Muscle Expression of a malonyl-CoA-insensitive Carnitine palmitoyltransferase-1 Protects Mice Against high-fat/high-sucrose Diet-Induced Insulin Resistance

Am J Physiol Endocrinol Metab. 2016 Sep 1;311(3):E649-60. doi: 10.1152/ajpendo.00020.2016. Epub 2016 Aug 9.

Abstract

Impaired skeletal muscle mitochondrial fatty acid oxidation (mFAO) has been implicated in the etiology of insulin resistance. Carnitine palmitoyltransferase-1 (CPT1) is a key regulatory enzyme of mFAO whose activity is inhibited by malonyl-CoA, a lipogenic intermediate. Whereas increasing CPT1 activity in vitro has been shown to exert a protective effect against lipid-induced insulin resistance in skeletal muscle cells, only a few studies have addressed this issue in vivo. We thus examined whether a direct modulation of muscle CPT1/malonyl-CoA partnership is detrimental or beneficial for insulin sensitivity in the context of diet-induced obesity. By using a Cre-LoxP recombination approach, we generated mice with skeletal muscle-specific and inducible expression of a mutated CPT1 form (CPT1mt) that is active but insensitive to malonyl-CoA inhibition. When fed control chow, homozygous CPT1mt transgenic (dbTg) mice exhibited decreased CPT1 sensitivity to malonyl-CoA inhibition in isolated muscle mitochondria, which was sufficient to substantially increase ex vivo muscle mFAO capacity and whole body fatty acid utilization in vivo. Moreover, dbTg mice were less prone to high-fat/high-sucrose (HFHS) diet-induced insulin resistance and muscle lipotoxicity despite similar body weight gain, adiposity, and muscle malonyl-CoA content. Interestingly, these CPT1mt-protective effects in dbTg-HFHS mice were associated with preserved muscle insulin signaling, increased muscle glycogen content, and upregulation of key genes involved in muscle glucose metabolism. These beneficial effects of muscle CPT1mt expression suggest that a direct modulation of the malonyl-CoA/CPT1 partnership in skeletal muscle could represent a potential strategy to prevent obesity-induced insulin resistance.

Keywords: fatty acid oxidation; glucose homeostasis; mitochondria; obesity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carnitine O-Palmitoyltransferase / antagonists & inhibitors
  • Carnitine O-Palmitoyltransferase / biosynthesis*
  • Carnitine O-Palmitoyltransferase / genetics
  • Diet, High-Fat / adverse effects*
  • Dietary Sucrose / adverse effects*
  • Energy Metabolism / drug effects
  • Glucose / metabolism
  • Insulin Resistance*
  • Male
  • Malonyl Coenzyme A / metabolism*
  • Malonyl Coenzyme A / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mitochondria, Muscle / drug effects
  • Mitochondria, Muscle / metabolism
  • Muscle, Skeletal / metabolism*
  • Mutation / genetics
  • Obesity / metabolism
  • Oxygen Consumption / drug effects
  • Signal Transduction / drug effects

Substances

  • Dietary Sucrose
  • Malonyl Coenzyme A
  • CPT1B protein, mouse
  • Carnitine O-Palmitoyltransferase
  • Glucose