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Diabetes. 2017 Aug;66(8):2072-2081. doi: 10.2337/db16-1334. Epub 2017 May 5.

Mitochondrial-Targeted Catalase Protects Against High-Fat Diet-Induced Muscle Insulin Resistance by Decreasing Intramuscular Lipid Accumulation.

Author information

1
Department of Molecular Medicine, School of Medicine, Gachon University, Incheon, Korea.
2
Korea Mouse Metabolic Phenotyping Center, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Korea.
3
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT.
4
Department of Comparative Medicine, University of Washington, Seattle, WA.
5
Department of Pathology, University of Washington, Seattle, WA.
6
Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT.
7
Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT.
8
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT varman.samuel@yale.edu.
9
Veterans Affairs Medical Center, West Haven, CT.

Abstract

We explored the role of reactive oxygen species (ROS) in the pathogenesis of muscle insulin resistance. We assessed insulin action in vivo with a hyperinsulinemic-euglycemic clamp in mice expressing a mitochondrial-targeted catalase (MCAT) that were fed regular chow (RC) or a high-fat diet (HFD) or underwent an acute infusion of a lipid emulsion. RC-fed MCAT mice were similar to littermate wild-type (WT) mice. However, HFD-fed MCAT mice were protected from diet-induced insulin resistance. In contrast, an acute lipid infusion caused muscle insulin resistance in both MCAT and WT mice. ROS production was decreased in both HFD-fed and lipid-infused MCAT mice and cannot explain the divergent response in insulin action. MCAT mice had subtly increased energy expenditure and muscle fat oxidation with decreased intramuscular diacylglycerol (DAG) accumulation, protein kinase C-θ (PKCθ) activation, and impaired insulin signaling with HFD. In contrast, the insulin resistance with the acute lipid infusion was associated with increased muscle DAG content in both WT and MCAT mice. These studies suggest that altering muscle mitochondrial ROS production does not directly alter the development of lipid-induced insulin resistance. However, the altered energy balance in HFD-fed MCAT mice protected them from DAG accumulation, PKCθ activation, and impaired muscle insulin signaling.

PMID:
28476930
PMCID:
PMC5521865
DOI:
10.2337/db16-1334
[Indexed for MEDLINE]
Free PMC Article

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