title: 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 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.
authors.affiliation: Metabolic Institute for the Study of Diabetes and Obesity, East Carolina University, Greenville, North Carolina 27834, USA.
authors.forename: Ethan J
authors.initials: EJ
authors.lastname: Anderson
authors.forename: Mary E
authors.initials: ME
authors.lastname: Lustig
authors.forename: Kristen E
authors.initials: KE
authors.lastname: Boyle
authors.forename: Tracey L
authors.initials: TL
authors.lastname: Woodlief
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Kane
authors.forename: Chien-Te
authors.initials: CT
authors.lastname: Lin
authors.forename: Jesse W
authors.initials: JW
authors.lastname: Price
authors.forename: Li
authors.initials: L
authors.lastname: Kang
authors.forename: Peter S
authors.initials: PS
authors.lastname: Rabinovitch
authors.forename: Hazel H
authors.initials: HH
authors.lastname: Szeto
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Houmard
authors.forename: Ronald N
authors.initials: RN
authors.lastname: Cortright
authors.forename: David H
authors.initials: DH
authors.lastname: Wasserman
authors.forename: P Darrell
authors.initials: PD
authors.lastname: Neufer
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D000293:Adolescent; D000328:Adult; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D015992:Body Mass Index; D002374:Catalase / Q000235:genetics; D004041:Dietary Fats / Q000494:pharmacology*; D004579:Electron Transport / Q000187:drug effects / Q000502:physiology; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D009765:Obesity / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012377:Rodentia / Q000502:physiology*; D055815:Young Adult
chemical_list: D000975:Antioxidants; D001786:Blood Glucose; D004041:Dietary Fats; D007328:Insulin; D009842:Oligopeptides; C506540:arginyl-2,'6'-dimethyltyrosyl-lysyl-phenylalaninamide; D000244:Adenosine Diphosphate; D006861:Hydrogen Peroxide; D002374:Catalase; D005978:Glutathione; D019803:Glutathione Disulfide