Obesity has become an epidemic health threat, the prevalence which is greater among African-American (AAW) than Caucasian (CW) women. Although environmental factors may be influential, it is apparent that inherent biochemical defects also underlie obesity in AAW. We have demonstrated that muscle fatty acid oxidation (FAO) is significantly lower in obese AAW vs. CW. This is important as reductions in muscle FAO leads to accumulation of bioactive lipids, which is strongly associated with insulin resistance and diabetes. Despite the significance of these findings, the cellular mechanisms to explain the racial/ethnic specific metabolic dysfunction remain undefined. However, using combinations of radiolabeled fatty acids, our research group has now identified a specific defect in skeletal muscle FAO present in obese AAW. In muscle homogenates, we have demonstrated that activation of palmitate to its acyl-CoA derivative by acyl-CoA synthetase (ACSL) is impaired to a greater extent in obese AAW vs. CW. We have also demonstrated that palmitate oxidation is impaired in cultured primary myocytes obtained from obese AAW vs. CW, suggesting that reduced ACSL activity is an inherited, race specific trait. Startlingly, this metabolic dysfunction may pre- exist in non-obese AAW, who also exhibit suppressed rates of palmitate oxidation. We hypothesize that the impairment in skeletal muscle FAO in AAW is due to a defect in acyl-CoA synthetase, the enzyme required for activating fatty acids prior to transport and oxidation in the mitochondria. This defect likely contributes to the greater incidence of obesity and diabetes in this racial group of women. However, in lean CW, endurance exercise training (EET) stimulates the muscle's capacity to oxidize long-chain fatty acids. Our secondary hypothesis is that AAW will respond to EET by increasing the capacity of skeletal muscle to oxidize lipids, due in part to a normalization of ACSL activity. To test our hypothesis, we propose the following specific aims: 1) to determine the cellular site and specific isoform(s) of ACSL responsible for reducing the fatty acid oxidative capacity of skeletal muscle from AAW 2) to extend our findings from specific aim 1 by determining the specific intramuscular lipid species that are altered by impaired ACSL activity and which contribute to muscle insulin resistance 3) using siRNA and adenovirus transfection technologies, we will demonstrate in human skeletal muscle cells that impaired ACSL activity is an inherited dysfunction in AAW which when corrected can restore fatty acid oxidation and insulin action and 4) to determine the potential for expanding ACSL activity and subsequently the oxidative capacity of skeletal muscle in AAW by aerobic exercise training. Our long term objective is to define the cellular mechanism(s) which pre-dispose AAW to obesity and diabetes. This research is clinically relevant as findings are likely to lead to the discovery of new therapeutic strategies for the treatment of obesity and diabetes in AAW.
