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-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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