Anderson 2009 J Clin Invest

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Anderson EJ, Lustig ME, Boyle KE, Woodlief TL, Kane DA, Lin C-T, Price JW, Kang L, Rabinovitch PS, Szeto HH, Houmard JA, Cortright RN, Wasserman DH, Neufer PD (2009) Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans. J Clin Invest 119:573-81.

» PMID: 19188683 Open Access

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 (2009) J Clin Invest

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 H2O2emission, 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.

Keywords: Miotochondrial bioenergetics, Insulin resistance, Transgenic mice, Stress sensitive signalling kinases, NF-κB pathway, Mitochondrial H2O2-emitting potential, Amplex Red

O2k-Network Lab: US NC Greenville Neufer PD, US NC Greenville Anderson EJ, US TN Nashville Wasserman DH, CA Antigonish Kane DA, US CO Aurora Boyle KE


Labels: MiParea: Respiration  Pathology: Diabetes  Stress:Oxidative stress;RONS  Organism: Human, Mouse, Rat  Tissue;cell: Skeletal muscle  Preparation: Permeabilized tissue  Enzyme: Complex I, Complex II;succinate dehydrogenase, Uncoupling protein  Regulation: Fatty acid  Coupling state: OXPHOS, ET 

HRR: Oxygraph-2k