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 February 2, 2009
Citation Information: J Clin Invest. 2009;119(3):573-581. https://doi.org/10.1172/JCI37048.
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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 4

Mitochondrial-targeted scavenging of H2O2 prevents high-fat diet–induced insulin resistance in skeletal muscle.

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Mitochondrial-targeted scavenging of H2O2 prevents high-fat diet–induced...
(A–D) Whole body insulin sensitivity is preserved in high-fat diet–fed rats treated with SS31. (A) Plasma glucose and (B) plasma insulin concentrations in response to oral glucose challenge. (C) AUC (arbitrary units) for both glucose and insulin and (D) HOMA, a fasting index of insulin action. Data represent mean ± SEM; n = 9–10; *P < 0.05 vs. Std chow; †P < 0.05 vs. SS31-treated. (E) Preserved insulin signaling in high-fat diet–fed animals treated with SS31. Phosphorylated Akt relative to total Akt in response to glucose challenge in red gastrocnemius muscle (representative blots shown in Supplemental Figure 2). Data represent mean ± SEM; n = 4–5; §P < 0.05 vs. before glucose challenge. (F–H) Targeted expression of MCAT prevents high-fat diet–induced increase in mitochondrial H2O2 emission and insulin resistance in transgenic mice. (F) Succinate stimulated H2O2 emission (as described in Figure 1) during state 4 respiration (10 μg/ml oligomycin) in permeabilized red gastrocnemius fibers prepared from wild-type and MCAT mice (4- to 5-hour fasted) fed standard chow or high-fat (60%) diet for 12 weeks. (G) Glucose infusion rate (GIR) during hyperinsulinemic-euglycemic clamps. (H) Rate of glucose uptake (Rg) in soleus (Sol), gastrocnemius (G), and vastus lateralis (VL) skeletal muscle from mice in G. Data represent mean ± SEM; n = 4 for mH2O2 and n = 9–11 for glucose-clamp experiments; P< 0.05 vs. WT–std chow; #P < 0.05 vs. MCAT-HF; ‡P < 0.05 vs. WT-HF and MCAT–std chow.