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

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 (Lead / Corresponding author)

Research output: Contribution to journalArticle

776 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)573-581
Number of pages9
JournalJournal of Clinical Investigation
Volume119
Issue number3
DOIs
Publication statusPublished - Mar 2009

Keywords

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

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  • Cite this

    Anderson, E. J., Lustig, M. E., Boyle, K. E., Woodlief, T. L., Kane, D. A., Lin, C-T., Price III, J. W., Kang, L., Rabinovitch, P. S., Szeto, H. H., Houmard, J. A., Cortright, R. N., Wasserman, D. H., & Neufer, P. D. (2009). Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans. Journal of Clinical Investigation, 119(3), 573-581. https://doi.org/10.1172/JCI37048