Mitochondria-Peroxisome Fatty Acid Oxidation in Obesity

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DESCRIPTION (provided by applicant): The Iong-term objective of this research is to better understand the defects in skeletal muscle (SKM) that contribute to the morbidity and mortality evident with obesity. There is evidence that obesity is associated with a reduced capacity for SKM lipid oxidation, which could be critical to the development of muscle insulin resistance and diabetes. Specifically, SKM from obese subjects possess an impaired mitochondrial (MitOSKM) capacity to oxidize long-chain fatty acids (LCFA). However, the potential for extra-mitochondrial mechanisms to respond to impaired MitOSKM fatty acid metabolism has been poorly investigated. In the liver, peroxisomes play an obligate role in defending against excess accumulation of cellular fatty acids by chain-shortening LCFA to acyl-carnitines, which are oxidized more efficiently by the mitochondria. In support, chemical inhibition of hepatocyte CPT-1 (rate limiting enzyme in mitochondrial LCFA import) in lean and the livers of obese animals are associated with elevated numbers of peroxisomes. Peroxisomes in extra-hepatic tissues are also responsive to states of altered LCFA metabolism as animals treated with hypolipidemic agents demonstrate clear increases in myocardial peroxisomal activity. We are proposing a similar role for peroxisomes in SKM lipid metabolism, and hypothesize that when MitOSKM oxidation of fatty acids is impaired, peroxisomal oxidation will be enhanced to compensate. Endurance exercise training (EET) in lean subjects and pharmacological treatment with hypolipidemic agents in obese subjects stimulate SKM fatty acid oxidation. Our secondary hypothesis is that SKM from obese subjects will be responsive to treatments that elevate lipid metabolism by elevating peroxisomal contributions toward complete oxidation of LCFA by existing MitOSKM Our Specific Aims are 1) To determine the contributions of peroxisomal activity toward LCFA oxidation in obese vs. lean skeletal muscle and 2) To determine the extent of metabolic flexibility of peroxisomal-mitochondrial oxidative capacity in obese vs. lean SKM. Methods: We will address these aims by 1) quantifying peroxisomal/mitochondrial contributions toward LCFA metabolism in SKM biopsies from hindlimb (rodent) and rectus abdominus (human) muscles of obese vs. lean subjects using electron microscopy/ immunocytochemistry and radioisotope assessment of fatty acid oxidation and 2) determining (in rodents) whether EET (8 weeks) and pharmacological treatment (3 weeks) with hypolipidemic agents (alone and/or in combination with EET) can improve the peroxisomal and MitOSKM capacity to metabolize LCFA. These investigations will 1) further elucidate the role of peroxisomal oxidation in obesity and diabetes 2) aid in the identification of new therapies for the treatment of obesity and other dyslipidemic diseases 3) provide valuable research training for our students and 4) generate data for subsequent RO1 applications.