Muscle-specific deletion of carnitine acetyltransferase compromises glucose tolerance and metabolic flexibility

Cell Metab. 2012 May 2;15(5):764-77. doi: 10.1016/j.cmet.2012.04.005.


The concept of "metabolic inflexibility" was first introduced to describe the failure of insulin-resistant human subjects to appropriately adjust mitochondrial fuel selection in response to nutritional cues. This phenomenon has since gained increasing recognition as a core component of the metabolic syndrome, but the underlying mechanisms have remained elusive. Here, we identify an essential role for the mitochondrial matrix enzyme, carnitine acetyltransferase (CrAT), in regulating substrate switching and glucose tolerance. By converting acetyl-CoA to its membrane permeant acetylcarnitine ester, CrAT regulates mitochondrial and intracellular carbon trafficking. Studies in muscle-specific Crat knockout mice, primary human skeletal myocytes, and human subjects undergoing L-carnitine supplementation support a model wherein CrAT combats nutrient stress, promotes metabolic flexibility, and enhances insulin action by permitting mitochondrial efflux of excess acetyl moieties that otherwise inhibit key regulatory enzymes such as pyruvate dehydrogenase. These findings offer therapeutically relevant insights into the molecular basis of metabolic inflexibility.

Publication types

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

MeSH terms

  • Acetyl Coenzyme A / metabolism
  • Acetylcarnitine / metabolism
  • Animals
  • Carbon / metabolism
  • Carnitine / analogs & derivatives
  • Carnitine / metabolism
  • Carnitine O-Acetyltransferase / deficiency*
  • Carnitine O-Acetyltransferase / metabolism*
  • Cells, Cultured
  • Energy Metabolism
  • Fatty Acids / metabolism
  • Glucose / metabolism*
  • Glucose Tolerance Test
  • Humans
  • Insulin / metabolism
  • Insulin Resistance
  • Mice
  • Mice, Knockout
  • Mitochondria / metabolism
  • Muscle Fibers, Skeletal / metabolism*


  • Fatty Acids
  • Insulin
  • acylcarnitine
  • Acetylcarnitine
  • Acetyl Coenzyme A
  • Carbon
  • Carnitine O-Acetyltransferase
  • Glucose
  • Carnitine