Project Number: 3062-51000-048-00-D
Project Type: In-House Appropriated
Start Date: May 27, 2010
End Date: Sep 30, 2014
1. Determine the extent to which dietary antioxidants alter obesity-induced and/or exercise-induced changes in mitochondrial function and insulin sensitivity. Sub-objective 1A. Determine the influence of anti-oxidant supplementation on changes in insulin sensitivity induced in the rat by high dietary fat and exercise. Sub-objective 1B. Determine the degree to which anti-oxidant supplementation alters exercise-induced changes in insulin sensitivity and mitochondrial function responses of overweight/obese individuals. 2. Identify sites and causes of obesity-induced and exercise-induced oxidative stress. Sub-objective 2A. Determine the effects of obesity and exercise on the temporal and cellular activation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf-2)/Anti-oxidant Response Element pathway. Sub-objective 2B. Identify and characterize obesity-induced and exercise-induced oxidative changes to insulin signaling pathway proteins. 3. Identify, characterize and compare sites of obesity-induced versus exercise-induced mitochondrial respiratory changes. Sub-objective 3A. Determine the degree to which anti-oxidant supplementation blunts exercised-induced and obesity-induced changes in mitochondria.
In order to complete the objectives of this proposal, we will utilize a combination of studies in humans, rodents that examine physiologic, metabolomic, genetic, and proteomic endpoints. In Objective 1, we will perform studies in humans and rodents to determine how antioxidant (vitamin E and vitamin C) supplementation affects insulin responses to exercise and obesity. The study in humans will involve analysis of exercise adaptation and insulin responses in previously untrained individuals and if antioxidant supplementation either enhances or negates these adaptations. Rodent studies will further examine molecular mechanisms underlying these adaptations. In Objective 2, we will determine the extent to which obesity, exercise, and anti-oxidant supplementation alter redox balance in animals and specific cells and to identify specific proteins whose thiol redox status is altered in obesity, exercise, and anti-oxidant supplementation. These studies will utilize transgenic mouse models and proteomic approaches. In Objective 3, we will determine the extent to which obesity, exercise, and anti-oxidant supplementation alter mitochondrial function. These studies will utilize rat models of exercise and obesity. Whole tissue and isolated mitochondria will be studied for changes in total mitochondrial content, mitochondrial gene expression, and respiration, and mitochondrial enzyme activities.