Obesity arguably represents the global healthcare challenge of the 21^st century.  The common underlying cause of obesity is a dysregulation of the energy balance equation in which more energy than is required is consumed and consequently stored as fat.  Critical pathways mediating the energy balance equation lie within the hypothalamus, which integrates key regulators of appetite such as the melanocortin and 5-HT signaling axes.  Within the arcuate nucleus of the hypothalamus (ARC) Pro-opiomelanocortin (Pomc) cells produce the endogenous melanocortin receptor agonists. Disruption of the Pomc gene in mouse and man produces positive energy balance, obesity and type 2 diabetes. We investigated the identity of the discrete subset of Pomc cells responsible for the regulation of energy and glucose homeostasis.  We observed that a critical source of Pomc driving appetite, physical activity and glucose homeostasis in male mice is a small subset of cells within the ARC expressing 5-HT_2C receptors (5-HT_2CRs). Restoring Pomc function only in these cells in male mice on a Pomc null background fully corrects energy balance, obesity and type 2 diabetes.  However, in female mice, this source of Pomc drives appetite and glucose homeostasis, but not physical activity.  Furthermore, this subset of Pomc cells only partially explains Pomc obesity/elevated fat mass in female mice. Having characterized the function of these Pomc cells in energy and glucose homeostasis, we next turned our attention to their role in obesity and type 2 diabetes treatment.  We report that hypothalamic Pomc neurons expressing 5-HT_2CRs are sufficient for communicating the full therapeutic appetite-suppressive and improved glucose and insulin tolerance effects of the new obesity medication lorcaserin in both male and female mice.  These findings reveal a critical source of Pomc in males and females regulating appetite and glucose homeostasis and furthermore, identify cells communicating lorcaserin’s therapeutic effects.  These results also provide the first demonstration of a sex difference in the function of discrete populations of Pomc in the regulation of physical activity and adiposity.

This work was supported by the Wellcome Trust (Grants WT081713 and WT098012).