Knockdown of JNK rescues 3T3-L1 adipocytes from insulin resistance induced by mitochondrial dysfunction

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 μM FCCP for 1 h, resulting in increased serine-307 phosphorylation of IRS-1 and decreased insulin-stimulated tyrosine phosphorylation, association of p85α subunit of phosphatidylinositol 3-kinase (PI 3-kinase) with IRS-1, decreased insulin-stimulated PI 3-kinase activity and H3-2-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 p85α 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.