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This version published online on December 5, 2002
Molecular Endocrinology, doi:10.1210/me.2002-0131
Molecular Endocrinology Vol. 0, No. 2002 200201311-
doi:10.1210/me.2002-0131
Copyright © 2002 by the Endocrine Society.
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Submitted on April 5, 2002
Accepted on November 26, 2002

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

Midori Fujishiro1, Yukiko Gotoh1, Hideki Katagiri1, Hideyuki Sakoda1, Takehide Ogihara1, Motonobu Anai1, Yukiko Onishi1, Hiraku Ono1, Miho Abe1, Nobuhiro Shojima1, Yasushi Fukushima1, Masatoshi Kikuchi1, Yoshitomo Oka1, and Tomoichiro Asano1*

1 Department of Diabetes and Metabolism, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan; Department of Molecular Biology, Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan; Institute for Adult Disease, Asahi Life Foundation, 1-9-14, Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan; and Division of Molecular Metabolism and Diabetes, Department of Internal Medicine, Tohoku University Graduate School of Medicine, Seiryo-machi, Sendai 980-8574, Japan

* To whom correspondence should be addressed. E-mail: asano-tky{at}umin.ac.jp.

TNF{alpha}, which activates three different MAPKs (ERK, p38 and 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 MEK1, 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 PI 3-kinase activity. The MKK6 mutant, which activates p38, moderately inhibited IRS-1 and IRS-2 expressions and IRS-1-associated PI 3-kinase 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 PI 3-kinase activity without affecting expression of the IR, IRS-1 or IRS-2. In the context of our earlier report showing down-regulation of GLUT4 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.
Key words: mitogen-activated protein kinases • tumor necrosis factor {alpha} • insulin resistance • insulin receptor substrate proteins • adipocytes




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