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Tumor Necrosis Factor -Mediated Insulin Resistance, but Not Dedifferentiation, Is Abrogated by MEK1/2 Inhibitors in 3T3-L1 Adipocytes

Department of Cell Biology and Diabetes Research and Training Center (A.H.B., R.Y.L., P.E.S.) Department of Molecular Pharmacology and Diabetes Research and Training Center (J.A.E., M.P.L.) Albert Einstein College of Medicine Bronx, New York 10461

Tumor necrosis factor- (TNF) has been implicated as a contributing mediator of insulin resistance observed in pathophysiological conditions such as obesity, cancer-induced cachexia, and bacterial infections. Previous studies have demonstrated that TNF confers insulin resistance by promoting phosphorylation of serine residues on insulin receptor substrate 1 (IRS-1), thereby diminishing subsequent insulin-induced tyrosine phosphorylation of IRS-1. However, little is known about which signaling molecules are involved in this process in adipocytes and about the temporal sequence of events that ultimately leads to TNF-stimulated IRS-1 serine phosphorylation. In this study, we demonstrate that specific inhibitors of the MAP kinase kinase (MEK)1/2-p42/44 mitogen-activated protein (MAP) kinase pathway restore insulin signaling to normal levels despite the presence of TNF. Additional experiments show that MEK1/2 activity is required for TNF-induced IRS-1 serine phosphorylation, thereby suggesting a mechanism by which these inhibitors restore insulin signaling.

We observe that TNF requires 2.5–4 h to markedly reduce insulin-triggered tyrosine phosphorylation of IRS-1 in 3T3-L1 adipocytes. Although TNF activates p42/44 MAP kinase, maximal stimulation is observed within 10–30 min. To our surprise, p42/44 activity returns to basal levels well before IRS-1 serine phosphorylation and insulin resistance are observed. These activation kinetics suggest a mechanism of p42/44 action more complicated than a direct phosphorylation of IRS-1 triggered by the early spike of TNF-induced p42/44 activity.

Chronic TNF treatment (>> 72 h) causes adipocyte dedifferentiation, as evidenced by the loss of triglycerides and down-regulation of adipocyte-specific markers. We observe that this longer term TNF-mediated dedifferentiation effect utilizes alternative, p42/44 MAP kinase-independent intracellular pathways.

This study suggests that TNF-mediated insulin resistance, but not adipocyte dedifferentiation, is mediated by the MEK1/2-p42/44 MAP kinase pathway.

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