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Submitted on March 2, 2004
Accepted on April 19, 2004
Departments of Medicine and Pediatrics, Columbia University College of Physicians & Surgeons, New York, N.Y.; Department of Pharmacology and Clinical Pharmacology, University of Turku, Turku, Finland
* To whom correspondence should be addressed. E-mail: sw22{at}columbia.edu.
The pro-opiomelanocortin (POMC) derived peptide, 
-melanocyte stimulating hormone (-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 in humans. To determine if long-term melanocortinergic activation has significant effects on body weight and composition and on insulin sensitivity, transgenic mice overexpressing N terminal POMC, including - and 
3-MSH, under the control of the CMV-promoter were generated. The transgene was expressed in multiple tissues including the hypothalamus, where both -MSH and 3-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 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 db3J/db3J 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 anti-diabetic therapy.
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