New insights into the complex metabolic circuitry of energy homeostasis have refined our understanding of the pathophysiology of obesity. Some of these insights regarding energy homeostasis are based on the identification of new functions for peptides that were discovered decades ago (see Figure). It is now known that α-melanocyte–stimulating hormone, a peptide derived from proopiomelanocortin and long recognized for its role in skin pigmentation through activity at the melanocortin 1 receptor (MC1R), decreases food intake and increases energy expenditure through interaction in the hypothalamus with another melanocortin receptor, MC4R. In mice, targeted deletion of the Mc4r gene results in obesity, . . .