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

Anderson EJ, Lustig ME, Boyle KE, Woodlief TL, Kane DA, Lin CT, Price JW, Kang L, Rabinovitch PS, Szeto HH, Houmard JA, Cortright RN, Wasserman DH, Neufer PD
J Clin Invest. 2009 119 (3): 573-81

PMID: 19188683 · PMCID: PMC2648700 · DOI:10.1172/JCI37048

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 H(2)O(2)-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 H(2)O(2) 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 H(2)O(2) 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.

MeSH Terms (33)

Adenosine Diphosphate Adolescent Adult Animals Antioxidants Blood Glucose Body Mass Index Catalase Dietary Fats Electron Transport Glucose Clamp Technique Glucose Tolerance Test Glutathione Glutathione Disulfide Humans Hydrogen Peroxide Insulin Insulin Resistance Male Mice Mice, Inbred C57BL Mice, Transgenic Mitochondria Muscle Fibers, Skeletal Obesity Oligopeptides Oxidation-Reduction Oxidative Stress Oxygen Consumption Rats Rats, Sprague-Dawley Rodentia Young Adult

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