Dysregulated Muscle Lipid Metabolism in African-Americans

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DESCRIPTION (provided by applicant): The prevalence of obesity and diabetes is greater among African-American (AAW) than Caucasian women (CW) in the United States. Although environmental factors may be influential, obese AAW have been shown to possess inherent metabolic defects that suppress lipid oxidation by skeletal muscle. More startling however, is the emerging evidence that these defects may pre-exist in non-obese AAW, predisposing this racial group toward a more rapid onset of fat gain vs. CW. This is fundamentally important because the resultant increase in intramuscular lipid content is strongly linked with insulin resistance and diabetes. Despite the significance of these findings, the cellular mechanisms to explain this racial/ethnic specific metabolic dysfunction remain undefined. Our primary hypothesis is that pre-obese/diabetic AAW possess skeletal muscle with an inherent impairment in the capacity to oxidize long-chain fatty acids (LCFA), leading to a cytotoxic accumulation of bioactive lipids, and precipitation of insulin resistance and diabetes. However, in lean CW, endurance exercise training (EET) stimulates mitochondrial biogenesis, elevating the muscles capacity to oxidize LCFA. Our secondary hypothesis is that AAW will respond to EET by increasing the capacity of skeletal muscle to oxidize lipids, thus reducing the propensity toward developing obesity and diabetes. The aims of the present investigation are 1) to identify the pre-existing cellular site(s) of dysfunction in skeletal muscle LCFA oxidation in lean AAW and 2) to determine whether AAW are responsive to EET. To accomplish our aims, we will investigate 12 sedentary, lean AAW and CW matched for age, BMI (< 25 kg/m2), and menstrual status. Obese subjects from both races will be assessed for comparisons. Skeletal muscle LCFA oxidative capacity will be measured by trapping labeled 14CO2 derived from oxidation by intact muscle strips and homogenates (rectus abdominus) in order to identify the specific cellular defects in lipid metabolism as being due to 1) pre-mitochondrial events 2) mitochondrial activation of LCFA to acyl-CoA 3) the transport of LCFA across the mitochondrial membrane and/or 4) the post-transport mitochondrial oxidative system. Measures of whole body insulin sensitivity will be made to determine the strength of association between the status of skeletal muscle lipid metabolism and insulin action. A subset of subjects from aim 1 and new recruits will undergo 7 days and 8 weeks of EET (cycling) to determine the impact of chronic muscle activity (vastus lateralis) on mitochondrial biogenesis, oxidation of LCFA, and insulin action in AAW. Our findings will be used for subsequent RO1 applications to achieve our Iong-term objective of understanding the mechanism(s) that underlie the greater morbidity and mortality associated with obesity and diabetes in AAW.