title: Nox2 mediates skeletal muscle insulin resistance induced by a high fat diet.
abstract: Inflammation and oxidative stress through the production of reactive oxygen species (ROS) are consistently associated with metabolic syndrome/type 2 diabetes. Although the role of Nox2, a major ROS-generating enzyme, is well described in host defense and inflammation, little is known about its potential role in insulin resistance in skeletal muscle. Insulin resistance induced by a high fat diet was mitigated in Nox2-null mice compared with wild-type mice after 3 or 9 months on the diet. High fat feeding increased Nox2 expression, superoxide production, and impaired insulin signaling in skeletal muscle tissue of wild-type mice but not in Nox2-null mice. Exposure of C2C12 cultured myotubes to either high glucose concentration, palmitate, or H2O2 decreases insulin-induced Akt phosphorylation and glucose uptake. Pretreatment with catalase abrogated these effects, indicating a key role for H2O2 in mediating insulin resistance. Down-regulation of Nox2 in C2C12 cells by shRNA prevented insulin resistance induced by high glucose or palmitate but not H2O2. These data indicate that increased production of ROS in insulin resistance induced by high glucose in skeletal muscle cells is a consequence of Nox2 activation. This is the first report to show that Nox2 is a key mediator of insulin resistance in skeletal muscle.
authors.affiliation: From the Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78229-3900.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Souto Padron de Figueiredo
authors.affiliation: The Sam and Ann Barshop Institute for Longevity and Aging Studies 15355 Lambda Drive, San Antonio, Texas 78245, and Audie L. Murphy Hospital, South Texas Veterans Health Care System, San Antonio, Texas 78229-3900.
authors.forename: Adam B
authors.initials: AB
authors.lastname: Salmon
authors.affiliation: From the Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78229-3900.
authors.forename: Francesca
authors.initials: F
authors.lastname: Bruno
authors.affiliation: From the Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78229-3900.
authors.forename: Fabio
authors.initials: F
authors.lastname: Jimenez
authors.affiliation: From the Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78229-3900.
authors.forename: Herman G
authors.initials: HG
authors.lastname: Martinez
authors.affiliation: From the Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78229-3900.
authors.forename: Ganesh V
authors.initials: GV
authors.lastname: Halade
authors.affiliation: From the Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78229-3900, Audie L. Murphy Hospital, South Texas Veterans Health Care System, San Antonio, Texas 78229-3900.
authors.forename: Seema S
authors.initials: SS
authors.lastname: Ahuja
authors.affiliation: From the Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78229-3900, Audie L. Murphy Hospital, South Texas Veterans Health Care System, San Antonio, Texas 78229-3900.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Clark
authors.affiliation: From the Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78229-3900, Audie L. Murphy Hospital, South Texas Veterans Health Care System, San Antonio, Texas 78229-3900.
authors.forename: Ralph A
authors.initials: RA
authors.lastname: DeFronzo
authors.affiliation: From the Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78229-3900, Audie L. Murphy Hospital, South Texas Veterans Health Care System, San Antonio, Texas 78229-3900.
authors.forename: Hanna E
authors.initials: HE
authors.lastname: Abboud
authors.affiliation: From the Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78229-3900, AkoulouzeBik@uthscsa.edu.
authors.forename: Amina
authors.initials: A
authors.lastname: El Jamali
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002478:Cells, Cultured; D059305:Diet, High-Fat; D015536:Down-Regulation; D020869:Gene Expression Profiling; D005947:Glucose / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance; D008297:Male; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000502:physiology*; D018384:Oxidative Stress / Q000187:drug effects; D010168:Palmitates / Q000494:pharmacology; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013549:Sweetening Agents / Q000494:pharmacology
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D008562:Membrane Glycoproteins; D010168:Palmitates; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D013549:Sweetening Agents; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D005947:Glucose
keywords: Diabetes; Insulin Resistance; NADPH Oxidase; Reactive Oxygen Species (ROS); Skeletal Muscle; Superoxide Ion
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