Nox2 mediates skeletal muscle insulin resistance induced by a high fat diet

Alvaro Souto Padron De Figueiredo, Adam B. Salmon, Francesca Bruno, Fabio Jimenez, Herman G. Martinez, Ganesh V. Halade, Seema S. Ahuja, Robert A. Clark, Ralph A. DeFronzo, Hanna E. Abboud, Amina El Jamali

Research output: Contribution to journalArticle

46 Scopus citations

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 wildtype mice but not in Nox2-null mice. Exposure of C2C12 cultured myotubes to either high glucose concentration, palmitate, or H<inf>2</inf>O<inf>2</inf> decreases insulin-induced Akt phosphorylation and glucose uptake. Pretreatment with catalase abrogated these effects, indicating a key role for H<inf>2</inf>O<inf>2</inf> in mediating insulin resistance. Down-regulation of Nox2 in C2C12 cells by shRNA prevented insulin resistance induced by high glucose or palmitate but not H<inf>2</inf>O<inf>2</inf>. 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.

Original languageEnglish (US)
Pages (from-to)13427-13439
Number of pages13
JournalJournal of Biological Chemistry
Volume290
Issue number21
DOIs
StatePublished - May 22 2015

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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