Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans
Ethan J. Anderson, … , David H. Wasserman, P. Darrell Neufer
Ethan J. Anderson, … , David H. Wasserman, P. Darrell Neufer
Published March 2, 2009; First published February 2, 2009
Citation Information: J Clin Invest. 2009;119(3):573-581. https://doi.org/10.1172/JCI37048.
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Categories: Research Article Metabolism

Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans

Abstract

High dietary fat intake leads to insulin resistance in skeletal muscle, and this represents a major risk factor for type 2 diabetes and cardiovascular disease. Mitochondrial dysfunction and oxidative stress have been implicated in the disease process, but the underlying mechanisms are still unknown. Here we show that in skeletal muscle of both rodents and humans, a diet high in fat increases the H2O2-emitting potential of mitochondria, shifts the cellular redox environment to a more oxidized state, and decreases the redox-buffering capacity in the absence of any change in mitochondrial respiratory function. Furthermore, we show that attenuating mitochondrial H2O2 emission, either by treating rats with a mitochondrial-targeted antioxidant or by genetically engineering the overexpression of catalase in mitochondria of muscle in mice, completely preserves insulin sensitivity despite a high-fat diet. These findings place the etiology of insulin resistance in the context of mitochondrial bioenergetics by demonstrating that mitochondrial H2O2 emission serves as both a gauge of energy balance and a regulator of cellular redox environment, linking intracellular metabolic balance to the control of insulin sensitivity.

Authors

Ethan J. Anderson, Mary E. Lustig, Kristen E. Boyle, Tracey L. Woodlief, Daniel A. Kane, Chien-Te Lin, Jesse W. Price III, Li Kang, Peter S. Rabinovitch, Hazel H. Szeto, Joseph A. Houmard, Ronald N. Cortright, David H. Wasserman, P. Darrell Neufer

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Figure 2

The mitochondrial-targeted antioxidant SS31 prevents the increase in mitochondrial H2O2-emitting potential caused by high-fat diet in red gastrocnemius skeletal muscle of rats.

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The mitochondrial-targeted antioxidant SS31 prevents the increase in mit...
(A and B) Dose-response curves for mitochondrial H2O2 (mH2O2) emission following in vitro or in vivo administration of SS31. (A) Permeabilized fibers were briefly incubated in a range of SS31 concentrations prior to being assayed for maximal H2O2 emission under state 4 conditions (5 mM pyruvate/2 mM malate, 10 μg/ml oligomycin) in the presence of the complex III inhibitor antimycin A (10 μM). (B) Permeabilized fibers were assayed for maximal succinate-induced (3 mM) mitochondrial H2O2 emission under state 4 conditions (10 μg/ml oligomycin) approximately 2 hours following an acute intraperitoneal injection of SS20 (control peptide, 5 mg/kg) or varied concentrations of SS31. (C and D) SS31 ameliorates the increased mitochondrial H2O2 emission caused by high-fat diet. Permeabilized fibers were prepared from rats fed (6 weeks) standard chow, high-fat diet, or high-fat diet with daily SS31 administration, and H2O2 emission was measured during state 4 respiration (10 μg/ml oligomycin) supported by (C) succinate (as described in Figure 1) or (D) palmitoylcarnitine (25 μM) and malate (2 mM). (E and F) High-fat diet increases basal respiration with NADH-linked substrates, but SS31 has no effect. Permeabilized fibers were prepared from rats treated as indicated above, and respiration was measured with (E) pyruvate/malate (5 mM/2 mM) or (F) palmitoylcarnitine/malate (25 μM/2 mM) in both basal respiratory state 4 (PM4, PCM4) and maximal ADP-stimulated (2 mM) respiratory state 3 (PM3, PCM3). Data represent mean ± SEM; n = 4–6, *P < 0.05 vs. Std chow; †P < 0.05 vs. Std. chow and SS31-treated.