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A Unique Metalolic Sysdrone Causes Obesity in the Melanocortin-3 Receptor-Deficient Mouse

Vollum Institute (A.B. B., K.K., R.D.C.) and Oregon Health Sciences University (OHSU) Transgenic Mouse Core Laboratory (J.D.M.B.) Portland, Oregon 97201-3098; Portland Oregon; Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine (R.A.K.) Nashville, Tennessee; Neurocrine Biosciences, Inc. (M.J.C. M.A.P.) San Diego, California

Address all correspondence and requests for reprints to: Dr. Roger D. Cone, Vollum Institute L-474, Oregon Health Sciences University, 3181 S.W. Sam Jackson Park Road, Portland, Oregon 97201.

The central meilanocortin system is critical for the long term regulation of energy homeostasis. Null mutations of the melanocortin-4 receptor (MC4-R) are associated with hyperphagia, obesity, and accelerated longitudinal growth in mice and humans. However, little is known about the function of another central melanocortin receptor, the MC3-R. To assess the role of the MC3-R in energy homeostasis, of the mc3r coding sequence was deleted from the mouse genome. In contrast to the MC4-R knockout, which exhibits increased food intake, increased somatic growth, and defects in metabolism, mc3r-/-mice exhibit an exclusively metabolic syndrome. Homozygous null mc3r mice, while not significantly overweight, exhibit an approximately 50% to 60% increase in adipose mass. Mc3r-/- mice also exhibit an unusual increase in respiratory quotient when transferred onto high fat chow, suggesting a reducec ratio of fat/carbohydrate oxidation. Furthermore, male mc3r-/- mice also exhibit an approximately 50% redution in locomotory behavior on the running wheel, suggesting reduced energy expenditure.

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