Grant: Operating Grant

Over 60 percent of Canadian adults are currently overweight or obese. Within the last generation, the percentage of overweight or obese children has also risen dramatically. The health risks associated with obesity are well known, and include type 2 diabetes mellitus (T2DM) and cardiovascular disease, both of which are increasingly an issue in young adults. An early risk factor for T2DM is 'insulin resistance' - a situation in which insulin is no longer effective in stimulating glucose entry into many cell types including muscle. Interventions that decrease insulin resistance can prevent the full development of T2DM. Causes underlying individual susceptibility to obesity and T2DM are complex and include many environmental and biological factors. The overall goal of this research is to address some biological mechanisms in muscle that protect against obesity and T2DM. Detailed mechanistic analyses will be conducted on the metabolic function of proteins that reside in the 'powerhouses' of cells, the mitochondria. Specific objectives will examine the molecular mechanisms of uncoupling protein-3 (UCP3) function. UCP3 is a mitochondrial protein that facilitates fat oxidation, and protects cells from oxidative stress - but the molecular mechanisms are as yet unknown. Recent findings from our laboratory identify novel roles for UCP3 in glucose metabolism on the surface of mitochondria, and in mitochondrial proton leak. The metabolic implications of these processes for the efficiency of energy transduction processes in muscle will be studied in mice lacking UCP3; mice that have higher than normal levels of UCP3 in muscle, and in normal control mice. An epigenetic model of obesity and T2DM susceptibility in mice will also be examined. Additional determinations will be conducted in biopsied muscle from obese adults. The research is expected to improve our limited understanding of the role of impaired mitochondrial metabolism in obesity and obesity-related disorders.