Grant: Foundation Grant

Bioenergetics; Diet; Exercise; Metabolic Programming; Mitochondria; Mitochondrial Disorders; Oxidative Stress; Protein Post-Translational Modification; Reactive Oxygen Species; Redox Reactions

<html> <body> <p>Obesity and associated chronic diseases affect increasing numbers of Canadians, and result in billions of dollars in health care costs. Our laboratory has made major contributions to the understanding of metabolic mechanisms that increase risk for obesity and its metabolic sequelae including type 2 diabetes mellitus (T2DM). Our unique and specific focus is on mechanisms controlling variable mitochondrial oxidative phosphorylation (OXPHOS) efficiency in skeletal muscle.<br> <br> Skeletal muscle is important to overall energy expenditure, and the development of insulin resistance in this tissue precedes and predicts the development of T2DM. OXPHOS efficiency is highly variable due to proton leak uncoupling. We have shown that glutathione redox state and levels of reactive oxygen species (ROS) are pivotal in the control of uncoupling protein 3 (UCP3) in skeletal muscle. When activated by ROS directly or indirectly, UCP3 allows a leak of protons, which uncouples fuel oxidation from ATP synthesis, thus decreasing ATP production efficiency. Low leak and loss-of-function UCP3 mutations are associated with oxidative stress, impaired fatty acid oxidation and obesity. Importantly, we have demonstrated that obese diet resistant subjects exhibit a unique cellular phenotype consisting of reductions in: proton leak, oxidative fibers, capacity for fatty acid oxidation, and the expression of UCP3 and OXPHOS genes in muscle.<br> <br> <b>Our goal</b> is to elucidate mechanisms controlling UCP3 leak uncoupling and its impact on redox and ROS production, relevant to prevention and treatment of obesity and metabolic disease. The proposed research combines hypothesis-driven mechanistic studies in experimental systems with translational projects in obese diet-resistant adults. <b>The 3 synergistic objectives</b> are to <b>1)</b> elucidate the molecular control mechanisms of UCP3 (glutathionylation; acetylation) in skeletal muscle, <b>2)</b> examine the role of metabolic programming and epigenetic mechanisms in disordered muscle mitochondrial energetics and diet-resistant obesity in mice and humans, and <b>3)</b> characterize whole body and muscle energetics in diet-resistant and diet-sensitive obese women in response to calorie-restriction or moderate exercise.<br> <br> To achieve these objectives, we bring together a team of basic scientists, clinicians and industrial partners. Our findings will reveal the molecular mechanisms of UCP3 activation, a segue into the development of novel therapeutic strategies for obesity and T2DM. This research will continue to improve the quality of care at the Ottawa Hospital Weight Management Clinic by unraveling the complex origins and phenotypes of obesity. Identification of patients least likely to respond to conventional interventions would conserve limited funding resources for bariatric surgery and expedite surgery for those who require it most. Ultimately a better understanding of the complex determinants of obesity, response to energy restriction and exercise will lead to more effective and individualized treatment regimens.<br> <br> Trainees will develop knowledge and skills in a vibrant and innovative multidisciplinary research environment. State-of-the-art equipment, methodologies and expertise will be provided. Trainees will interact on a regular basis with clinicians and industrial collaborators in Canada and internationally.</p> </body> </html>