Melanocortin System

The hypothalamic melanocortin system is perhaps the most extensively documented family of GPCRs (melanocortin receptors or MCRs) and ligands implicated in the central regulation of feeding behavior and energy homeostasis.1,2 Mounting pharmacologic and genetic data indicate that MC3R and MC4R are the key modulators of this system.34 The melanocortin system is distinctive in that both natural agonists and antagonists have been identified.

Bioactive peptides (melanocyte-stimulating hormones or MSHs) derived from the pro-opiomelanocortin prohormone are synthesized and processed in hypothalamic neurons56 and act as endogenous ligands for these receptors,7 activating the signaling cascade and eliciting anorexigenic (weight loss) responses.

Agouti-related peptide (AGRP), an endogenous antagonist of MC3R and MC4R, produces orexigenic effects through the PVN. The melanocortin system can be viewed as an integration point for several pathways that determine energy expenditure, including responses to leptin, the key indicator of body fat stores. This polypeptide hormone, produced in adipose tissue, acts to stimulate expression of a-MSH

and suppresses expression of AGRP through its non-GPCR receptor.8 Furthermore, correlations between the competence of MC4R signaling and expression of the anorexigenic brain-derived neurotrophic factor (BDNF) suggest that MC4R may, in fact, control energy balance through BDNF and its receptor.9

In rodents, pharmacologic blockade of the MC4R or haploinsufficiency of the gene increases feeding and leads to obesity. The phenotypes of MC3R- and MC4R-knockout mice indicate that each receptor plays a similar role in energy balance.10-16 Although targeted deletion of either or both receptors results in increased adiposity, their functions are not wholly redundant; MC4R-null mice are hyperphagic and hyper-insulinemic, whereas MC3R-null mice are hypophagic and only mildly hyperinsuline-mic. Chen et al.13 and Cummings and Schwartz17 have proposed that MC4R primarily regulates food intake and possibly energy expenditure, whereas MC3R influences feed efficiency and the deposition of fat. The role of the melanocortin system in the regulation of body weight has been validated in humans. A mutation in MC4R has been found to be the most common genetic cause of severe obesity in children.18

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Dieting Dilemma and Skinny Solutions

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