Effects of exercise and elevated fatty acid availability on muscle lipid metabolism and insulin sensitivity

Elevated systemic fatty acid availability is a key factor underlying obesity-related insulin resistance and type 2 diabetes. A single session of exercise can protect against fatty acid-induced insulin resistance, possibly via altered muscle lipid metabolism. The overall purpose of this dissertation was to examine the effects of exercise and/or elevated fatty acid availability on the regulation of muscle lipid metabolism and changes in insulin sensitivity. The major findings of my dissertation studies were as follows: In STUDY 1, compared with a saline infusion after exercise, an overnight (16h) lipid infusion/heparin infusion after a single session of exercise increased muscle triacylglycerol (TAG) concentration by ---30%, without any change in muscle diacylglycerol (DAG) or ceramide. Despite minimal changes in activity of TAG-synthesis enzymes, greater membrane-associated abundance of the fatty acid transporter FAT/CD36 may have facilitated the enhanced muscle TAG storage. In STUDY 2, a modest single session of low intensity exercise (70 min at 50% VO2peak) was sufficient to improve insulin sensitivity into the next day in obese adults. Although we did not find any change in muscle lipids after exercise, reduced systemic fatty acid uptake after exercise may have been important for the improvement in insulin sensitivity. Unlike STUDY 1 and STUDY 2, which were performed in human subjects, STUDY 3 was conducted in cultured C2C12 muscle cells, in vitro. In STUDY 3 we found that compared with the deleterious effects of palmitate incubation, muscle cells acutely (12h) incubated with physiologic mixtures of several fatty acids showed little impairment in insulin signaling, likely due to a robust capacity to store the available fatty acid as TAG and accumulate virtually no DAG. Importantly, providing a relatively high proportion of saturated fatty acids in this fatty acid mixture did not abnormally affect fatty acid "partitioning" or insulin signaling. Together these major findings of my dissertation projects suggest that preferential storage of excess fatty acid as muscle TAG may limit accumulation of harmful lipid intermediates and protect against fatty acid-induced insulin resistance; however, the mechanisms underlying preferential TAG storage remain elusive.