Ganglioside GM3 participates in the pathological conditions of insulin resistance
Ganglioside GM3 participates in the pathological conditions of insulin resistance
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DOI：
10.1074/jbc.m103705200
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发表时间：
2002-02-01
影响因子：
4.8
通讯作者：
Igarashi, Y
中科院分区：
文献类型：
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作者：
Tagami, S;Inokuchi, J;Igarashi, Y
神经节苷脂通过调节各种受体功能而被称为跨膜信号传导的调节剂。我们发现，肿瘤坏死因子 -α（TNF -α）在3T3 - L1脂肪细胞中诱导的胰岛素抵抗伴随着因GM3合酶活性及其mRNA升高而导致的GM3神经节苷脂表达增加。我们还证明，TNF -α通过使胰岛素受体对胰岛素受体底物 - 1（IRS - 1）的活性解偶联以及抑制胰岛素敏感性葡萄糖转运，同时产生胰岛素抵抗。通过葡糖神经酰胺合酶抑制剂对脂肪细胞中GM3进行药理耗竭，可防止TNF -α诱导的IRS - 1胰岛素依赖性酪氨酸磷酸化缺陷，并抵消TNF -α诱导的IRS - 1丝氨酸磷酸化。此外，当脂肪细胞与外源性GM3一起孵育时，观察到胰岛素受体和IRS - 1的酪氨酸磷酸化以及对胰岛素刺激的葡萄糖摄取受到抑制，这表明GM3本身能够模拟TNF对胰岛素信号传导的影响。我们使用肥胖的 Zucker fa/fa大鼠和ob/ob小鼠（已知其在脂肪组织中过度产生TNF -α mRNA）作为胰岛素抵抗的典型模型。我们发现这些动物脂肪组织中GM3合酶mRNA的水平明显高于其瘦型同类动物。综上所述，TNF导致的细胞GM3合成增加可能参与2型糖尿病胰岛素抵抗的病理状况。
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.