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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\u2010related protein (AGRP), proopiomelanocortin (POMC), cocaine\u2010and amphetamine\u2010regulated transcript (CART), orexin, brain\u2010derived neurotropic factor (BDNF), phosphatase with tensin homology (Pten), melanocortin\u20103 receptor (MC3R), and NPY\u2010Y1R 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\u2010type 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\u2010Y1R, 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\u20104 receptor\u2010associated obesity and diabetes.\u2014Haskell\u2010Luevano, 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\u20104 receptor knockout mouse.\n                    <jats:italic>FASEB J<\/jats:italic>\n                    . 23, 642\u2013655 (2009)\n                  <\/jats:p>","DOI":"10.1096\/fj.08-109686","type":"journal-article","created":{"date-parts":[[2008,10,29]],"date-time":"2008-10-29T20:46:39Z","timestamp":1225313199000},"page":"642-655","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":54,"title":["Voluntary exercise prevents the obese and diabetic metabolic syndrome of the melanocortin\u20104 receptor knockout mouse"],"prefix":"10.1096","volume":"23","author":[{"given":"Carrie","family":"Haskell\u2010Luevano","sequence":"first","affiliation":[{"name":"Department of Pharmacodynamics, College of Pharmacy University of Florida Gainesville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jay W.","family":"Schaub","sequence":"additional","affiliation":[{"name":"Department of Pharmacodynamics, College of Pharmacy University of Florida Gainesville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Andreasen","sequence":"additional","affiliation":[{"name":"Department of Pharmacodynamics, College of Pharmacy University of Florida Gainesville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kim R.","family":"Haskell","sequence":"additional","affiliation":[{"name":"Department of Pharmacodynamics, College of Pharmacy University of Florida Gainesville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus C.","family":"Moore","sequence":"additional","affiliation":[{"name":"Department of Pharmacodynamics, College of Pharmacy University of Florida Gainesville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorraine M.","family":"Koerper","sequence":"additional","affiliation":[{"name":"Department of Pharmacodynamics, College of Pharmacy University of Florida Gainesville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francois","family":"Rouzaud","sequence":"additional","affiliation":[{"name":"Department of Pharmacodynamics, College of Pharmacy University of Florida Gainesville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henry V.","family":"Baker","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology University of Florida Gainesville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William J.","family":"Millard","sequence":"additional","affiliation":[{"name":"Department of Pharmacodynamics, College of Pharmacy University of Florida Gainesville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Glenn","family":"Walter","sequence":"additional","affiliation":[{"name":"Department of Physiology and Functional Genomics University of Florida Gainesville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. 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