In order to determine if long-term melanocortinergic activation can attenuate the metabolic effects of a high fat diet, mice overexpressing an N-terminal POMC transgene, that includes - and 3-MSH, were studied on either a 10% low fat diet (LFD) or 45% high fat diet (HFD). Weight gain was modestly reduced in transgenic (Tg-MSH) male and female mice vs. wild-type (WT) on HFD (p<0.05) but not LFD. Substantial reductions in body fat percentage were found in both male and female Tg-MSH mice on LFD (p<0.05) which were more pronounced on HFD (p<0.001). These changes occurred in the absence of significant feeding differences in most groups, consistent with effects of Tg-MSH on energy expenditure and partitioning. This is supported by indirect calorimetry studies demonstrating higher resting oxygen consumption and lower RQ in Tg-MSH mice on the HFD. Tg-MSH mice had lower fasting insulin levels and improved glucose tolerance on both diets. Histological and biochemical analyses revealed that hepatic fat accumulation was markedly reduced in Tg-MSH mice on the HFD. Tg-MSH also attenuated the increase in corticosterone induced by HFD. Higher levels of Agrp mRNA, which might counteract effects of the transgene, were measured in Tg-MSH mice on LFD (p=0.02) but not HFD. These data show that long-term melanocortin activation reduces body weight, adiposity and hepatic fat accumulation and improves glucose metabolism, particularly in the setting of diet-induced obesity. Our results suggest that long-term melanocortinergic activation could serve as a potential strategy for the treatment of obesity and its deleterious metabolic consequences.