Figure 7.Pathway for bAR-mediated activation of thermogenesis in brown adipocytes (30). a-adrenergic receptor (a-AR) agonists stimulate generation of cAMP which in turn activates protein kinase A (PKA). PKA phosphorylates CREB (cAMP regulatory element binding protein) which leads to increased gene transcription. It is hypothesized that activated CREB directly induces expression of PGC-1 and the type II thyroxine deiodinase (DII). PGC-1 coactivates transcription factors assembled on the UCP1 enhancer, thus increasing UCP1 gene expression. In addition, DII increases synthesis of triiodothyronine (T3), the ligand for the thyroid hormone receptor, further increasing UCP1 gene expression. PKA also activates hormone sensitive lipase (HSL), increasing the concentration of free fatty acids (FFAs) which in turn activate UCP1 protein activity. PGC-1 also coactivates the transcription factor, NRF-1 (nuclear respiratory factor-1), which leads to an increase in genes required for mitochondrial biogenesis, including NRF-1 and NRF-2. This results in marked stimulation of mitochondrial biogenesis. Abbreviations: PPAR, peroxisome proliferator-activated receptor; RXR, retinoid X receptor; RAR, retinoic acid receptor; 9c-RA; 9-cis-retinoic acid; RA, retinoic acid; TG, triglyceride This figure was adapted from reference (29).