Obesity Epidemiology

438 EPIDEMIOLOGIC STUDIES OF DETERMINANTS OF OBESITYAdipose tissueLeptinLep-RAnabolic pathwayNeuronsAGRPHypothalamus+MC4RCatabolic pathwayNeuronsPOMCPC1α-MSH+Food intakeFigure 21.1 Leptin and melanocortin pathways. Lep-R, leptin receptor; POMC, proopiomelanocortin;α-MSH, α-melanocyte-stimulating hormone; AGRP, agouti-related protein; MC4R,melanocortin-4 receptor; PC1, proconvertase 1; →, location of mutations responsible formonogenic obesity in man; →, AGRP is a natural antagonist of MC4R; +, pathway activated; –,pathway inhibited. Reproduced with permission from Clement K. Genetics of human obesity.Proc Nutr Soc. 2005;64:133-142. 5of neurons. 2 The catabolic pathway includes the anorexigenic peptides proopiomelanocortin(POMC) and cocaine- and amphetamine-related transcript (CART), which reduceappetite and food intake. Increased leptin secretion stimulates the production of POMC,which is converted to α-melanocortin-stimulating hormone (α-MSH) through proconvertase1 (PC1). The actions of melanocortins are mediated by a family of melanocortinreceptors. The melanocrotin 4 receptor (MC4R) is largely expressed in the brainand central nervous system; activation of MC4R inhibits appetite and increases energyexpenditure. The anabolic pathway includes neuropeptide-Y (NPY) and agouti-relatedprotein (AGRP). Activation of NPY/AGRP neurons promotes positive energy balance byincreasing appetite and food intake and decreasing energy expenditure. Reduced leptinsecretion activates NPY/AGRP signaling and reduces MC4R signaling, thus stimulatingfood intake and promoting weight gain. Ghrelin, a gastrointestinal peptide hormoneproduced mainly by the stomach, opposes the action of leptin through disinhibition ofNPY/AGRP, thereby stimulating short-term food intake and decreasing energy expenditure.10 Rare genetic mutations on the leptin and melanocortin pathways can disruptboth production and function of catabolic and anabolic neuropeptidies, leading to severeearly-onset obesity and a variety of neuroendocrine abnormalities. In the following sections,we briefly review the major genetic mutations within these pathways that contributeto monogenic obesity (Table 21.1). For further information, readers can refer toseveral comprehensive reviews. 4-7LEP Gene MutationsLeptin, a hormone produced by adipose tissue and the product of the obese (ob) gene,plays a key role in regulating food intake and energy homeostasis. Ob/ob mice with a