Overexpression of Carnitine Palmitoyltransferase-1 in Skeletal Muscle Is Sufficient to Enhance Fatty Acid Oxidation and Improve High-Fat Diet–Induced Insulin Resistance

Overexpression of Carnitine Palmitoyltransferase-1 in Skeletal Muscle Is Sufficient to Enhance Fatty Acid Oxidation and Improve High-Fat Diet–Induced Insulin Resistance Clinton R. Bruce 1 2 , Andrew J. Hoy 2 , Nigel Turner 2 , Matthew J. Watt 3 4 , Tamara L. Allen 1 , Kevin Carpenter 5 6 , Gregory J. Cooney 2 , Mark A. Febbraio 1 and Edward W. Kraegen 2 1 Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia 2 Diabetes and Obesity Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia 3 St. Vincent's Institute of Medical Research and Department of Medicine, University of Melbourne, Fitzroy, Victoria, Australia 4 Department of Physiology, Monash University, Clayton, Victoria, Australia 5 Department of Biochemical Genetics, The Children's Hospital at Westmead, Sydney, New South Wales, Australia 6 Discipline of Genetic Medicine, University of Sydney, New South Wales, Australia Corresponding author: Clinton R. Bruce, clinton.bruce{at}baker.edu.au Abstract OBJECTIVE— Skeletal muscle insulin resistance is associated with lipid accumulation, but whether insulin resistance is due to reduced or enhanced flux of long-chain fatty acids into the mitochondria is both controversial and unclear. We hypothesized that skeletal muscle–specific overexpression of the muscle isoform of carnitine palmitoyltransferase 1 (CPT1), the enzyme that controls the entry of long-chain fatty acyl CoA into mitochondria, would enhance rates of fatty acid oxidation and improve insulin action in muscle in high-fat diet insulin-resistant rats. RESEARCH DESIGN AND METHODS— Rats were fed a standard (chow) or high-fat diet for 4 weeks. After 3 weeks, in vivo electrotransfer was used to overexpress the muscle isoform of CPT1 in the distal hindlimb muscles (tibialis anterior and extensor digitorum longus [EDL]). Skeletal muscle insulin action was examined in vivo during a hyperinsulinemic-euglycemic clamp. RESULTS— In vivo electrotransfer produced a physiologically relevant increase of ∼20% in enzyme activity; and although the high-fat diet produced insulin resistance in the sham-treated muscle, insulin action was improved in the CPT1-overexpressing muscle. This improvement was associated with a reduction in triacylglycerol content, the membrane-to-cytosolic ratio of diacylglycerol, and protein kinase C θ activity. Importantly, overexpression of CPT1 did not affect markers of mitochondrial capacity or fu