Loss of Hepatic Mitochondrial Long-Chain Fatty Acid Oxidation Confers Resistance to Diet-Induced Obesity and Glucose Intolerance

Cell Rep. 2017 Jul 18;20(3):655-667. doi: 10.1016/j.celrep.2017.06.080.


The liver has a large capacity for mitochondrial fatty acid β-oxidation, which is critical for systemic metabolic adaptations such as gluconeogenesis and ketogenesis. To understand the role of hepatic fatty acid oxidation in response to a chronic high-fat diet (HFD), we generated mice with a liver-specific deficiency of mitochondrial long-chain fatty acid β-oxidation (Cpt2L-/- mice). Paradoxically, Cpt2L-/- mice were resistant to HFD-induced obesity and glucose intolerance with an absence of liver damage, although they exhibited serum dyslipidemia, hepatic oxidative stress, and systemic carnitine deficiency. Feeding an HFD induced hepatokines in mice, with a loss of hepatic fatty acid oxidation that enhanced systemic energy expenditure and suppressed adiposity. Additionally, the suppression in hepatic gluconeogenesis was sufficient to improve HFD-induced glucose intolerance. These data show that inhibiting hepatic fatty acid oxidation results in a systemic hormetic response that protects mice from HFD-induced obesity and glucose intolerance.

Keywords: Fgf21; Gdf15; NAFLD; NASH; diabetes; fatty acid oxidation; gluconeogenesis; hormesis; ketogenesis; obesity; steatosis.

Publication types

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

MeSH terms

  • Animals
  • Carnitine O-Palmitoyltransferase / deficiency
  • Carnitine O-Palmitoyltransferase / genetics
  • Carnitine O-Palmitoyltransferase / metabolism*
  • Fatty Acids / genetics
  • Fatty Acids / metabolism*
  • Glucose Intolerance / enzymology*
  • Glucose Intolerance / genetics
  • Glucose Intolerance / pathology
  • Liver / enzymology*
  • Liver / pathology
  • Metabolism, Inborn Errors / genetics
  • Metabolism, Inborn Errors / metabolism
  • Metabolism, Inborn Errors / pathology
  • Mice
  • Mice, Knockout
  • Mitochondria, Liver / enzymology*
  • Mitochondria, Liver / genetics
  • Mitochondria, Liver / pathology
  • Obesity / enzymology*
  • Obesity / genetics
  • Obesity / pathology
  • Oxidation-Reduction


  • Fatty Acids
  • Carnitine O-Palmitoyltransferase

Supplementary concepts

  • Carnitine palmitoyl transferase 2 deficiency