title: 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.affiliation: First Department of Medicine, Hokkaido University School of Medicine, Kita 15-jo, Nishi 7-chome, Kita-ku, Japan.
authors.forename: Seiichi
authors.initials: S
authors.lastname: Tagami
authors.forename: Jin-ichi
authors.initials: J
authors.lastname: Inokuchi Ji
authors.forename: Kazuya
authors.initials: K
authors.lastname: Kabayama
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Yoshimura
authors.forename: Futoshi
authors.initials: F
authors.lastname: Kitamura
authors.forename: Satoshi
authors.initials: S
authors.lastname: Uemura
authors.forename: Chie
authors.initials: C
authors.lastname: Ogawa
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ishii
authors.forename: Masaki
authors.initials: M
authors.lastname: Saito
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Ohtsuka
authors.forename: Shinji
authors.initials: S
authors.lastname: Sakaue
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Igarashi
mesh_terms: D016475:3T3 Cells; D017667:Adipocytes / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002454:Cell Differentiation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005679:G(M3) Ganglioside / Q000494:pharmacology / Q000502:physiology*; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics; D007328:Insulin / Q000494:pharmacology*; D007333:Insulin Resistance / Q000502:physiology*; D051379:Mice; D008820:Mice, Obese; D051381:Rats; D011924:Rats, Zucker; D012799:Sialyltransferases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D005679:G(M3) Ganglioside; D007328:Insulin; D014409:Tumor Necrosis Factor-alpha; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase; D012799:Sialyltransferases; C021343:haematoside synthetase