Loss of Muscle Carnitine Palmitoyltransferase 2 Prevents Diet-Induced Obesity and Insulin Resistance despite Long-Chain Acylcarnitine Accumulation

To assess the effects of acylcarnitine accumulation on muscle insulin sensitivity, a model of muscle acylcarnitine accumulation was generated by deleting carnitine palmitoyltransferase 2 (CPT2) specifically from skeletal muscle (Cpt2(Sk−/−) mice). CPT2 is an irreplaceable enzyme for mitochondrial long-chain fatty acid oxidation, converting matrix acylcarnitines to acyl-CoAs. Compared with controls, Cpt2(Sk−/−) muscles do not accumulate anabolic lipids but do accumulate ~22-fold more long-chain acylcarnitines. High-fat-fed Cpt2(Sk−/−) mice resist weight gain, adiposity, glucose intolerance, insulin resistance, and impairments in insulin-induced Akt phosphorylation. Obesity resistance of Cpt2(Sk−/−) mice could be attributed to increases in lipid excretion via feces, GFD15 production, and energy expenditure. L-carnitine supplement intervention lowers acylcarnitines and improves insulin sensitivity independent of muscle mitochondrial fatty acid oxidative capacity. The loss of muscle CPT2 results in a high degree of long-chain acylcarnitine accumulation, simultaneously protecting against diet-induced obesity and insulin resistance.