Schematic representation of the central control mechanisms of energy homeostasis and monogenic obesity disorders. Leptin interacts with leptin receptor in neurons in the arcuate nucleus and modulates expression of POMC, AGRP, or NPY, which in turn influences feeding behavior and energy expenditure. Alpha-MSH derived from POMC stimulates MC4-R in neurons in the dorsomedial hypothalamic nucleus. The a-MSH/MC4-R interaction is inhibited by AGRP and ASP (ectopically expressed in agouti mutation), and it may also be inhibited by mahogany gene product directly or indirectly. NPY stimulates NPY receptor in neurons in the periventricular hypothalamic neucleus. Known mutations that cause obesity in humans are depicted in bold. Abbreviations: AGRP, agouti-related peptide; ASP, agouti signaling protein (ectopically expressed in agouti mutation); CPE, carboxypeptidase; mahogany, mahogany gene product; leptin-R, leptin receptor; MC4-R, melanocortin-4 receptor; a-MSH, a-melanocyte-stimulating hormone; NPY, neuropeptide Y; NPY-R, neuropeptide Y receptor; PC1, prohormone convertase 1; POMC, proopiomelanocortin. (->) indicates stimulatory effect; (|) indicates inhibitory effect.