Leptin and melanocortin signaling in the hypothalamus

The regulation of body weight in humans is coordinated by the interplay between food intake and energy expenditure. The identification of the adipocyte-secreted hormone leptin as a key regulator on both of these processes has shed new light on the pathways involved in their regulation. Indeed, mutations in the gene's encoding leptin and its cognate receptor cause severe obesity in humans. Leptin's actions are mediated principally by target neurons in the hypothalamus where it acts to alter food intake, energy expenditure, and neuroendocrine-function. Recently, it has become clear that a number of critical neuropeptides are regulated by leptin in the hypothalamus. Among these is the proopiomelanocortin (POMC)-derived peptide, alpha-melanocyte-stimulating hormone (alpha-MSH), which is produced in the arcuate nucleus and is a potent negative regulator of food intake. Like leptin, mutations in POMC or in central melanocortin receptors lead to obesity in humans. Thus, an understanding of the mechanisms by which the leptin and melanocortin pathways signal in the hypothalamus is critical in order to begin to clarify the pathways involved in regulating body weight in humans.