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The Effect of the Melanocortin Agonist, MT-II, on the Defended Level of Body Adiposity

Department of Psychiatry (R.J.S., K.A.W.), Genome Research Institute, University of Cincinnati, and Procter & Gamble Pharmaceuticals (M.L.B., C.C.Ma., O.R., C.C.Mc., D.P.T., M.C.G., R.J.S.), Mason, Ohio 45040

Address all correspondence and requests for reprints to: Randy J. Seeley, Department of Psychiatry, Genome Research Institute, University of Cincinnati, 2170 East Galbraith Road, Cincinnati, Ohio 45226. E-mail: Randy.Seeley{at}uc.edu.

A wide range of experimental evidence implicates a critical role for melanocortin signaling in the control of food intake and body adiposity. Melanocortin receptor agonists such as MT-II potently reduce food intake and body weight, making such agonists potential therapeutics for obesity. The critical concept addressed by the present experiments is whether the homeostatic effects of melanocortin agonists directly regulate food intake or whether the effects on food intake are secondary, with the primary effects being the regulation of body weight and adiposity. To investigate this, we compared the effect of various doses of MT-II given via osmotic minipump for 28 d to alter food intake, body weight, and body fat in dietary-induced obese rats. In addition, before the implantation of the minipump, dietary-induced obese rats were weight reduced by differing amounts using varying levels of food restriction. The results show that in food-restricted rats, MT-II-treated rats consume significantly more calories than those receiving MT-II after ad libitum access to food. More importantly, regardless of the widely differing levels of body fat among the different dietary treatments employed, body fat at the end of the study was determined exclusively by the dose of MT-II, with MT-II-treated rats having less body fat than vehicle-treated rats. These experiments support the hypothesis that melanocortin signaling primarily regulates total body adiposity and that food intake is adjusted as necessary to achieve a specific level of body adiposity.

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