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J. Biol. Chem. 277 (5): 3085-3092

© 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

Ganglioside GM3 Participates in the Pathological Conditions of Insulin Resistance*

Seiichi TagamiDagger §, Jin-ichi Inokuchi§||, Kazuya Kabayama, Haruhiko YoshimuraDagger , Futoshi Kitamura, Satoshi Uemura, Chie Ogawa, Atsushi Ishii**, Masaki Saito**, Yoshinori OhtsukaDagger , Shinji SakaueDagger , and Yasuyuki Igarashi

From the Dagger  First Department of Medicine, Hokkaido University School of Medicine, Kita 15-jo, Nishi 7-chome, Kita-ku, the  Department of Biomembrane and Biofunctional Chemistry, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita 12-jo, Nishi 6-chome, Kita-ku, Sapporo 060-0812, and the ** Virology and Glycobiology Division, National Cancer Center Institute, Chuo-ku, Tokyo-104-0045, Japan

Gangliosides are known as modulators of transmembrane signaling by regulating various receptor functions. We have found that insulin resistance induced by tumor necrosis factor-alpha (TNF-alpha ) in 3T3-L1 adipocytes was accompanied by increased GM3 ganglioside expression caused by elevating GM3 synthase activity and its mRNA. We also demonstrated that TNF-alpha simultaneously produced insulin resistance by uncoupling insulin receptor activity toward insulin receptor substrate-1 (IRS-1) and suppressing insulin-sensitive glucose transport. Pharmacological depletion of GM3 in adipocytes by an inhibitor of glucosylceramide synthase prevented the TNF-alpha -induced defect in insulin-dependent tyrosine phosphorylation of IRS-1 and also counteracted the TNF-alpha -induced serine phosphorylation of IRS-1. Moreover, when the adipocytes were incubated with exogenous GM3, suppression of tyrosine phosphorylation of insulin receptor and IRS-1 and glucose uptake in response to insulin stimulation was observed, demonstrating that GM3 itself is able to mimic the effects of TNF on insulin signaling. We used the obese Zucker fa/fa rat and ob/ob mouse, which are known to overproduce TNF-alpha mRNA in adipose tissues, as typical models of insulin resistance. We found that the levels of GM3 synthase mRNA in adipose tissues of these animals were significantly higher than in their lean counterparts. Taken together, the increased synthesis of cellular GM3 by TNF may participate in the pathological conditions of insulin resistance in type 2 diabetes.

* This work was supported by Grants-in-Aid 12033201 for Scientific Research on Priority Areas and 11672155 for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan (both to J. I.) and by the Yamada Science Foundation (to J. I.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ These authors contributed equally to this work.

|| To whom correspondence should be addressed. Tel.: 81-11-706-3764; Fax: 81-11-706-4986; E-mail: inokuchi@kinou02.pharm.hokudai.ac.jp.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

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