This Article Full Text Full Text (PDF) All Versions of this Article: 145/8/3881    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Savontaus, E. Articles by Wardlaw, S. L. Search for Related Content PubMed PubMed Citation Articles by Savontaus, E. Articles by Wardlaw, S. L.

Metabolic Effects of Transgenic Melanocyte-Stimulating Hormone Overexpression in Lean and Obese Mice

Departments of Medicine and Pediatrics (T.L.B., A.K., L.M.Y., S.C.C., S.L.W.), Columbia University College of Physicians and Surgeons, New York, New York 10032; and Department of Pharmacology and Clinical Pharmacology (E.S.), University of Turku, Turku 20520, Finland

Address all correspondence and requests for reprints to: Sharon L. Wardlaw, M.D., Department of Medicine, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, New York 10032. E-mail: sw22{at}columbia.edu.

The proopiomelanocortin-derived peptide, -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 - and ₃-MSH, under the control of the cytomegalovirus-promoter were generated. The transgene was expressed in multiple tissues including the hypothalamus, in which 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 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.

This article has been cited by other articles:

				T. A. Czyzyk, M. A. Sikorski, L. Yang, and G. S. McKnight Disruption of the RII subunit of PKA reverses the obesity syndrome of agouti lethal yellow mice PNAS, January 8, 2008; 105(1): 276 - 281. [Abstract] [Full Text] [PDF]

				L. E. Pritchard and A. White Neuropeptide Processing and Its Impact on Melanocortin Pathways Endocrinology, September 1, 2007; 148(9): 4201 - 4207. [Abstract] [Full Text] [PDF]

				M. Lee, A. Kim, S. C. Chua Jr., S. Obici, and S. L. Wardlaw Transgenic MSH overexpression attenuates the metabolic effects of a high-fat diet Am J Physiol Endocrinol Metab, July 1, 2007; 293(1): E121 - E131. [Abstract] [Full Text] [PDF]

				A. P. Coll, B. G. Challis, M. Lopez, S. Piper, G. S.H. Yeo, and S. O'Rahilly Proopiomelanocortin-Deficient Mice Are Hypersensitive to the Adverse Metabolic Effects of Glucocorticoids Diabetes, August 1, 2005; 54(8): 2269 - 2276. [Abstract] [Full Text] [PDF]