The proopiomelanocortin-derived peptide, α-MSH, inhibits feeding via melanocortin receptors in the hypothalamus and genetic defects inactivating the melanocortin system have been shown to lead to obesity in experimental animals and humans. To determine whether long-term melanocortinergic activation has significant effects on body weight and composition and insulin sensitivity, transgenic mice overexpressing N-terminal proopiomelanocortin, including α- and γ3-MSH, under the control of the cytomegalovirus-promoter were generated. The transgene was expressed in multiple tissues including the hypothalamus, in which both α-MSH and γ3-MSH levels were increased approximately 2-fold, compared with wild-type controls. Transgene homozygous mice were also crossed with obese leptin receptor-deficient db3J and obese yellow Ay mice. MSH overespression led to uniform, dose-dependent darkening of coat color. MSH overexpression reduced weight gain and adiposity and improved glucose tolerance in lean male mice. In female transgenic mice, there was no significant effect on body weight, but there was a significant decrease in insulin levels. Obesity was attenuated in obese db3Jldb3J male and female mice, but there was no improvement in glucose metabolism. In contrast, the MSH transgene improved glucose tolerance in male Ay mice. These results support the hypothesis that long-term melanocortinergic activation could serve as a potential strategy for anti-obesity and/or antidiabetic therapy.
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