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Voluntary exercise prevents the obese and diabetic metabolic syndrome of the melanocortin-4 receptor knockout mouse

Carrie Haskell-Luevano^*,1, Jay W. Schaub^*, Amy Andreasen^*, Kim R. Haskell^*, Marcus C. Moore^*, Lorraine M. Koerper^*, Francois Rouzaud^*, Henry V. Baker, William J. Millard^*, Glenn Walter, S. A. Litherland and Zhimin Xiang^*

^* Department of Pharmacodynamics, College of Pharmacy,

Department of Molecular Genetics and Microbiology,

Department of Physiology and Functional Genomics, and

Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, Florida, USA

¹Correspondence: Department of Pharmacodynamics, University of Florida, PO Box 100487, Gainesville, FL 32610, USA. E-mail: carrie{at}cop.ufl.edu

Exercise is a mechanism for maintenance of body weight in humans. Morbidly obese human patients have been shown to possess single nucleotide polymorphisms in the melanocortin-4 receptor (MC4R). MC4R knockout mice have been well characterized as a genetic model that possesses phenotypic metabolic disorders, including obesity, hyperphagia, hyperinsulinemia, and hyperleptinemia, similar to those observed in humans possessing dysfunctional hMC4Rs. Using this model, we examined the effect of voluntary exercise of MC4R knockout mice that were allowed access to a running wheel for a duration of 8 wk. Physiological parameters that were measured included body weight, body composition of fat and lean mass, food consumption, body length, and blood levels of cholesterol and nonfasted glucose, insulin, and leptin. At the termination of the experiment, hypothalamic mRNA expression levels of neuropeptide Y (NPY), agouti-related protein (AGRP), proopiomelanocortin (POMC), cocaine- and amphetamine-regulated transcript (CART), orexin, brain-derived neurotropic factor (BDNF), phosphatase with tensin homology (Pten), melanocortin-3 receptor (MC3R), and NPY-Y1R were determined. In addition, islet cell distribution and function in the pancreas were examined. In the exercising MC4R knockout mice, the pancreatic islet cell morphology and other physiological parameters resembled those observed in the wild-type littermate controls. Gene expression profiles identified exercise as having a significant effect on hypothalamic POMC, orexin, and MC3R levels. Genotype had a significant effect on AGRP, POMC, CART, and NPY-Y1R, with an exercise and genotype interaction effect on NPY gene expression. These data support the hypothesis that voluntary exercise can prevent the genetic predisposition of melanocortin-4 receptor-associated obesity and diabetes.—Haskell-Luevano, C., Schaub, J. W., Andreasen, A., Haskell, K. R., Moore, M. C., Koerper, L. M., Rouzaud, F., Baker, H. V., Millard, W. J., Walter, G., Litherland, S. A., Xiang, Z. Voluntary exercise prevents the obese and diabetic metabolic syndrome of the melanocortin-4 receptor knockout mouse.

Key Words: energy homeostasis • leptin • insulin • -melanocyte stimulating hormone

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