| Human obesity, defined as possessing a body mass index value of greater than 30, is reaching critical levels world wide. Obese individuals are at greater risk for other diseases including cardiovascular disease, type 2 diabetes, and certain types of cancer. In addition to environmental and lifestyle causes, certain genetic mutations have been shown to result in obesity.;Genetic deletion of the melanocortin-3 and -4 receptors (MC3R and MC4R respectively) have been shown to result in altered metabolisms and phenotypes in mice. Voluntary exercise has been shown by the Haskell-Luevano laboratory to delay the onset of the obesity of melanocortin-4 receptor knockout (KO) mice, preventing early onset weight gain and increases in fat mass. Running wheel exercise was also found to change hypothalamic expression levels of genes involved in energy homeostasis.;This dissertation investigates the effects of voluntary exercise on the phenotypes and gene expression profiles of male mice lacking the MC3R, the MC4R, or both the MC3 and MC4 receptors (DKO mice). Additionally the effects of MC4R deletion and voluntary exercise were investigated in male and female mice to determine what effects, 33 if any, gender had on the phenomenon seen in male MC4R KO mice allowed to exercise.;Genotype and exercise both had significant effects on both phenotype and gene expression in male mice lacking the one or both of the central melanocortin receptors. Voluntary exercise resulted in a significant decrease in body weight in MC4R KO and DKO mice (P<0.001) and total fat mass in exercising MC3R KO, MC4R KO, and DKO mice (P<0.05) compared to the same genotypes in conventional cages. Furthermore, changes in expression levels of genes involved in liver fatty acid metabolism seen in sedentary MC4R KO mice were prevented by voluntary exercise. Significant differences in phenotype and hypothalamic gene expression were seen between male and female MC4R KO mice. The obese phenotype was diminished in female mice, in part due to the lack of hyperphagia generally associated with MC4R KO dysfunction.;Overall, voluntary exercise had a beneficial effect on central melanocortin receptor KO mice, delaying the onset of the associated phenotypes and preventing changes in gene expression. |
