Hypothalamic γ-melanocyte stimulating hormone gene delivery reduces fat mass in male mice

γ-Melanocyte stimulating hormone (γ-MSH) is an endogenous agonist of the melanocortin 3-receptor (MC3R). Genetic disruption of MC3Rs increases adiposity and blunts responses to fasting, suggesting that increased MC3R signaling could be physiologically beneficial in the long term. Interestingly, several studies have concluded that activation of MC3Rs is orexigenic in the short term. Therefore, we aimed to examine the short- and long-term effects of γ-MSH in the hypothalamic arcuate nucleus (ARC) on energy homeostasis and hypothesized that the effect of MC3R agonism is dependent on the state of energy balance and nutrition. Lentiviral gene delivery was used to induce a continuous expression of γ-Msh only in the ARC of male C57Bl/6N mice. Parameters of body energy homeostasis were monitored as food was changed from chow (6 weeks) to Western diet (13 weeks) and back to chow (7 weeks). The γ-MSH treatment decreased the fat mass to lean mass ratio on chow, but the effect was attenuated on Western diet. After the switch back to chow, an enhanced loss in weight (−15% vs −6%) and fat mass (−37% vs −12%) and reduced cumulative food intake were observed in γ-MSH-treated animals. Fasting-induced feeding was increased on chow diet only; however, voluntary running wheel activity on Western diet was increased. The γ-MSH treatment also modulated the expression of key neuropeptides in the ARC favoring weight loss. We have shown that a chronic treatment intended to target ARC MC3Rs modulates energy balance in nutritional state-dependent manner. Enhancement of diet-induced weight loss could be beneficial in treatment of obesity.