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Metabolic effects of transgenic melanocyte-stimulating hormone overexpression in lean and obese mice
Eriika Savontaus1, Tracy L Breen, Andrea Kim
1Department of Medicine and Pediatrics, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
Abstract:
The proopiomelanocortin-derived peptide, alpha-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 alpha- and gamma(3)-MSH, under the control of the cytomegalovirus-promoter were generated. The transgene was expressed in multiple tissues including the hypothalamus, in which both alpha-MSH and gamma(3)-MSH levels were increased approximately 2-fold, compared with wild-type controls. Transgene homozygous mice were also crossed with obese leptin receptor-deficient db(3J) and obese yellow A(y) mice. MSH overexpression 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 db(3J)/db(3J) male and female mice, but there was no improvement in glucose metabolism. In contrast, the MSH transgene improved glucose tolerance in male A(y) mice. These results support the hypothesis that long-term melanocortinergic activation could serve as a potential strategy for anti-obesity and/or antidiabetic therapy.
Insights
Melanocortin system activation, through MSH overexpression, reduced obesity and improved glucose tolerance in mice. This suggests potential anti-obesity and antidiabetic therapies targeting the melanocortin pathway.
Area of Science:
- Endocrinology
- Neuroscience
- Genetics
Background:
- The melanocortin system, involving alpha-melanocyte-stimulating hormone (alpha-MSH), regulates feeding and body weight via hypothalamic melanocortin receptors.
- Genetic defects in the melanocortin system are linked to obesity in animal models and humans.
Purpose of the Study:
- To investigate the long-term effects of melanocortin system activation on body weight, composition, and insulin sensitivity.
- To assess the therapeutic potential of MSH overexpression in genetic models of obesity and metabolic dysfunction.
Main Methods:
- Generation of transgenic mice overexpressing N-terminal proopiomelanocortin (including alpha-MSH and gamma(3)-MSH) under a cytomegalovirus promoter.
- Crossing MSH-overexpressing mice with leptin receptor-deficient (db(3J)) and yellow (A(y)) obese mouse models.
- Analysis of body weight, adiposity, glucose tolerance, and insulin levels in wild-type, transgenic, and crossbred mice.
Main Results:
- MSH overexpression led to a 2-fold increase in hypothalamic alpha-MSH and gamma(3)-MSH levels.
- Lean male transgenic mice exhibited reduced weight gain, decreased adiposity, and improved glucose tolerance.
- Obesity was attenuated in db(3J)/db(3J) mice, and glucose tolerance improved in male A(y) mice, though metabolic benefits varied by sex and genetic background.
Conclusions:
- Long-term activation of the melanocortin system through MSH overexpression demonstrates potential as an anti-obesity strategy.
- Melanocortin system activation may offer therapeutic benefits for metabolic disorders, including type 2 diabetes.
- Sex-specific and genetic background-dependent effects highlight the complexity of targeting the melanocortin system for therapeutic interventions.
