Insulin Signaling

Inhibited by Ganglioside

Science's STKE  05 Feb 2002:
Vol. 2002, Issue 118, pp. tw59-TW59
DOI: 10.1126/stke.2002.118.tw59

Tumor necrosis factor α (TNF-α) inhibits insulin signaling and, in vivo, is believed to be one mechanism underlying insulin resistance in type II diabetes. Tagami et al. show that TNF signaling promotes the synthesis by increasing the expression of the GM3 synthase, leading to increased amounts of the ganglioside GM3 at the plasma membrane of 3T3-L1 adipocytes. TNF-α also inhibited insulin receptor-mediated phosphorylation of the insulin receptor substrate 1 (IRS-1). This effect could be mimicked by application of exogenous GM3 and blocked by treatment of the cells with an inhibitor of the biosynthesis of glycosphingolipids. The GM3 synthase transcript was expressed at higher levels in fat from obese mice (ob/ob and Zucker strains) than from lean fat tissue from control animals, further supporting a role for GM3 in insulin-resistance phenotypes. Thus, changes in the lipid composition of the membrane appear to be one mechanism underlying TNF-α-mediated inhibition of insulin signaling, which may lead to insulin resistance and obesity in vivo.

S. Tagami, J.-i. Inokuchi, K. Kabayama, H. Yoshimura, F. Kitamura, S. Uemura, C. Ogawa, A. Ishii, M. Saito, Y. Ohtuska, S. Sakaue, Y. Igarashi, Ganglioside GM3 participates in the pathological conditions of insulin resistance. J. Biol. Chem. 277, 3085-3092 (2002). [Abstract] [Full Text]