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Introduction

Energy balance requires that an organism match caloric intake relatively precisely with caloric expenditure. In humans, an error of only +11 kcal/day results in a one pound weight gain over the course of a year. Over the past 40 years, the average body weight of American adults has increased at rate of less than that one pound per year, but the steady increase has yielded an increase of an average of 3 BMI points, bringing the average adult from a healthy weight into the overweight category (1). This increase brings with it a significantly increased risk of a number of health problems, including type 2 diabetes, high blood pressure, and cardiovascular and has a total financial cost estimated at $139 billion per year (2). To attempt to identify potential biological causes and treatments for this widely-occurring disorder, it is critical to understand the mechanisms which regulate energy homeostasis. In this chapter, we will review both peripheral and central signaling mechanisms relating to the food intake side of the equation, including how these signals may function with respect to specific aspects of food intake-related behavior, and a brief overview of how this system may become dysregulated during states of chronic overconsumption and obesity.

Environmental Signals

There are a variety of external factors which play a role in food intake, including social situations, time cues, food-related stimuli (e.g., sight, smell) and other learned information. While it is evident that these types of signals can have a definite impact on when to consume a meal, what foods to choose and how much to eat, the focus of this chapter will be on the molecular mechanisms involved in controlling these ingestive behaviors.

Peripheral Signals

Gastric mechanoreceptors

After food in ingested, it moves into the gastrointestinal tract where the volume and the nutritive content of the meal is detected via mechanical and chemosensory mechanisms. The results of sham feeding experiments indicate clearly that detection of food in the GI tract plays a large role in determining the amount consumed. In these studies, animals with open gastric fistulas which allow food to drain out of the stomach consume much larger volumes than animals consuming food normally, an effect which can be overcome by concurrently infusing nutritive solutions directly into the duodenum (3, 4). Gastric mechanoreceptors are located on vagal afferent and splanchnic nerve fibers and detect food volume by responding to stretch or pressure in the walls of the stomach (5, 6). Experiments in rats using pyloric occlusion to prevent contents from emptying into the intestines have demonstrated that satiety, as indicated by reduction in subsequent food intake, can occur based on gastric signals, that this is due predominantly to food volume, rather than caloric content, and that this effect is dependent on an intact vagus (7-9). However, it appears that the volumes required to reduce food intake are substantially greater than the volumes generally consumed in a single meal. Further, under the majority of self-controlled feeding conditions in rodents, intake was not significantly altered by pyloric occlusion (10, 11), indicating that, while gastric distension can act as a satiety signal, it may not be an important regulator during normal feeding situations. Although the idea that gastric distension may contribute to meal termination is consistent with data supporting a volumetric control of food intake, the data on gastric mechanoreceptors and satiety suggest that other mechanisms are likely at work in this phenomenon.

Gastrointestinal satiety signals

Although the stomach is thought to be primarily responsive to food volume, nutrient entry into the stomach also induces the release of gastrin releasing peptide (GRP), a member of the bombesin-like peptide family, which acts to decrease food intake by reducing meal size in both humans and animals, as well as prolonging the time to begin the next meal (12).

The intestinal tract is highly sensitive to the caloric content of ingested foods. Beginning in the duodenum, the detection of nutrients activates the release of a number of peptides, often termed "satiety signals", which act primarily to terminate consumption of a meal. The most well known of these is cholescystokinin (CCK), an octapeptide that is released from the duodenum and, to a lesser extent, the ileum in response to nutrients (13). CCK activates receptors on the vagus nerve which terminates in the hindbrain at the nucleus of the solitary tract (NTS). As nutrients enter into and move through the GI tract, peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) are secreted from the ileum and colon, while apolipoprotein A-IV (Apo A-IV) is synthesized in response to intestinal fat absorption (14-16). CCK and other GI peptides are differentially responsive to the macronutrient composition of a meal, with CCK and gastrin released more readily by protein ingestion, consumption of carbohydrates and fats yield greater GLP-1 release, PYY is most responsive to protein and fats and Apo A-IV synthesis is induced exclusively by fat absorption (17-19). Since most meals consist of multiple nutrient components, this allows for the integration of nutrient and caloric information, and the varying profile of satiety signal activation may contribute to the apparent differences in satiety value of the macronutrients, as well as possibly affecting macronutrient intake at later meals.

All of these GI "satiety signals" reduce food intake when administered to animals either systemically or centrally, and when administered peripherally in humans (20-26), although it should be noted that there is some controversy surrounding the efficacy of the active form of PYY (3-36) to reduce food intake and body weight in a rodent model (27). These peptides effect reductions in food intake primarily by acting to terminate the current meal, although longer-term effects have been suggested for GLP-1 and PYY (28). The observation that antagonists of CCK and GLP-1 receptors results in increased food intake further suggest that these hormones have endogenous satiety functions. This notion is also supported by the observation that subsequent to normal food intake, infusion of calories into the GI tract and exogenous administration of several of these peptides, including CCK and bombesin/GRP, animals display a similar set of behaviors, termed the "behavioral satiety sequence" (29-31). Genetic deletion of these peptides or their receptors yields mixed results, however, with OLETF rats, which lack the CCK-1 receptor due to a spontaneous mutation, and PYY knock-out mice displaying marked hyperphagia and obesity, while GLP-1 receptor-null mice display normal feeding behaviors and body weight (32-34), suggesting that some of these peptides have more critical functions in the control of energy intake, while the roles of others may be more readily compensated for.

Pancreatic satiety hormones

Outside of the GI tract, the pancreas also secretes peripheral meal-related hormones that act to reduce food intake. Insulin and amylin are co-secreted from pancreatic ß-cells in proportion to the amount of food consumed (35, 36). While the function of insulin seems to relate more to the long-term regulation of body adiposity (see below), amylin serves as a short-term signal that acts to reduce food intake by decreasing meal size (37). Exogenous, peripherally administered amylin reduces food intake, while systemic antagonists have the opposite effect, again indicating an endogenous role for this hormone in satiety (38-40). Glucagon is secreted from pancreatic A-cells very rapidly following meal onset, particularly meals high in protein, and acts via the liver to limit meal size in rodents and humans, an effect which can be reversed by administration of a glucagon-specific antibody (41-46).

Ghrelin

To date there is only one identified orexigenic gut peptide. Ghrelin is an endogenous ligand for the growth hormone secretogogue receptor (GHSR) that is synthesized in and secreted from gastric epithelium (47). Administration of exogenous ghrelin increases food intake in both humans and animals (48-51), while GHSR antagonism increases food intake and body weight in rodents (52). Further supporting the notion that this hormone plays an endogenous role in food intake, in both humans and non-human animals, peripheral ghrelin levels rise with fasting and prior to either scheduled or spontaneous meal ingestion and are reduced following nutrient consumption (48, 53-60), with a greater suppression in response to carbohydrate or protein ingestion compared to fat (61-65). Genetic ghrelin deletion, however, suggests that this peptide may have more critical effects on metabolic functions than on food intake and body adiposity, as these parameters are normal in these mice (66, 67), however, mice lacking the GHSR display resistance to high-fat diet-induced obesity (68). Recently, another peptide has been identified from the gene encoding ghrelin, dubbed obestatin or ghrelin-associated peptide (69). Obestatin has been found to reduce food intake and gastrointestinal motility, is reduced by fasting, and may mediate the hyperphagic effects of ghrelin administration (69, 70). Although the circumstances under which this peptide act on food intake and its specific site of action are currently under debate (71, 72), obestatin has potential to be added to the list of gut peptides that function as "satiety signals".

Adiposity Signals

Signals from the GI tract are acutely sensitive to nutrients entering the system and function primarily to regulate short-term intake on a meal-to-meal basis. However, the body also stores fuel for times of food shortage, mainly in the form of fat. One early hypothesis for the long-term regulation of body weight was that food intake and metabolic rate was adjusted based on the detection and regulation of the amount of adipose tissue present in the body (i.e., the "lipostatic hypothesis", 73, 74). To date, two major hormones have been identified and found to meet the criteria qualifying them as adiposity signals: insulin, which is produced in pancreatic ß-cells, and leptin, which is secreted directly from adipocytes. These two peptides are secreted in proportion to the amount of body fat and have access to the brain where they act via central effector systems in the hypothalamus, as well as the hindbrain, to reduce food intake (75, 76). Receptors for both insulin and leptin are found in the arcuate nucleus of the hypothalamus, a critical region for the control of energy homeostasis and central administration of both hormones potently reduces food intake (77-85). Hypothalamic administration of insulin antibodies has the opposite effect, increasing food intake and body weight (85,86) and rodents which are genetically incapable of leptin production (ob/ob mice) or have a dysfunctional leptin receptor (Zucker fatty or fa/fa rats and db/db mice) display an obese, hyperphagic phenotype (87-89), as do mice with a brain-specific deletion of the insulin receptor or disruption of pancreatic beta-cell and hypothalamic insulin receptor substrate 2 (90,91). Similarly, congenitally leptin-deficient humans are morbidly obese and markedly hyperphagic, as are those with leptin receptor mutations, although the symptoms are less severe (92, 93). In the hypothalamus, leptin receptors are located on both orexigenic neurons (i.e., neuropeptide Y (NPY)/agouti-related peptide (AgRP); 80) and anorexigenic neurons (i.e., proopiomelanocortin (POMC)/cocaine- and amphetamine-related transcript (CART); 94), while insulin receptor expression is high in the arcuate nucleus with insulin receptor substrate-2, a key component for insulin effects on food intake, co-localizing with NPY and α-melanocyte stimulating hormone (α-MSH) (95,96). Increases in the level of stored fat therefore increase circulating levels of insulin and leptin which, in turn, reduce orexigenic signaling and increase anorexigenic signaling, yielding a central mechanism by which these adiposity signals can influence food intake (see below).

Central Regulation

Hypothalamus

The primary forebrain regulation of food intake behavior is thought to occur in the hypothalamus. Early evidence indicated that lesions in this area had profound effects on ingestive behavior. Lesions of the ventromedial hypothalamus (VMH) result in drastically increased food intake and obesity, while lateral hypothalamic area (LHA) lesions yield hypophagia and reduced growth. These findings led to the hypothesis that these two areas controlled food intake by acting as the "satiety" and "feeding" centers, respectively, in the brain (97). Although this is now acknowledged to be a vast oversimplification of the regulation of food intake and body weight, the hypothalamus is still considered the key region for central control of energy homeostasis. A good deal more is now known regarding the molecular mechanisms at work in this area that act to control energy intake. The arcuate nucleus contains two populations of neurons that seem to be the first-order relay neurons in responding to adiposity signals from the periphery. The first arcuate neuronal population co-expresses the peptides NPY and the melanocortin receptor antagonist AgRP, while the second population of neurons contains POMC, the pre-cursor to the melanocortin receptor agonist α-MSH, and CART. Central infusion of NPY or AgRP potently stimulates food intake (98-100), while icv administration of α-MSH or CART inhibits food intake (101,102), suggesting that these two neuronal populations represent a primary orexigenic and its opposing anorexigenic pathway, respectively, in the central regulation of energy homeostasis. In support of the endogenous function of these peptides, food deprivation increases expression of AgRP and NPY mRNA, while decreasing POMC and CART gene expression (103-106). Overexpression of agouti or AgRP yields hyperphagia and obesity, as does disruption of the genes encoding the melanocortin-4 receptor, POMC or CART (107-111). Finally, while there is compensation for developmental deletion of the NPY or AgRP genes or neonatal destruction of NPY/AgRP neurons, ablation of these neurons in adult mice yields dramatic reductions in food intake and bodyweight, while the reverse occurs with ablation of POMC neurons (112-115). In humans, through relatively rare, genetic POMC deficiency also leads to an obese phenotype, as do a number of mutations of the MC-4 receptor. In addition, it has been suggested that variations in the POMC gene may be a contributing factor in obesity in the larger population (116).

As discussed above, leptin and insulin receptors are located on both of these types of neurons, suggesting that they are responsive to circulating levels of these hormonal signals, acting as effectors for altering food intake in response to alterations in energy balance as indicated by body adiposity. Leptin and insulin both cross the blood-brain barrier via independent, saturable transport mechanisms (117,118), indicating that peripheral production of these hormones can have central action. Indeed, as predicted, central insulin and leptin increase hypothalamic POMC expression, leptin increases activity in POMC neurons and melanocortin antagonists can block leptin-induced anorexia (119-122). These melanocortinergic neurons project from the arcuate to other areas of the hypothalamus, such as the paraventricular nucleus (PVN) and the LHA where several additional peptides that influence food intake and body weight are synthesized. The second-order neurons acting to regulate energy homeostasis in the PVN synthesize and release anorexigenic compounds, such as corticotrophin-releasing hormone (CRH), TRH, and oxytocin (123-128), while those in the LHA and adjacent perifornical area (PFA) are orexigenic, such as melanin-concentrating hormone (MCH) and orexin A and B (aka hypocretin 1 and 2) (129-132). In addition to leptin and insulin, receptors for ghrelin are also located on arcuate AgRP/NPY neurons, which are activated by central ghrelin administration (133-135). Furthermore, peripheral ghrelin administration activates neurons in the ARC and AgRP and NPY have been demonstrated to be requisite mediators of the hyperphagia induced by systemic ghrelin (136, 137). Recently, a new peptide was identified in the hypothalamus and named nesfatin-1 (NEFA/nucleobindin 2-encoded satiety factor). Central injection of this peptide reduced food intake and body weight, while infusion of targeted antisense oligonucleotides produce the opposite effect and fasting decreased nesfatin expression in the PVN (138). However, other, non-specific, effects of nesfatin have yet to be assessed and it is uncertain where this novel peptide fits into the scheme of physiological regulation of energy balance.

Hindbrain

In contrast to adiposity signals, short-term signals arising from the GI tract tend to be received and integrated in the hindbrain. Receptors for mechanical and chemical signals in the gut are found on afferent terminals of the vagus nerve, which tranduces these sensory signals and relays information to the nucleus of the solitary tract (NTS) (139). Studies using a chronic decerebrate rat model have demonstrated that these signals from the periphery (e.g., gastric preloads, CCK) can act to reduce meal size in the absence of hypothalamic input (140,141), however, there are a number of reciprocal connections between hypothalamic and hindbrain nuclei which suggest an integration of information from both sites acts to control food intake and energy balance (142-144). In addition, there are neurons expressing receptors for leptin, melanocortins and NPY, as well as POMC/α-MSH found in brainstem nuclei (145-150). Administration of synthetic MC receptor agonists and antagonists, AgRP, or NPY or its receptor agonists to the fourth ventricle all yield similar effects on food intake as when they are delivered to hypothalamic sites via the third ventricle (151-154). Leptin appears to exert a modulatory influence on brainstem controls of feeding, as well, as its administration alters the responsiveness of NTS neurons to gastric distension and CCK, as well as mediating the effects of these and other peripheral factors on food intake (155-159). Although the evidence clearly demonstrates a role for both hypothalamic and hindbrain sites in the regulation of food intake, it is still unclear which aspects are controlled by each of these areas and how these regions interact to ultimately regulate energy balance.

"Gut" peptides in the CNS

Along with leptin and insulin, a number of other peptides identified primarily as peripheral signals also function directly at CNS sites to affect energy homeostasis. Receptors for these peptides are often found in hindbrain areas, such as the NTS and DMH as well as in the circumventricular organs, allowing for central monitoring of the status of these circulating hormones (160). Whereas CCK-1 receptors predominate in the GI tract, CCK-2 receptors are largely found in the CNS. It appears that CCK-1 receptors are the primary mediators of food intake and satiety both peripherally and centrally, CCK-2 receptors in the brain may make some contribution, (161,162). Central CCK receptors, however, do not appear to be necessary for the intake suppressive effects of peripheral CCK, indicating an independent role for centrally-produced CCK, found throughout the brain, although interestingly, not the hypothalamus, and known to be involved in a variety of functions, as well as for systemic CCK detected via circumventricular organs, such as the area postrema (163-167). Peripheral PYY 3-36 may cross the blood-brain barrier to act at Y₂ receptors in the ARC, inhibiting NPY activity and stimulating POMC neurons (22,168). Direct central administration of PYY, however, produces a strong hyperphagic effect, likely acting via Y-family receptors, which also mediate NPY actions, in other brain regions, such as the PVN and hindbrain (153, 169, 170). GLP-1 and its receptors are also located in the hypothalamus as well as the brainstem and icv infusion of GLP-1 reduces food intake in fasted rats, likely acting in the PVN, while the receptor agonist exendin (9-39) increased feeding behavior (171,172).

Other

There are a number of other peptides that affect food intake outside of those listed above. Estrogen has inhibitory effects on food intake that are observed both as cyclic changes in caloric consumption with hormonal fluctuations in females and as a dramatic increase in food intake following ovariectomy. In addition, pharmacological experiments suggest a modulatory effect of estrogen on the function of a number of other food intake-related peptides (e.g., leptin, insulin, ghrelin, CCK) (173). The effects of estrogen on food intake and body weight can be explored more thoroughly. Monoamine systems, including dopamine (DA) and serotonin (5-HT) have also been shown to be involved in food intake. Activation of serotonin receptors using subtype-specific agonists or reuptake inhibitors (SSRIs) has been clearly demonstrated to reduce food intake and has been strongly targeted as an effective weight-loss treatment (174). Animals treated with DA receptor agonists also exhibit reductions in food intake with activation of D1, D2 and D3 receptor subtypes seeming to alter different aspects of appetitive and consummatory behaviors (175,176). The mesolimbic DA system in particular is posited to be strongly involved in food anticipation and learned appetitive behaviors, particularly those related to highly palatable foods (177,178). The opioid system also has a potent effect on food intake, although this system seems to reflect the hedonic impact of food with greater responsiveness to the palatability of the food than the energy status of the organism (179,180). Endogenous cannabinoids are also known to play a role in food intake, perhaps in both homeostatic and non-homeostatic types of feeding. Activation of CB1 receptors by either exogenous or endogenous ligands (e.g. ∆9-THC, anandamide) stimulates food intake, while pharmacological CB1 antagonists (e.g., rimonabant) reduce food intake generally fasted animals. Endocannabinoid levels are elevated in the hypothalamus during food deprivation and are reduced by food consumption and by leptin, indicating their involvement in homeostatic control of food intake (181,182). Rimonabant has also been demonstrated to be effective at producing weight loss in humans (183). The presence of endocannabinoids in limbic regions and their interaction with opioids to modulate food intake suggests that this system also functions in the non-homeostatic control of consummatory behavior (184).

Behavioral Effects of Molecular Signals

There are a number of ways by which these various peptides and neural systems may act to alter food intake. They may alter meal initiation (i.e., the likelihood of beginning an eating bout), which is generally observed as a change in meal frequency, or they may alter meal termination (i.e., how much is consumed prior to ending a meal), which is generally observed as a change in meal size. They may also affect the subjective feelings that an individual interprets as "hunger" or "fullness" and uses to determine when to begin or end a meal or the subjective palatability or reward value associated with eating particular foods.

Meal pattern analysis indicates that size of individual meals is the mechanism by which total food intake is generally altered. Increased meal size is the primary response to fasting and is almost exclusively responsible for the elevated caloric intake in rats bred for their susceptibility to diet-induced obesity (185-187). Furthermore, although some reports show overweight and obese humans consume both larger and more frequent meals, there is some evidence that it is meal size that differs most significantly between those gaining weight and those maintaining their current weights (188,189). When analyzing the component of food intake that is influenced by peptides found either peripherally or centrally, it is meal size that is most often found to be affected, leading some to suggest that meal termination is more strongly controlled by biological processes, while there a vast number of environmental influences that are more likely to be involved in meal initiation (i.e., availability of food, time of day, cognitive factors, learned associations/signals) (190). The majority of the peripheral satiety hormones, including CCK, gastrin releasing peptide/bombesin, GLP-1 agonist exendin-4, amylin and leptin, appear to act by reducing meal size with little or no effect on meal frequency (20,21,37,191-195), while ghrelin acts to increase intake by playing a role in meal initiation (53,57). Not surprisingly, as central leptin effectors, melanocortin agonists have been shown to reduce meal size, while MC antagonists have the opposite effect (196,197). Similarly, icv administration of CART decreased and NPY increased meal size (198,199).

In addition to influencing total energy intake via changes in these basic meal parameters when a constant test diet is used, some systems also differentially affect food selection or intake based on the macronutrient compositions of the diet. While NPY and AgRP both increase total caloric intake, NPY appears to induce greater appetitive and consummatory behaviors for foods high in carbohydrates, while the melanocortin system selectively affects fat intake and responding for fat-associated stimuli (169,200-203). Not surprisingly, leptin, acting to inhibit both NPY and AgRP, reduces intake of carbohydrates and fats (204).

While the peripheral and hypothalamic systems have largely been viewed as involved in the homeostatic aspects of food intake based on energy balance, other systems, primarily the dopaminergic, opioidergic and, more recently, cannabinoid systems, seem to influence intake based on palatability, or subjective "reward value" of the food being consumed (179,180,184,205). However, the involvement of cannabinoids in metabolic processes, the interconnection of hypothalamic circuits with those in mesolimbic and striatal regions involved in reward, the presence of "feeding peptides" in the nucleus accumbens, and evidence of interaction between these systems is further blurring the lines (181,206-208).

A number of these peripheral signals seem to be responsible for the subjective feelings of "hunger" or "satiety". This was determined using a experimental design known as the "deprivation intensity discrimination paradigm", in which rats are trained to discriminate between internal cues associated with 24 hours or 1 hour of food deprivation by receiving a reinforcer in a specific environment under only one of these conditions (209,210). The generalization between these deprivation states and those of a variety of potential hunger- or satiety-inducing peptides is tested by administering an exogenous does of the peptide of interest and measuring the animal’s behavior in the training environment. These types of experiments have suggested that ghrelin produces interoceptive cues similar to that of 24-hr food deprivation, while CCK and leptin produce cues similar to 1-hr food deprivation (211-213). Other peptides that influence food intake, such as NPY, bombesin, and MC-R agonists and antagonists do not appear to produce cues that generalize to either deprivation state, suggesting that their mechanism of action is independent of inducing a subjective feeling of "hunger" or "satiety" (212, 214-216). In humans, rating scales are often used to measure the subjective sensations perceived by subjects administered pharmacological agents associated with food intake regulation. These ratings are frequently, but not always, correlated with or predictive of consummatory behaviors, suggesting that, as in animals, these reported sensory stimuli may represent only one mechanism of altering food intake (217,218). Mechanical distention of the stomach and systemic infusion of CCK seem to produce consistent increases in self-reported ratings of "fullness" and decreases in ratings of "hunger", while the effects of infusions of GLP-1 and PYY on these sensations are not as clear (219-224), while increased "hunger" ratings have been observed following treatment with peripheral ghrelin and CCK-A receptor antagonists (49,225). Ghrelin levels are also correlated with reported hunger levels and meal initiation in humans in the absence of external cues associated with meals, including time and food-related stimuli (57).

Regulatory Disturbances Associated With Obesity

Diet-induced obesity in both humans and non-human animal models alters the endogenous profiles and the efficacy of a number of these energy balance-related signaling molecules. As would be expected, leptin and insulin levels are elevated in overweight subjects, as these adiposity signals circulate in levels proportional to the amount of body fat (226-228). Obese humans and rodents consuming diets high in fat also display peripheral reductions in circulating ghrelin, and fasting PYY levels (229-232). Rodents who have been maintained on a diet high in saturated fat exhibit reduced expression of NPY and AgRP mRNA in the hypothalamus (233,234), although levels of these peptides measured in the cerebrospinal fluid of humans did not differ significantly between lean and obese subjects (235). These increases in the anorexigenic signals leptin and insulin and decreases in orexigens, such as ghrelin, AgRP and NPY would be predicted based on the state of positive energy balance in obese individuals and would be expected to reduce food intake and body weight. However, these individuals tend to remain at elevated weights and, frequently, continue to gain weight, suggesting that these systems become dysfunctional in obesity. In fact, there is a large body of evidence supporting just that notion. Studies have clearly demonstrated that diet-induced obese humans and animals become resistant to the anorectic effects of both peripheral and central leptin, as well as central insulin (227, 236-241). A number of experiments have demonstrated the effects of obesity and high-fat diet consumption to impair the transport of leptin across the blood-brain barrier, reduce the sensitivity of intracellular signaling pathways activated by insulin and leptin, as well as a reduce the capacity of these hormones to act through central effector systems such as NPY and melanocortin pathways (242-248). Diet-induced obese rodents also appear to be less sensitive to the food intake-reducing effects of centrally administered melanocortin agonists (227).

Although peripheral satiety signals tend to maintain normal basal levels in obese subjects, several of these peptides, including CCK, PYY and Apo A-IV are less responsive to nutrient influx into the gut, with decreased release following meals and reduced satiety effects, while postprandial ghrelin levels tend to remain high further contributing to reduced feelings of satiety (249-252). Neuroimaging assays have also indicated a reduction in central dopamine D2 receptors in obese humans, leading to speculation that this may result in decreased reward sensitivity and compensation for this deficit in the form of overeating (253,254).

However, a major difficulty with these types of studies, in which comparisons are made between obese and lean populations, is the inability to dissociate whether these alterations cause obesity or are a subsequent effect (e.g., 255). One particularly useful tool in addressing this issue has been the development of selectively bred rats either prone or resistant to obesity induced by the consumption of high-fat, calorically dense diets (256). Studies of these animals on standard low-energy-density diets prior to divergence in weight gain and body adiposity have demonstrated that animals prone to diet-induced obesity also have a pre-disposition to insulin and leptin resistance, reduced central leptin signaling, reduced central insulin and leptin receptor binding, and increased expression of hypothalamic NPY, indicating that these factors may play a role in the development of obesity (238,241,257-261). On the other hand, no differences were observed in melanocortin binding and ghrelin and GHSR expression was reduced in obesity-prone relative to obesity-resistant rats, suggesting that these systems are not implicated in the onset of hyperphagia and weight gain (257,259).

Conclusion

The control of food intake involves the detection and integration of many different stimuli beginning with gastrointestinal detection of food volume and nutrient content acting to limit consumption within meals and peripheral adiposity signals acting via central sites and interacting with other peptides and hormones to balance short-term intake with long-term energy stores. In addition, there are a number of systems which act to select particular foods based on their nutrient content or, outside of homeostatic regulation, based on their palatability or reward value. These signals can alter a number of behaviors, including appetitive behavior, consumption, food selection, and the interoceptive states labeled "hunger" and satiety" to ultimately control energy intake. In spite of this complex regulatory system, a large proportion of the population of the United States is currently overweight or obese, suggesting a dysfunction. In fact, obesity and the consumption of high-fat diets appear to induce resistance to a number of the signals designed to limit intake in the face of positive energy balance, complicating the search for effective treatments. However, furthering our understanding of ingestive behaviors and the biological mechanisms that underlie them is the best hope for identifying a way to reverse the current obesity epidemic.