women, and children are also affected (253).

 

There are different types of MSL described initially by two different groups and reclassified in 2018 based on a German cohort of 45 patients (Table 11 and Figure 10) (91). 

 

Table 11. Types of Multiple Symmetric Lipomatosis (Locations of Abnormal Fat Tissue)
Types	Old Classification (254)	Old Classification (255)	New German Classification (91)
I	Neck, shoulders, supraclavicular triangle, and proximal upper limbs	Neck, upper back, shoulder girdle, and upper arms	Ia: Neck
			Ib: Neck, shoulder girdle, upper arms
			Ic: Neck, shoulder girdle, upper arms, chest, abdomen, upper and lower back
II	Abdomen and thighs	Shoulder girdle, deltoid region, upper arms, and thorax	Hips, bottom, and upper legs
III	Thigh or female type similar to lipedema	Gynecoid type: Thighs and medial side of the knees	General distribution skipping head, forearms, and lower legs
IV	NA	Abdominal type: Abdomen	NA

Women tend to have Type II MSL and the authors state that it is difficult to differentiate women with lipedema from women with MSL type II. Criteria the authors used to distinguish the two are “the hips and bottom are affected [in Type II MSL] which are not affected in patients suffering from lipedema.”  Lipedema, however, does affect the hips and buttocks in Types I-III lipedema (Figure 3). Finding a gene or biomarker for lipedema and MSL will be ultimately be helpful in distinguishing these adipofascial disorders.

In rare cases, MSL SAT can invade the muscles of the tongue (256,257), vocal cords (258), and periorbital area (259). Tracheal or esophageal compression can occur resulting in superior vena cava syndrome (260).

 

Prevalence of MSL

 

Multiple symmetric lipomatosis is considered rare occurring 1:25,000 in a primarily male Italian population (261) and 1:25,000 in a German population where females outnumbered men 2.5:1 (91).

 

Genetics of MSL

 

Multiple deletions of mitochondrial DNA, and the myoclonus epilepsy and ragged red fibers (MERRF) tRNA(Lys) A>G(8344) mutation have been found in some cases of MSL (262,263) but not in others (264,265). Chalk et al. found no mitochondrial pathology or mutations in four siblings with MSL with a pattern favoring autosomal recessive (265). Another study examined individuals with mitochondrial mutations and found that MSL was a rare sign of mitochondrial disease with a strong association between multiple lipomas and lysine tRNA mutations (266). If triglyceride cannot be mobilized from fat, then along with adipogenesis (via microRNAs), fat would be expected to increase. Indeed, a mutation in the LIPE gene coding for hormone sensitive lipase was found to be mutated in a family with MSL and lipodystrophy (267).

 

Mutations in the MFN2 gene coding for mitofusin 2 have been found to cause MSL with Charcot Marie Tooth Disease (268). Mitofusin 2 helps to regulate the morphology of mitochondria by controlling the fusion process. Individuals with mutations in MFN2 have increased fat on the upper part of the body and a lipodystrophy or lack of fat on other aspects of the body. These data support pathophysiology of MSL hypothesis 1 above for the development of MSL but also support hypothesis 2 in that alcohol may cause widespread damage to mitochondria.

 

Pathophysiology of MSL

 

HYPOTHESIS 1: BROWN ADIPOSE TISSUE

 

The dorsocervical fat pad (buffalo hump) is thought to be a location of brown adipose tissue found both in MSL (264,269,270) and HIV-associated lipodystrophy (271-274) suggesting that the abnormal fat tissue in both of these conditions arises from brown adipocytes (275).  Uncoupling protein (UCP)-1 has been shown to be activated in HIV-associated lipodystrophy and in agreement, calcyphosine-like (CAPSL), important in early adipogenesis, was down-regulated and uncoupling protein (UCP)-1 upregulated in eleven individuals, one with familial MSL and ten with sporadic MSL disease (276). Stromal vascular cells grown out of MSL fat tissue resulted in multiloculated adipocytes consistent with brown adipocytes (277,278). These data suggest that altered pre-adipocyte mesenchymal stem cells, adipogenesis and energy metabolism are important in development of MSL fat. In support, microRNAs miR-125a-3p and miR-483-5p are significantly increased in the fat of patients with MSL. These microRNAs promote adipogenesis through regulating the RhoA/ROCK1/ERK1/2 pathway (279). Finally, stem cells from MSL tissue showed significantly higher proliferative activity (280) suggesting a defect in regulation of adipogenesis. That brown fat was not found by ¹⁸ F-fluorodeoxyglucose (¹⁸ F-FDG) uptake using PET/CT in areas of MSL tissue (281) does not rule out the brown fat hypothesis as there may be browning of MSL fat rather than as strict replication of brown adipocytes.

 

HYPOTHESIS 2: INFLAMMATION, ALCOHOL AND THE LYMPHATIC SYSTEM

 

Further research is needed to determine the exact pathophysiology involved in the development of MSL fat tissue, but the fact that alcohol is damaging to many tissues in the body suggests that inflammation may play a role. Interleukin-6 levels were elevated in MSL tissue compared to unaffected tissue (280), and ethanol intake increases CYP2E1 activity in adipose tissue, leading to apoptosis of adipocytes through activation of the pro-apoptotic Bcl-2 family protein Bid, resulting in activation of complement via C1q, and adipose tissue inflammation (282).

 

The liver produces over 50% of lymphatic fluid that enters the thoracic lymphatic ducts in the great veins in the neck (283).  When the liver is fatty or cirrhotic, the liver produces even more lymphatic fluid (284). That many men with men with MSL develop fat around the neck in the location of the thoracic ducts or abdomen where the digestive tract transports approximately 2/3 of lymphatic fluid, becomes intriguing and may suggest involvement of the lymphatic system.  Women have more developed vasculature, including lymphatics, in subcutaneous adipose tissue and therefore, if lymphatic vessels are important in the pathophysiology of MSL, they could be expected to have a different phenotype than men.  Rats provided acute alcohol intoxication were found to have mesenteric lymphatic hyperpermeability (thoracic duct was not examined), a peri-lymphatic adipose tissue inflammatory response, and an altered systemic adipokine profile (285). When lymphatic vessels leak, fat grows (52). Alcohol and other mediators of lymphatic vessel leakage may therefore play a role in MSL.

 

Disorders Associated with MSL

 

Associated disorders include liver disease, dyslipidemia, metabolic syndrome, hypertriglyceridemia, hypothyroidism, diabetes mellitus, and peripheral and autonomic neuropathy (Figure 11).

Morbidity and mortality in MSL is thought to be high with sudden non-coronary death accounting for a large percentage of deaths in one series of primarily men (254). The neuropathology of MSL is a distal axonal demyelination different from that associated with alcohol intake and impairment of autonomic function has been suggested as a possible cause of sudden death; this impairment seems to prevalently involve the autonomic nervous system and not related to a high alcohol intake.

 

Treatment of MSL

 

Anyone with MSL should be encouraged to stop intake of alcohol. The only definitive treatment of MSL is liposuction or excision of the MSL tissue. The advantages of lipectomy is more complete removal of MSL tissue and better control of iatrogenic damage to nearby structures. Liposuction, however, achieves good cosmetic results and is simpler and less invasive than lipectomy (287). Multiple symmetric lipomatosis tissue tends to recur after liposuction and even excision. Therefore, other treatments are needed to slow down the progression of this disease to improve quality of life. Some believe that combining excision with liposuction can reduce recurrence (288).

 

Mesotherapy is a procedure that involves injections of multiple substances such as pharmaceuticals and/or vitamins into subcutaneous fat to reduce the fat tissue or cellulite. Such substances include phosphatidylcholine, multivitamins, pentoxifylline, aminophylline, hyaluronic acid, yohimbine, collagenase and others. Mesotherapy has been used to treat MSL but the injections can cause fibrosis which can make excision or liposuction difficult (289).

 

Concluding Remarks on MSL

 

Multiple symmetric lipomatosis is a rare adipofasial disorder associated with alcohol use, but not always. The pathophysiology is unknown but may involve early adipogenesis, mitochondrial dysfunction, and brown adipose tissue formation. Women with MSL may have lipedema and vice versa, therefore a gene or biomarker is needed to identify people with different types of MSL. Surgical treatment remains the only therapy for MSL.

 

OVERALL CONCLUSIONS ON ADIPOFASCIAL DISEASES

 

Aipofascial diseases occur when there is an increase in adipofascial tissue on the body that becomes fibrotic and is resistant to loss by lifestyle change. Until such time that better understanding of the pathophysiology of these disorder hints at other treatment modalities, these disorders often require removal by surgical means. Many of the diseases overlap, making identification difficult and will remain so until additional genes or biomarkers are clinically available. 

 

A comparison table of the five adipofascial disorders presented in this chapter can be helpful (Table 12).

 

Table 12.  Comparison of Adipofascial Diseases
Characteristic	Lipedema	DD	MSL	FML	Angiolipomas
Fat Location	Limbs	Global	Upper body	Trunk, arms, thighs	Global
Diet-resistant fat	Yes	Yes	Yes	Yes	Yes
Lipomas	+	+++	+++	+++	+++
Time SAT change	Puberty	Adult	Adult	Child, adult	Young adult
Painful SAT	Yes	Yes	Not usually	Not usually	Yes
Sex	Female	Female	Male	Male, female	Male, female
Lymphatic dysfunction	Yes	Yes	Yes	Possible	Unknown
Prevalence	Common	Rare	Rare	Rare	Rare
Associated conditions	Lymphedema	Autoimmune; diabetes	Neuropathy	Moles; neuropathy	Unknown
Inheritance Pattern	Autosomal dominant; incomplete penetrance	Autosomal dominant; sex-specific influence	Autosomal dominant or recessive	Autosomal dominant	Autosomal dominant; spontaneous
Gene	None	None	LIPE (267) MFN2 (268) tRNALys(266)	PALB2(156)	None
Biomarkers	None	None	miRNA (279)	None	None

Abbreviations: miRNA: microRNA; PALB2; Partner and localizer of BRCA2

 

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ABSTRACT

 

The evidence for social and environmental factors that contribute to obesity are often underappreciated. Obesity prevalence is significantly associated with sex, racial ethnic identity, and socioeconomic status, which creates complex relationships between each of these characteristics. Food availability remains an important factor associated with obesity that relates to differences in prevalence seen across geographical areas and higher rates of obesity within low socioeconomic status individuals. Proliferation of high calorie, energy dense food options that are or perceived as more affordable combined with reductions in occupational and transportation related physical activity can contribute to a sustained positive energy balance.  Additionally, environments experiencing deprivation, disorder, or high crime have been shown to be associated with higher odds of obesity, which may appear more frequently in low social status individuals. Both objective and subjective measures of social status and inequality are associated with increased energy intake and decreased energy expenditure, which could place individuals of low social status at greater risk for obesity development. Given the complexity of this multifactorial disease, effective obesity care requires knowledge of these complex relationships and an integration between the health systems and surrounding community. Resources for practicing clinicians regarding methods of screening for social and environmental factors in clinical care are provided in addition to information on a program that has been widely dispersed and made accessible to those who may be the most at risk. 

 

INTRODUCTION

 

Many medical providers appreciate the significant social and environmental determinants of obesity but are unsure how to address them. Others consider these factors outside of their control and scope of practice, and are thus hesitant to even broach the topic with their patients. Finally, many medical providers still attribute obesity to causes within a person’s control, such as dietary choices, amount of exercise, or willpower, (1, 2) which perpetuates a stigma that accompanies this disease.  Specifically, the prevailing stigma is that those who suffer from obesity represent a population who lack the willingness to change their poor lifestyle habits or harbor a character flaw that, at its extreme, infers immoral behaviors (e.g., gluttony). In reality, obesity is a multifactorial disease (3) that is caused by a combination of biological, genetic, social, environmental, and behavioral determinants. In order to address this gap in the understanding of the social and environmental determinants of obesity and improve the care of patients with obesity, this chapter will review the evidence for the social and environmental determinants of obesity development. The specific areas to be covered include social identity, social status, societal trends, and influences of the built, industrial, and social environments, all factors that are closely associated with the prevalence or incidence of obesity or that impact efforts to prevent and treat this disease.  Resources for the busy clinician that will support implemental changes in one’s practice to improve the care and management of patients with obesity, as well as evidenced-based opportunities for advocacy in the community, will be included in the final section.

 

This chapter is divided into three primary sections based on the progression of thought and evidence surrounding the social and environmental determinants of obesity: individual characteristics, environmental characteristics, and social hierarchy influences. Individual characteristics are those that are attributed to the individual with obesity such as their sex, age, race, ethnicity, and socioeconomic status (SES). Environmental characteristics surround the individual, including the physical spaces where people live, work, and play, as well as sociocultural norms. The social hierarchy refers to social status or social rank of individuals within larger society or a local community.

 

INDIVIDUAL CHARACTERISTICS

 

The prevalence of obesity varies according to key individual characteristics such as age, sex, race and ethnicity, and SES. The prevalence of obesity increases cross-sectionally across the lifespan: from 13.9%, in early childhood (2-5 years old)  to 18.4% in childhood (6-11 years old),  20.6% in adolescence (12-19 years old), 35.7%, in young adulthood (20-39 years old),  42.8% in adulthood (40-59 years old), and 41.0% in older adulthood (≥60 years old) (4).  As of 2016, the prevalence of adult obesity in women in the United States was 41.1% and in men was 37.9% (4).  In the decade between 2007-2008 and 2015-2016, obesity significantly increased only in women (4), suggesting a sex-specific vulnerability to expression of this disease. Additionally, when race and ethnicity are considered, significant interactions between race and sex emerge. Non-Hispanic black, non-Hispanic Asian, and Hispanic women all have significantly higher prevalence of obesity than men with the same racial ethnic identity (5). In men and women, non-Hispanic Asians have significantly lower prevalence of obesity compared to all other major races and ethnicities in the United States (Note: not adjusted for ethnic specific cut points for Asians), and Non-Hispanic blacks and Hispanics have significantly higher prevalence of obesity compared to Non-Hispanic whites (5). It is not fully clear why differences in obesity prevalence by race and ethnicity are present, but some evidence points to differences in genetic backgrounds that affect body composition and fat distribution (6, 7), and to differences in cultural body image standards (8). Additionally, in the United States, race and ethnicity are confounded with SES, which is one of the most potent indicators of overall health in the United States (9).

 

A significantly greater proportion of underrepresented racial ethnic minorities are considered low SES compared to non-Hispanic Asians and non-Hispanic whites in the United States. Socioeconomic status is a composite measure that can be represented by measures of income, educational attainment, or occupational status. In the 2017 Census, 21.2% of non-Hispanic blacks and 18.3% of Hispanics lived below the poverty level compared to 8.7% of non-Hispanic whites and 10% of non-Hispanic Asians (10). Non-Hispanic Asians (53.9%) and non-Hispanic whites (36.2%) are more likely to earn a bachelor’s degree than non-Hispanic blacks (22.5%) and Hispanics (15.5%) (11). In terms of health, low SES in childhood is associated with adult development of cardiovascular risk factors and a 20% increase in the odds of having central obesity (as defined by a waist circumference >102 cm for men or > 88 cm for women) (12). In adult women, obesity prevalence increases with decreasing income and educational attainment; however, in non-Hispanic black women, obesity prevalence differs by education gradients but not by income gradients (13). Conversely, non-Hispanic black men have a higher prevalence of obesity in the highest income group, but all the men’s racial ethnic groups showed similar relationships between obesity rates and education gradients as women (13). Higher SES is also associated with healthy lifestyle behaviors that are often the first line of prevention or treatment for obesity. On the other hand, low SES is associated with less leisure time physical activity (14) and consumption of energy-dense diets that are nutrient poor (15); however, SES is not the only factor that influences these behaviors. Further exploration of how SES affects resources and the ability to practice healthy behaviors is expounded upon in the next section.

 

ENVIRONMENTAL CHARACTERISTICS   

 

Geography

 

Obesity prevalence differs by geographical region in the United States with the South and the Midwest having the highest level of obesity among adults (16). The Midwest and South also have high rates of diabetes and metabolic syndrome, which frequently accompany obesity (16).  Approximately 55% of global increases in BMI can be attributed to rising BMI in rural areas, and this may be as high as 80% in low- and middle-income countries (17). Rural areas are associated with 1.36 higher odds of obesity compared to urban areas; however, mediation analysis shows that individual educational attainment, neighborhood median household income, and neighborhood-built environment features reduce these odds by 94% and render the relationship statistically insignificant (18). Rural areas tend to have farther distances between residences and supermarkets, clinical settings, and recreational opportunities, which may be impacting the ability to practice healthy behaviors that prevent obesity. This is one example of the “built environment”, which alludes to the infrastructure of a geographic area that influences proximity to and types of resources, transportation methods, and neighborhood quality.

 

Food Availability

 

The frequency and type of food vendors in a neighborhood determines the types of foods that residents can purchase. Historically, evidence has suggested that fast food restaurant density is associated with obesity prevalence. A state-level analysis of fast food restaurant density and the number of residents per restaurant accounted for 6% of the variance in state obesity prevalence (19). Individual-level factors can interact with built environmental factors (like fast food restaurant density) to increase the odds of obesity. For example, one study in older adults showed that residents who ate 1-2 times per week at a fast food restaurant (odds ratio [OR]: 1.878), did not meet current physical activity guidelines (OR: 1.792), had low self-efficacy for eating healthy food (OR: 1.212), or identified as non-Hispanic black (OR: 8.057) and lived in a high density fast food neighborhood were more likely to have obesity than older adults who lived in a low density fast food neighborhood (20). On the other hand, recent research suggests that fast food restaurant density is not associated with obesity prevalence and the food consumed in these establishments’ accounts for less than 20% of the total energy intake (21). This could reflect the widespread availability of fast food nationally, which weakens the ability to dissect links between its presence and increased consumption specific to obesity.

 

The term “food desert” is often used to describe areas with limited access to affordable and nutritious food (e.g. supermarkets) and these vary significantly according to neighborhood socioeconomic and racial/ethnic composition (22, 23). Food desert designation has been positively linked to obesity in the United States and simply switching from a non-food desert census tract to a food desert census tract can increase the odds of obesity by 30%, when all other relevant factors are held constant (24). Conversely, access to supermarkets does not automatically result in healthier eating behavior and weight status. A systematic review showed that five out of six studies looking at supermarket access did not find increased fruit and vegetable consumption with greater accessibility; however, four out of five studies looking at changes in weight status found lower BMI and prevalence of obesity in areas with high access to supermarkets compared to low access areas (25). A large natural experiment found that the opening of a new supermarket improved overall diet quality in the neighborhood, but did not affect fruit and vegetable intake or BMI (26). Interestingly, the only positive outcome directly associated with regular use of the new supermarket was higher perceived access to healthy food (26). Although these findings are mixed, it is important to acknowledge that changes in food choices at a neighborhood level might occur too slowly to be captured in these studies.

 

In addition to food availability and quality, the shift in food type, amount, and pricing is also relevant to the obesity epidemic. For example, available evidence strongly supports a greater risk of weight gain and type 2 diabetes with increased consumption of sugar-sweetened beverages (27). North America still has the highest per capita sales of calorie sugar-sweetened beverages, but is slowly starting to shift to low-calorie sugar sweetened beverages, though sports and energy drink consumption continue to increase (28). Portion sizes in the most popular fast-food, take-out, and family style restaurants exceed current USDA and FDA standard-recommended portion amounts as well as what had been historically served in past decades (29). Increased portion sizes have been robustly linked to increases in energy intake in both adults and children; however, evidence is limited that decreasing portion size results in decreased energy intake (30). In addition, fast foods, snack foods, and foods available through convenience stores are typically ultra-processed (high in processed grains and added sugars; low in fiber and unsaturated fats).  A recent study found that keeping macronutrient content the same, meals that were ultra-processed resulted in greater food intake and weight gain over a two-week follow-up compared to consumption of non-processed foods (31). Contributing to increased intake of fast-foods and ultra-processed foods is the marketing techniques implemented by food industries across multiple mediums. Though adults have shown to be less susceptible to the effects of food advertising, experimental studies with children produce a moderate effect size for increased food consumption after food advertising exposure (32). Food advertising targeted at children is focused on brand building and emotive messages may not be discerned as such by this vulnerable population (33). Another common misconception confronting consumers is that healthy foods are more expensive, but research suggests this perception is based on misleading price metrics as well as changes in fruit and vegetable convenience and level of preparedness (34). Price per calorie metrics show fruits and vegetables to be more expensive than less healthy foods; however, price per average portion and price per edible 100 grams actually shows that fruits and vegetables are less expensive (34). In times of financial constraint, socioeconomically disadvantaged groups maximize energy value for money resulting in energy-dense, nutrient poor diets that contribute to obesity (35).

 

Transportation

 

Infrastructure can dictate means of transportation and neighborhood walkability, which is associated with weight status. High neighborhood walkability has been found to be associated with decreased prevalence of overweight and obesity (36), which can link back to structural differences discussed earlier between urban and rural areas (urban areas having higher walkability). Transport-related physical activity decreased by 17.8% between 1965 and 2009 in the United States, which could be due to growing ubiquity of car ownership and supportive infrastructure for automotive transport in the United States (37). Proximity to recreational facilities, recreational facility density, access to sidewalks and paths that remove pedestrians from traffic hazards, and access to parks, have all been reported to be facilitators of physical activity in qualitative and quantitative research (38, 39).

 

The quality of infrastructure in a neighborhood and the perceived aesthetics of homes, shops, and recreational facilities can impact the use of these facilities. A study in a high-income neighborhood and a low-income neighborhood showed that even though the number of recreational facilities was equitable in the neighborhoods, the residents of the low-income neighborhood perceived that they had less access to recreational facilities (40).

 

Additional neighborhood descriptors that are associated with obesity include neighborhood deprivation, disorder, and crime. Neighborhood deprivation, a composite score of socioeconomic position of individuals in a neighborhood that is used to assign a rank to that neighborhood, shows that high levels of deprivation are associated with a 20% increased odds of overweight (41). Neighborhood physical disorder refers to the presence of vandalism, abandoned lots or vehicles, garbage, and quality of building conditions. Women in an urban area with high neighborhood physical disorder have a 1.43 greater odds of obesity (42). Persons living in areas of high crime have a 28% reduced odds of achieving higher levels of physical activity and, conversely, perceived safety increases the odds of achieving higher levels of physical activity by 27% (43). Living in a neighborhood with high crime has been found to be associated with increased weekly snack consumption in women (42). The relevance of the neighborhood environment to obesity is further exemplified in the Moving to Opportunities Study (44). The Department of Housing and Urban Development randomly assigned just under 5000 families in Chicago, Baltimore, Boston, Los Angeles, and New York public housing to 3 possible conditions: receive a housing voucher to move to a low-poverty census track with moving counseling, receive a standard unrestricted housing voucher and no moving counseling, or receive nothing. Despite the fact that this study was not focused on weight or diabetes outcomes, participants that received the voucher to move to a low-poverty census track had 4.61 percentage points lower prevalence of BMI > 35, BMI > 40, and glycated hemoglobin ≥ 6.5% than participants who received nothing (44), showing that a mere change in environment from high- to low-poverty rates was enough to have a significant impact.

 

Work Environment and Advances in Communication Technology

 

As the built environment and food environment have changed in the United States, so has the work environment. From 1960 to 2010, jobs in the U.S. private industry shifted from 50% requiring at least moderate to vigorous physical activity to less than 20% requiring this level of activity intensity (45). National Health and Nutrition Examination Survey data has documented an association between decreases in work-related energy expenditure and weight gain over the same time period (45). These changes in occupation related physical activity could be due to improvements in labor-saving technology. Technology advances are not confined to the work environment and have spread into many facets of daily life, such as improvements in smart personal communication devices, internet media platforms, marketing techniques, and enhanced audio-visual media.  Studies show that marketing for unhealthy foods is often targeted at more vulnerable populations such as Non-Hispanic blacks (46) and Hispanics (47). Additionally, the availability of information about healthy weight-loss behaviors on the internet is poor when searched for in Spanish (48).  “Screen time” or the time spent using technology that utilizes a screen interface has been found to be associated with increased risk for obesity (49-51); however, many app companies and academic researchers are now using that same technology to help with obesity prevention and treatment (52-54). 

 

SOCIAL HIERARCHY     

 

Animal research consistently shows that animals of subordinate status experience adverse physiological and behavioral changes compared to their high status counterparts: higher levels of cortisol (primates) (55), elevated blood pressure (rats, rabbits, baboons, macaques) (56), elevated heart rate (primates) (56), accumulation of visceral fat (rats) (57), increased ad-libitum energy-dense food consumption (macaques, rats) (57, 58), cardiovascular disease (mice) (59), and shortened lifespan (mice) (59). This implies that social standing, regardless of species, has physiological implications and could be contributing to obesity development and poor health. The findings from animal models thus serve as the basis for parallel outcomes reported in humans of low social status.

 

Social status can be measured objectively or subjectively. Objective measures typically include socioeconomic status (SES) variables, such as income, education, or occupation, which were discussed as individual level factors at the beginning of this chapter. Social status can also be represented by manifestations of status differentials, including inequality between groups or measurable differences in the ability for someone to obtain basic life necessities, such as food security. High levels of absolute income/wealth may be related to health not only through better material conditions, but also through social position.  However, in an analysis of two nationally representative British panel studies, ranked position of income/wealth, not absolute income/wealth, predicted adverse health outcomes such as obesity, presence of chronic disease, and poor ratings of physical functioning and pain (60). In a worldwide study of physical activity, countries with large activity inequality predicted obesity better than the total volume of physical activity within the country (61). Activity inequality is identified by calculating a Gini coefficient for population step count data from each country, 0 = complete equality, 1= complete inequality. Individuals in the top five countries for physical activity inequality (Saudi Arabia, USA, Egypt, Canada, Australia) were 196% more likely to have obesity than individuals from more equal societies that did not have large disparities in step counts across the population. Gender differences account for 43% of the inequality observed, however, this effect was mitigated in societies that rated higher in walkability (61). Inequality can also drive calorie consumption. Individuals who are experimentally induced to view themselves as poor in reference to others exhibited increased calorie intake (62). Additionally, individuals who believed they were poorer or wealthier than an interaction partner exhibited higher levels of anxiety in regards to that difference in status that, in turn, led to increased calorie consumption (62).

 

Food insecurity affects approximately 11.8 percent of families in the United States and has been linked to obesity and diabetes. Food insecurity occurs when “the intake of one or more members of a household is reduced and eating patterns are disrupted (sometimes resulting in hunger) because of insufficient money and other resources for food” (63). In women, food insecurity status predicts overweight/obese status differentially across racial ethnic groups. Non-Hispanic white women who are food insecure are 41% more likely to have overweight or obesity whereas Hispanic women who are food insecure are 29% more likely to have overweight and obesity (64). Among non-Hispanic black women and men, food insecurity did not predict overweight or obesity status (64). A population-based study in Canada revealed that persons in food insecure households had double the risk of developing type 2 diabetes compared to persons in food secure households, even after controlling for age, gender, income, race, physical activity, smoking status, alcohol consumption, diet quality, and BMI (65). Reduced food availability is theorized to initiate compensatory biological mechanisms that boost caloric intake, decrease resting metabolic rate, and increase storage of adipose tissue as a protective mechanism for survival (66). Research in youth has provided evidence for a moderating effect of food insecurity on the relationship between income and subjective social status (67). This means that low income is more strongly associated with low subjective social status when the household is also food insecure.

 

Subjective measures of social status (SSS) are typically measured by asking individuals to place themselves on 10-rung ladders based on where they perceive their rank within society and the community. Experimental evidence demonstrates a relationship between feelings of low social status and increased calorie intake. Cornil and Chandon showed that hometowns of National Football League teams consumed more calories after a team loss than hometowns of winning teams or of hometowns where teams didn’t play (68). Manipulations of social status in an experimental setting show that acute eating behavior post experimental manipulation consists of higher calorie food choices and higher total calorie intake in the low status group (69). Additionally, individuals randomized to a low social status condition, had increased levels of ghrelin, a hormone that stimulates appetite, as compared to the high social status condition, suggesting a physiological hunger response to low perceived social status (70). Studies of physical activity and SSS show that low SSS is associated with significantly lower levels of moderate to vigorous physical activity (71, 72), which could contribute to a lower overall energy expenditure. Closely related to SSS are other perceptive representations of status differentials, such as perceived discrimination, which is associated with increased weight and BMI in women (73) and increased abdominal adiposity in non-Hispanic whites (74).

 

Researchers have integrated individual and environmental factors into design and development of interventions to improve weight outcomes or weight-related behaviors (healthy eating, physical activity); however, not all of them are successful. For example, a study among low-income women with children in rural Mexico randomly assigned families to cash or in-kind transfers (food baskets) and found that women in the food basket and cash groups actually gained weight compared to women in the control group (75). This study and others that show weight gain occurring in spite of access to resources or poverty relief imply accounting for individual and environmental factors alone may not paint a complete picture of obesity development. Granted, it is important to consider that systemic environmental changes, such as placement of sidewalks or fruits and vegetables in a corner store, may not be adequately captured in a short time frame typical of academic studies. However, the small or nonexistent changes observed when resources are supplied warrants further investigation into deeper realms of social hierarchical constructs, as well as continued study of individual and environmental factors to improve treatment and prevention of obesity.

 

CLINICAL IMPLICATIONS AND CONCLUSIONS

 

Given the extent of the information on individual, environmental, and social hierarchy constraints on obesity development, it is important to understand how these can merge with clinical care. It is evident that there is no one simple solution and effective care requires knowledge of these complex relationships and an integration between the health system and the surrounding community. For example, based on the knowledge that the social determinants of health can influence diabetes and its comorbidities, the American Diabetes Association recommends in its clinical guidelines that providers “assess the social context… and apply that information to treatment decisions” (76). In conjunction with recognition of the impact of social and environmental determinants on multiple chronic diseases, some researchers propose that “community vital signs” be integrated into the electronic health record (EHR) (77) and some community health centers have begun pilot testing a social determinants questionnaire in their HER (78). Knowledge provided by these “vital signs” and social determinants could help providers make appropriate lifestyle-tailored recommendations for the patient.

 

Discussing context surrounding food in a patient’s life can provide insight into the realistic expectations for a patient’s diet.  Food insecurity can be identified with a short two question screener (79) and implementation in clinics has shown that screening improves clinician awareness of food insecurity, helping to better understand the lengths to which it affects patient treatment (80). Positive responses from physicians after pilot testing that incorporates screening into clinical practice mitigates concerns that discussions about food security would be stigmatizing to the patient (80). Patients who identify as food insecure can be referred to local food banks or community programs that will connect patients with resources at a federal and community level.

 

Patients that are finding it difficult to follow lifestyle modification recommendations to lose weight to prevent diabetes development may benefit from the Diabetes Prevention Program. The Diabetes Prevention Program is a lifestyle program focused on weight loss through dietary change and increased physical activity. While the overall weight loss was modest (~4% after 4 years), participants lowered their chances of developing diabetes by 58% during long-term follow-up (81). This program has been adapted for implementation and dissemination purposes and now the CDC’s National Diabetes Prevention (National DPP) program is available at almost 2,000 sites across the United States including many YMCAs, with a mix of online and in-person options.  This program is covered for eligible individuals by Medicare and many private insurers and cost for non-covered patients is variable and often income-based or free.  Initial evaluation of the real-world evidence for implementation of the National DPP have been promising with 35% achieving 5% weight loss and 42% meeting the activity goal of 150 minutes per week (82). Locations with the best participant retention and attendance share the following qualities: referrals from healthcare providers or health systems, provision of non-monetary incentives for participation, and use of cultural adaptations to address participant needs (83). The National DPP provides an affordable, easy and local referral source so that the provider can be assured their patients are receiving evidence-based lifestyle management in an ongoing program.  

 

RESOURCES

 

Figure 1 below shows the age-adjusted prevalence of obesity in adults by race and ethnicity, and sex from the Centers for Disease Control 2017 National Center for Health Statistics Data Brief (5).

Questions to Incorporate into Your EHR About Food Insecurity

1. “We worried whether (my/our) food would run out before (I/we) got money to buy more” Was that often true, sometimes true, or never true for (you/your household) in the last 12 months?
2. “The food that (I/we) bought just didn't last and (I/we) didn't have money to get more” Was that often true, sometimes true, or never true for (you/your household) in the last 12 months?

Information on the Diabetes Prevention Program

https://nccd.cdc.gov/DDT_DPRP/Registry.aspx

 

Opportunities for Advocacy 

The Obesity Action Coalition: https://www.obesityaction.org/

The Obesity Society:  https://www.obesity.org/

STOP Obesity Alliance: http://stop.publichealth.gwu.edu/

Rudd Center for Food Policy and Obesity: http://www.uconnruddcenter.org/weight-bias-stigma

 

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