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

Jieun Lee; Joseph Choi; Ebru S Selen Alpergin; Liang Zhao; Thomas Hartung; Susanna Scafidi; Ryan C Riddle; Michael J Wolfgang

doi:10.1016/j.celrep.2017.06.080

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.

Authors

Jieun Lee¹, Joseph Choi¹, Ebru S Selen Alpergin¹, Liang Zhao², Thomas Hartung³, Susanna Scafidi⁴, Ryan C Riddle⁵, Michael J Wolfgang⁶

Affiliations

¹ Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
² Department of Environmental Health and Engineering, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.
³ Department of Environmental Health and Engineering, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Biology, University of Konstanz, 78464 Konstanz, Germany.
⁴ Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁵ Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Baltimore Veterans Administration Medical Center, Baltimore, MD 21201, USA.
⁶ Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: [email protected].

Abstract

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 (Cpt2^L-/- mice). Paradoxically, Cpt2^L-/- 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

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

Authors

Affiliations

Abstract

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MeSH terms

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Supplementary concepts

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