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

Cell Rep. 2020 Nov 10;33(6):108374. doi: 10.1016/j.celrep.2020.108374.

Abstract

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 (Cpt2Sk-/- mice). CPT2 is an irreplaceable enzyme for mitochondrial long-chain fatty acid oxidation, converting matrix acylcarnitines to acyl-CoAs. Compared with controls, Cpt2Sk-/- muscles do not accumulate anabolic lipids but do accumulate ∼22-fold more long-chain acylcarnitines. High-fat-fed Cpt2Sk-/- mice resist weight gain, adiposity, glucose intolerance, insulin resistance, and impairments in insulin-induced Akt phosphorylation. Obesity resistance of Cpt2Sk-/- 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.

Keywords: acylcarnitine; beta-oxidation; carnitine palmitoyltransferase 2; carnitine supplementation; fatty acid oxidation; insulin resistance; long-chain fatty acids; mitochondria; muscle; obesity resistance.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carnitine / analogs & derivatives*
  • Carnitine / metabolism
  • Carnitine O-Palmitoyltransferase / metabolism*
  • Female
  • Humans
  • Insulin Resistance / physiology*
  • Mice
  • Obesity / drug therapy
  • Obesity / prevention & control*

Substances

  • acylcarnitine
  • Carnitine O-Palmitoyltransferase
  • Carnitine