LIPID METABOLISM IN OBESITY, WEIGHT LOSS AND EXERCISE

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DESCRIPTION: (Adapted from the applicant's abstract):The long-term objective of this research is to better understand defects in human skeletal muscle that contribute to the morbidity and mortality evident with obesity. There is evidence that lipid metabolism in the skeletal muscle of obese individuals is altered in a manner favoring lipid storage. For example, some data indicate that obese skeletal muscle has a reduced capacity to oxidize lipid. There is also evidence that muscle-associated triglyceride concentration increases with obesity. These are important observations as the accumulation of lipid in skeletal muscle is associated with insulin resistance. The storage of lipid in skeletal muscle may thus predispose obese individuals toward insulin resistance and the many conditions linked with insulin resistance (hypertension, coronary artery disease, diabetes mellitus). Despite these important implications, the cellular mechanism that promotes lipid accretion in obese skeletal muscle is not evident. In the current application experiments are proposed that will determine the mechanism(s) responsible for promoting lipid storage in skeletal muscle with obesity and if intervention compensates or corrects the initial defect(s). The primary hypothesis is that postabsorptive (fasting) lipid metabolism in skeletal muscle is altered with obesity in a manner that promotes lipid accumulation in this tissue. This hypothesis is based upon preliminary work, where it was observed that lipid oxidation is depressed in the muscle of obese individuals in conjunction with reductions in oxidative enzyme activities. These preliminary data form the basis for the working hypothesis that lipid oxidation is depressed in skeletal muscle with obesity which promotes lipid storage. The secondary hypothesis is that weight loss does not enhance lipid oxidation, but reduces muscle triglyceride stores by an alternative mechanism. The tertiary hypothesis is that exercise training reverses the initial decrement in lipid oxidation evident with obesity, promoting lipid utilization. To test these hypotheses it will be determined: Specific Aim I - if postabsorptive lipid metabolism is impaired in skeletal muscle from obese individuals in a manner that promotes the accumulation of lipid; Specific Aim II - if the impairment in postabsorptive lipid metabolism in the skeletal muscle of obese individuals is corrected or compensated for with weight loss and; Specific Aim III - if exercise training enhances postabsorptive lipid metabolism in obese individuals and the cellular mechanisms responsible. Findings will be important as little is known concerning the mechanisms responsible for the defects in lipid metabolism with obesity and the impact of intervention.