Inhibition of the TNF-α-induced serine phosphorylation of IRS-1 at 636/639 by AICAR

Amp-activated protein kinase (ampk) contributes to the acceleration of insulin signaling. however,the mechanism by which ampk regulates insulin signaling remains unclear. serine phosphorylation of insulin receptor substrate (irs)-1 negatively regulates insulin signaling. here we investigated the role of ampk in serine phosphorylation of irs-1 at 636/639 and 307,which is induced by tumor necrosis factor (tnf)-α in 3t3l1 adipocytes. we demonstrated that the ampk activator 5-aminoimidazole-4-carboxamide-1-d-ribofuranoside (aicar) significantly inhibited the tnf-α-induced serine phosphorylation of irs-1 at 636/639 and 307 by suppression of extracellular signal-regulated kinase (erk) phosphorylation but not c-jun-nh2-terminal kinase (jnk) phosphorylation. in addition,aicar stimulation resulted in enhanced interaction between erk and map kinase phosphatase-4 (dusp9/mkp-4) without affecting dusp9/mpk4 mrna synthesis. moreover,intraperitoneal administration (0.25 g/kg) of aicar to db/db mice improved blood glucose levels and inhibited the phosphorylation of erk in adipose tissue. in conclusion,we propose a new mechanism in which aicar suppresses tnf-α-induced serine phosphorylation of irs-1 at 636/639 and 307 by enhancing the interaction between erk and dusp9/mkp-4. taken together,these findings provide evidence that ampk plays a crucial role in improving of type 2 diabetes. © 2013 the japanese pharmacological society.