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Glycobiology Advance Access published online on August 11, 2004
Glycobiology, doi:10.1093/glycob/cwh135
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Received May 26, 2004
Revised August 2, 2004
Accepted August 4, 2004

ORIGINAL ARTICLES

TNF alpha-induced insulin resistance in adipocytes as a membrane microdomain disorder: involvement of ganglioside GM3

Kazuya Kabayama 1, Takashige Sato 2, Futoshi Kitamura 2, Satoshi Uemura 2, Byoung Won Kang 2, Yasuyuki Igarashi 2, Jin-ichi Inokuchi 1*

1 Department of Biomembrane and Biofunctional Chemistry, Graduate School of Pharmaceutical Sciences, Frontier Research Center for Post-Genomic Science and Technology, Hokkaido University, Kita 21-Nishi 11, Kita-ku, Sapporo 001-0021, Japan; Core Research for Evaluational Science and Technology program (CREST), Japan Science and Technology Corporation (JST), Graduate School of Pharmaceutical Sciences, Frontier Research Center for Post-Genomic Science and Technology, Hokkaido University, Kita 21-Nishi 11, Kita-ku, Sapporo 001-0021, Japan
2 Department of Biomembrane and Biofunctional Chemistry, Graduate School of Pharmaceutical Sciences, Frontier Research Center for Post-Genomic Science and Technology, Hokkaido University, Kita 21-Nishi 11, Kita-ku, Sapporo 001-0021, Japan

* To whom correspondence should be addressed. E-mail: inokuchi{at}kinou02.pharm.hokudai.ac.jp.


  Abstract

Membrane microdomains (lipid rafts) are now recognized as critical for proper compartmentalization of insulin signaling, but their role in the pathogenesis of insulin resistance has not been investigated. Detergent-resistant membrane microdomains (DRMs), isolated in the low density fractions, are highly enriched in cholesterol, glycosphingolipids and various signaling molecules. TNF{alpha} induces insulin resistance in type 2 diabetes, but its mechanism of action is not fully understood. We have found a selective increase in the acidic glycosphingolipid ganglioside GM3 in 3T3-L1 adipocytes treated with TNF{alpha}, suggesting a specific function for GM3 (Tagami S., Inokuchi J., Kabayama K., Yoshimura H., Uemura S., Ogawa C., Ishii A., Saito M., Ohtsuka Y., Sakaue S., and Igarashi Y., J. Biol. Chem., 277, 3085-3092, 2002). In the DRMs from TNF{alpha}-treated 3T3-L1 adipocytes, GM3 levels were doubled, compared to results in normal adipocytes. Additionally, insulin receptor (IR) accumulations in the DRMs were diminished, while caveolin and flotillin levels were unchanged. Furthermore, insulin-dependent IR internalization and intracellular movement of the IR substrate 1(IRS-1) were both greatly suppressed in the treated cells, leading to an uncoupling of IR-IRS-1 signaling. GM3 depletion was able to counteract the TNF{alpha}-induced inhibitions of IR internalization and accumulation into DRMs. Together, these findings provide compelling evidence that in insulin resistance the insulin metabolic signaling defect can be attributed to a loss of IRs in the microdomains due to an accumulation of GM3.

Keywords: insulin receptor; insulin resistance; ganglioside GM3; lipid rafts; detergent-resistant microdomain (DRM).
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