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.