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Three Mitogen-Activated Protein Kinases Inhibit Insulin Signaling by Different Mechanisms in 3T3-L1 Adipocytes

Department of Diabetes and Metabolism (M.F., H.K., T.O., M.Ab., N.S., Y.F., T.A.), Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan; Department of Molecular Biology (Y.G.), Institute of Molecular and Cellular Biosciences, University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan; Institute for Adult Disease (H.S., M.An., Y.On., H.O., M.K.), Asahi Life Foundation, Shinjuku-ku, Tokyo 160-0023, Japan; and Division of Molecular Metabolism and Diabetes (Y.Ok.), Department of Internal Medicine, Tohoku University Graduate School of Medicine, Seiryo-machi, Sendai 980-8574, Japan

Address all correspondence and requests for reprints to: Tomoichiro Asano, Department of Diabetes and Metabolism, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail: asano-tky{at}umin.ac.jp.

TNF, which activates three different MAPKs [ERK, p38, and jun amino terminal kinase (JNK)], also induces insulin resistance. To better understand the respective roles of these three MAPK pathways in insulin signaling and their contribution to insulin resistance, constitutively active MAPK/ERK kinase (MEK)1, MAPK kinase (MKK6), and MKK7 mutants were overexpressed in 3T3-L1 adipocytes using an adenovirus-mediated transfection procedure. The MEK1 mutant, which activates ERK, markedly down-regulated expression of the insulin receptor (IR) and its major substrates, IRS-1 and IRS-2, mRNA and protein, and in turn reduced tyrosine phosphorylation of IR as well as IRS-1 and IRS-2 and their associated phosphatidyl inositol 3-kinase (PI3K) activity. The MKK6 mutant, which activates p38, moderately inhibited IRS-1 and IRS-2 expressions and IRS-1-associated PI3K activity without exerting a significant effect on the IR. Finally, the MKK7 mutant, which activates JNK, reduced tyrosine phosphorylation of IRS-1 and IRS-2 and IRS-associated PI3K activity without affecting expression of the IR, IRS-1, or IRS-2. In the context of our earlier report showing down-regulation of glucose transporter 4 by MEK1-ERK and MKK6/3-p38, the present findings suggest that chronic activation of ERK, p38, or JNK can induce insulin resistance by affecting glucose transporter expression and insulin signaling, though via distinctly different mechanisms. The contribution of ERK is, however, the strongest.

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