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

  • Anderson E
  • Lustig M
  • Boyle K
 et al. 
  • 249

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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 impli- cated 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 mito- chondrial 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 mito- chondrial 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.

Author-supplied keywords

  • Adenosine Diphosphate/pharmacology
  • Adolescent
  • Adult
  • Animals
  • Antioxidants/pharmacology
  • Blood Glucose/drug effects/metabolism
  • Body Mass Index
  • Catalase/genetics
  • Dietary Fats/*pharmacology
  • Electron Transport/drug effects/physiology
  • Glucose Clamp Technique
  • Glucose Tolerance Test
  • Glutathione Disulfide/metabolism
  • Glutathione/metabolism
  • Humans
  • Hydrogen Peroxide/*metabolism
  • Inbred C57BL
  • Insulin Resistance/*physiology
  • Insulin/blood
  • Male
  • Mice
  • Mitochondria/drug effects/*metabolism
  • Muscle Fibers
  • Obesity/metabolism
  • Oligopeptides/pharmacology
  • Oxidation-Reduction/drug effects
  • Oxidative Stress
  • Oxidative Stress/drug effects/*physiology
  • Oxygen Consumption/drug effects/physiology
  • Rats
  • Rodentia/*physiology
  • SS31
  • Skeletal/drug effects/metabolism
  • Sprague-Dawley
  • Transgenic
  • Type 2 diabetes
  • Young Adult
  • cardiovascular disease
  • diabetes
  • insulin resistance
  • mitochondrial dysfunction

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Authors

  • Ethan J. Anderson

  • Mary E. Lustig

  • Kristen E. Boyle

  • Tracey L. Woodlief

  • Daniel A. Kane

  • Chien-te T. Lin

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