Ganglioside GM3 participates in the pathological conditions of insulin resistance.

Abstract

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.

• Authors: Seiichi Tagami, Jin-ichi Inokuchi Ji, Kazuya Kabayama, Haruhiko Yoshimura, Futoshi Kitamura, Satoshi Uemura, Chie Ogawa, Atsushi Ishii, Masaki Saito, Yoshinori Ohtsuka, Shinji Sakaue, Yasuyuki Igarashi
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 277 Issue 5 Pg. 3085-92 (Feb 01 2002) ISSN: 0021-9258 [Print] United States
• PMID: 11707432 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• G(M3) Ganglioside
• Insulin
• Tumor Necrosis Factor-alpha
• Glucosyltransferases
• ceramide glucosyltransferase
• Sialyltransferases
• haematoside synthetase

Topics

• 3T3 Cells
• Adipocytes (drug effects, physiology)
• Animals
• Cell Differentiation
• Enzyme Inhibitors (pharmacology)
• G(M3) Ganglioside (pharmacology, physiology)
• Glucosyltransferases (antagonists & inhibitors, genetics)
• Insulin (pharmacology)
• Insulin Resistance (physiology)
• Mice
• Mice, Obese
• Rats
• Rats, Zucker
• Sialyltransferases (metabolism)
• Signal Transduction (drug effects)
• Transcription, Genetic
• Tumor Necrosis Factor-alpha (genetics, pharmacology)