title: Knockdown of JNK rescues 3T3-L1 adipocytes from insulin resistance induced by mitochondrial dysfunction.
abstract: Mitochondrial dysfunction has been linked to etiology of insulin resistance, however the mechanism remains unknown. In this study we investigated whether mitochondrial dysfunction induced by cyanide p-trifluoromethoxyphenyl-hydrazone (FCCP) alters insulin sensitivity in 3T3-L1 adipocytes and which cellular signaling molecules might be involved. Fully differentiated 3T3-L1 adipocytes were treated with 10 microM FCCP for 1h, resulting in increased serine-307 phosphorylation of IRS-1 and decreased insulin-stimulated tyrosine phosphorylation, association of p85alpha subunit of phosphatidylinositol 3-kinase (PI 3-kinase) with IRS-1, decreased insulin-stimulated PI 3-kinase activity and H(3)-2-deoxyglucose (2DOG) uptake. A partial (46%) knockdown of JNK1 blocked FCCP-induced serine phosphorylation of IRS-1 and restored insulin-stimulated tyrosine phosphorylation of IRS-1, association of p85alpha subunit of PI 3-kinase with IRS-1, activation of PI 3-kinase, and stimulation of 2DOG uptake. Thus, FCCP-induced mitochondrial dysfunction may cause insulin resistance that is ameliorated by reduction of JNK1 expression.
authors.affiliation: Department of Pediatrics, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA.
authors.forename: Toni
authors.initials: T
authors.lastname: Kim
authors.forename: J
authors.initials: J
authors.lastname: Wayne Leitner
authors.forename: Rebecca
authors.initials: R
authors.lastname: Adochio
authors.forename: Boris
authors.initials: B
authors.lastname: Draznin
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000201:enzymology*; D000818:Animals; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000633:toxicity; D003847:Deoxyglucose / Q000378:metabolism; D055785:Gene Knockdown Techniques; D007328:Insulin / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D051379:Mice; D028361:Mitochondrial Diseases / Q000139:chemically induced / Q000150:complications* / Q000201:enzymology; D048055:Mitogen-Activated Protein Kinase 8 / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics; D012694:Serine / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
chemical_list: D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D014443:Tyrosine; D012694:Serine; D003847:Deoxyglucose; D019869:Phosphatidylinositol 3-Kinases; D048055:Mitogen-Activated Protein Kinase 8