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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:

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

A mutation in a ganglioside biosynthetic enzyme, ST3GAL5, results in salt & pepper syndrome, a neurocutaneous disorder with altered glycolipid and glycoprotein glycosylation.
L. Boccuto, K. Aoki, H. Flanagan-Steet, C.-F. Chen, X. Fan, F. Bartel, M. Petukh, A. Pittman, R. Saul, A. Chaubey, et al. (2014)
Hum. Mol. Genet. 23, 418-433
   Abstract »    Full Text »    PDF »
Ceramides and Glucosylceramides Are Independent Antagonists of Insulin Signaling.
J. A. Chavez, M. M. Siddique, S. T. Wang, J. Ching, J. A. Shayman, and S. A. Summers (2014)
J. Biol. Chem. 289, 723-734
   Abstract »    Full Text »    PDF »
Insulin Resistance, Ceramide Accumulation and Endoplasmic Reticulum Stress in Experimental Chronic Alcohol-Induced Steatohepatitis.
T. Ramirez, L. Longato, M. Dostalek, M. Tong, J. R. Wands, and S. M. de la Monte (2013)
Alcohol Alcohol. 48, 39-52
   Abstract »    Full Text »    PDF »
Cyclin-dependent Kinase-5 Is a Key Molecule in Tumor Necrosis Factor-{alpha}-induced Insulin Resistance.
A. Nohara, S. Okada, K. Ohshima, J. E. Pessin, and M. Mori (2011)
J. Biol. Chem. 286, 33457-33465
   Abstract »    Full Text »    PDF »
Glycosphingolipid Functions.
C. A. Lingwood (2011)
Cold Spring Harb Perspect Biol 3, a004788
   Abstract »    Full Text »    PDF »
Adamantyl Glycosphingolipids Provide a New Approach to the Selective Regulation of Cellular Glycosphingolipid Metabolism.
M. Kamani, M. Mylvaganam, R. Tian, B. Rigat, B. Binnington, and C. Lingwood (2011)
J. Biol. Chem. 286, 21413-21426
   Abstract »    Full Text »    PDF »
GD1b-Derived Gangliosides Modulate Fc{varepsilon}RI Endocytosis in Mast Cells.
V. M. Mazucato, A. M. M. Silveira e Souza, L. M. Nicoletti, M. C. Jamur, and C. Oliver (2011)
Journal of Histochemistry & Cytochemistry 59, 428-440
   Abstract »    Full Text »    PDF »
The Cytoplasmic Tail of GM3 Synthase Defines Its Subcellular Localization, Stability, and In Vivo Activity.
S. Uemura, S. Yoshida, F. Shishido, and J.-i. Inokuchi (2009)
Mol. Biol. Cell 20, 3088-3100
   Abstract »    Full Text »    PDF »
PAQRs: A Counteracting Force to Ceramides?.
W. L. Holland and P. E. Scherer (2009)
Mol. Pharmacol. 75, 740-743
   Abstract »    Full Text »    PDF »
{beta}-Glycosphingolipids improve glucose intolerance and hepatic steatosis of the Cohen diabetic rat.
E. Zigmond, S. W. Zangen, O. Pappo, M. Sklair-Levy, G. Lalazar, L. Zolotaryova, I. Raz, and Y. Ilan (2009)
Am J Physiol Endocrinol Metab 296, E72-E78
   Abstract »    Full Text »    PDF »
Targeted analysis of ganglioside and sulfatide molecular species by LC/ESI-MS/MS with theoretically expanded multiple reaction monitoring.
K. Ikeda, T. Shimizu, and R. Taguchi (2008)
J. Lipid Res. 49, 2678-2689
   Abstract »    Full Text »    PDF »
Fluorescence-topographic NSOM directly visualizes peak-valley polarities of GM1/GM3 rafts in cell membrane fluctuations.
Y. Chen, J. Qin, and Z. W. Chen (2008)
J. Lipid Res. 49, 2268-2275
   Abstract »    Full Text »    PDF »
The Glucosylceramide Synthase Inhibitor N-(5-Adamantane-1-yl-methoxy-pentyl)-deoxynojirimycin Induces Sterol Regulatory Element-Binding Protein-Regulated Gene Expression and Cholesterol Synthesis in HepG2 Cells.
N. Bijl, S. Scheij, S. Houten, R. G. Boot, A. K. Groen, and J. M. F. G. Aerts (2008)
J. Pharmacol. Exp. Ther. 326, 849-855
   Abstract »    Full Text »    PDF »
Gene expression in human NAFLD.
D. Greco, A. Kotronen, J. Westerbacka, O. Puig, P. Arkkila, T. Kiviluoto, S. Laitinen, M. Kolak, R. M. Fisher, A. Hamsten, et al. (2008)
Am J Physiol Gastrointest Liver Physiol 294, G1281-G1287
   Abstract »    Full Text »    PDF »
Dissociation of the insulin receptor and caveolin-1 complex by ganglioside GM3 in the state of insulin resistance.
K. Kabayama, T. Sato, K. Saito, N. Loberto, A. Prinetti, S. Sonnino, M. Kinjo, Y. Igarashi, and J.-i. Inokuchi (2007)
PNAS 104, 13678-13683
   Abstract »    Full Text »    PDF »
N-Azidoacetylmannosamine-mediated chemical tagging of gangliosides.
A. P. Bussink, P. F. van Swieten, K. Ghauharali, S. Scheij, M. van Eijk, T. Wennekes, G. A. van der Marel, R. G. Boot, J. M. F. G. Aerts, and H. S. Overkleeft (2007)
J. Lipid Res. 48, 1417-1421
   Abstract »    Full Text »    PDF »
Thematic review series: Adipocyte Biology. Adipose tissue function and plasticity orchestrate nutritional adaptation.
J. K. Sethi and A. J. Vidal-Puig (2007)
J. Lipid Res. 48, 1253-1262
   Abstract »    Full Text »    PDF »
Inhibiting Glycosphingolipid Synthesis Improves Glycemic Control and Insulin Sensitivity in Animal Models of Type 2 Diabetes.
H. Zhao, M. Przybylska, I-H. Wu, J. Zhang, C. Siegel, S. Komarnitsky, N. S. Yew, and S. H. Cheng (2007)
Diabetes 56, 1210-1218
   Abstract »    Full Text »    PDF »
Cutting Edge: Oseltamivir Decreases T Cell GM1 Expression and Inhibits Clearance of Respiratory Syncytial Virus: Potential Role of Endogenous Sialidase in Antiviral Immunity.
M. L. Moore, M. H. Chi, W. Zhou, K. Goleniewska, J. F. O'Neal, J. N. Higginbotham, and R. S. Peebles Jr. (2007)
J. Immunol. 178, 2651-2654
   Abstract »    Full Text »    PDF »
Epidermal growth factor receptor tyrosine kinase is modulated by GM3 interaction with N-linked GlcNAc termini of the receptor.
S.-J. Yoon, K.-i. Nakayama, T. Hikita, K. Handa, and S.-i. Hakomori (2006)
PNAS 103, 18987-18991
   Abstract »    Full Text »    PDF »
Diabetes Alters Sphingolipid Metabolism in the Retina: A Potential Mechanism of Cell Death in Diabetic Retinopathy.
T. E. Fox, X. Han, S. Kelly, A. H. Merrill Jr., R. E. Martin, R. E. Anderson, T. W. Gardner, and M. Kester (2006)
Diabetes 55, 3573-3580
   Abstract »    Full Text »    PDF »
Altered Adipose and Plasma Sphingolipid Metabolism in Obesity: A Potential Mechanism for Cardiovascular and Metabolic Risk.
F. Samad, K. D. Hester, G. Yang, Y. A. Hannun, and J. Bielawski (2006)
Diabetes 55, 2579-2587
   Abstract »    Full Text »    PDF »
Ganglioside GM3 is involved in neuronal cell death.
H. Sohn, Y.-S. Kim, H.-T. Kim, C.-H. Kim, E.-W. Cho, H.-Y. Kang, N.-S. Kim, C.-H. Kim, S. E. Ryu, J.-H. Lee, et al. (2006)
FASEB J 20, 1248-1250
   Abstract »    Full Text »    PDF »
Effect of Ganglioside and Tetraspanins in Microdomains on Interaction of Integrins with Fibroblast Growth Factor Receptor.
M. S. Toledo, E. Suzuki, K. Handa, and S. Hakomori (2005)
J. Biol. Chem. 280, 16227-16234
   Abstract »    Full Text »    PDF »
Lipid Microdomains and Insulin Resistance: Is There a Connection?.
E. Ikonen and S. Vainio (2005)
Sci. STKE 2005, pe3
   Abstract »    Full Text »    PDF »
a-Series Gangliosides Mediate the Effects of Advanced Glycation End Products on Pericyte and Mesangial Cell Proliferation: A Common Mediator for Retinal and Renal Microangiopathy?.
E. Masson, L. Troncy, D. Ruggiero, N. Wiernsperger, M. Lagarde, and S. E. Bawab (2005)
Diabetes 54, 220-227
   Abstract »    Full Text »    PDF »
TNF{alpha}-induced insulin resistance in adipocytes as a membrane microdomain disorder: involvement of ganglioside GM3.
K. Kabayama, T. Sato, F. Kitamura, S. Uemura, B. W. Kang, Y. Igarashi, and J.-i. Inokuchi (2005)
Glycobiology 15, 21-29
   Abstract »    Full Text »    PDF »
Exogenous Ganglioside GD1a Enhances Epidermal Growth Factor Receptor Binding and Dimerization.
Y. Liu, R. Li, and S. Ladisch (2004)
J. Biol. Chem. 279, 36481-36489
   Abstract »    Full Text »    PDF »
Overexpression of Plasma Membrane-associated Sialidase Attenuates Insulin Signaling in Transgenic Mice.
A. Sasaki, K. Hata, S. Suzuki, M. Sawada, T. Wada, K. Yamaguchi, M. Obinata, H. Tateno, H. Suzuki, and T. Miyagi (2003)
J. Biol. Chem. 278, 27896-27902
   Abstract »    Full Text »    PDF »
Enhanced insulin sensitivity in mice lacking ganglioside GM3.
T. Yamashita, A. Hashiramoto, M. Haluzik, H. Mizukami, S. Beck, A. Norton, M. Kono, S. Tsuji, J. L. Daniotti, N. Werth, et al. (2003)
PNAS 100, 3445-3449
   Abstract »    Full Text »    PDF »
Sialylation and sulfation of lactosylceramide distinctly regulate anchorage-independent growth, apoptosis, and gene expression in3LL Lewis lung carcinoma cells.
S. Uemura, K. Kabayama, M. Noguchi, Y. Igarashi, and J.-i. Inokuchi (2003)
Glycobiology 13, 207-216
   Abstract »    Full Text »    PDF »
Regulation of Growth Factor Receptors by Gangliosides.
E. A. Miljan and E. G. Bremer (2002)
Sci. STKE 2002, re15
   Abstract »    Full Text »    PDF »
Combinatorial Ganglioside Biosynthesis.
T. Kolter, R. L. Proia, and K. Sandhoff (2002)
J. Biol. Chem. 277, 25859-25862
   Full Text »    PDF »

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