This K01 application proposes an integrated research and training plan to develop expertise in exercise and cellular metabolism in subjects with nonalcoholic fatty liver disease (NAFLD). NAFLD affects -20% of adults in the United States and is associated with insulin resistance and the metabolic syndrome. Decreasing calorie intake and increasing physical activity have been recommended as primary therapy for NAFLD, but the independent effect of aerobic exercise is unknown. The current exercise guidelines for disease prevention and weight management range from 150 min/wk, recommended by the Centers for Disease Control and the American College of Sports Medicine, to 300 min/wk, recommended by the Institute of Medicine. However, it is not known whether aerobic exercise alone can improve NAFLD, and which recommended dose of exercise might have the most beneficial effects. The purpose of this proposal is to determine the effect of two levels of aerobic exercise on the following specific aims: 1) hepatic fat content;2) hepatic lipoprotein kinetics;3) insulin sensitivity;and 4) potential cellular mechanism that regulate insulin action. We hypothesize that aerobic exercise will decrease hepatic fat content, improve hepatic, skeletal muscle, and adipose tissue insulin sensitivity in a dose-dependent fashion. This proposal involves conducting a randomized controlled trial that will randomize 30 obese subjects with NAFLD (>10% hepatic fat content) to one of three groups for four months: Group 1 (Control, no exercise), Group 2 (Low-Dose Aerobic Exercise, 150 min/wk of supervised exercise performed at 45-55% of V02max (brisk walking)), and Group 3 (Moderate-Dose Aerobic Exercise, 300min/wk of supervised exercise performed at 45-55% of V02max). These hypotheses will be tested using: 1) magnetic resonance spectroscopy (MRS) to assess intrahepatic lipid content, 2) infusion of stable isotope tracers to measure hepatic VLDL-TG and VLDL-apoB secretion rates, 3) a two-stage euglycemic hyperinsulinemic clamp procedure to measure both hepatic, adipose tissue and skeletal muscle insulin sensitivity, 4) immunohistochemistry to determine content and localization of metabolic variables in muscle and fat. The relavance [sic] of this investigation to public health is it will help determine exercise guidelines for obese patients with NAFLD, and lay the groundwork for future studies evaluating the effects of exercise on metabolic diseases associated with obesity.
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