Tumor necrosis factor-alpha-induced insulin resistance in 3T3-L1 adipocytes is accompanied by a loss of insulin receptor substrate-1 and GLUT4 expression without a loss of insulin receptor-mediated signal transduction
Tumor necrosis factor-alpha-induced insulin resistance in 3T3-L1 adipocytes is accompanied by a loss of insulin receptor substrate-1 and GLUT4 expression without a loss of insulin receptor-mediated signal transduction
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DOI：
10.1074/jbc.272.2.971
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发表时间：
1997-01-10
影响因子：
4.8
通讯作者：
Pilch, PF
中科院分区：
文献类型：
--
作者：
Stephens, JM;Lee, J;Pilch, PF
许多研究表明，肿瘤坏死因子-α (TNF-α) 与脂肪细胞中的严重胰岛素抵抗相关，并且可能在肥胖和非胰岛素依赖型糖尿病的胰岛素抵抗中发挥关键作用。关于 TNF-α 作用机制的报道有些矛盾，GLUT4 下调被认为是胰岛素抵抗的可能原因，因为胰岛素受体的激酶功能降低。在这里，我们研究了肿瘤坏死因子对被认为参与脂肪细胞中胰岛素刺激的葡萄糖转运的蛋白质成分的影响，即胰岛素受体、其主要底物 IRS-1 和胰岛素反应性葡萄糖转运蛋白 GLUT4。 3T3-L1脂肪细胞长时间暴露于TNF-α（72-96小时）会导致IRS-1和GLUT4 mRNA和蛋白质显着减少（>80%），以及胰岛素受体数量较少减少（>50%）。然而，其余蛋白质在生化上似乎与未经处理的脂肪细胞中的蛋白质没有区别。胰岛素受体和 IRS-1 都被酪氨酸磷酸化，以响应细胞 TNF-α 暴露后的急性胰岛素刺激。此外，从 TNF-α 处理的细胞中分离出来后，试管中胰岛素受体磷酸化外源底物的能力也正常。在 TNF-α 处理的脂肪细胞中观察到的胰岛素依赖性葡萄糖转运和 GLUT4 易位水平明显降低，证实了这些结果。我们得出的结论是，暴露于TNF-α 72-96小时的3T3-L1脂肪细胞中葡萄糖转运的胰岛素抵抗是由于参与胰岛素作用的必需蛋白质的数量减少所致。这些结果与早期研究一致，表明TNF-α降低了小鼠脂肪细胞中GLUT4基因的转录活性，并且许多相关基因的mRNA转录减少可能是TNF-α导致脂肪细胞中胰岛素抵抗的一般机制。
A number of studies have demonstrated that tumor necrosis factor-alpha (TNF-alpha) is associated with profound insulin resistance in adipocytes and may also play a critical role in the insulin resistance of obesity and non-insulin-dependent diabetes mellitus, Reports on the mechanism of TNF-alpha action have been somewhat contradictory, GLUT4 down-regulation has been implicated as a possible cause of insulin resistance as has been the reduced kinase function of the insulin receptor. Here we examine the effects of tumor necrosis factor on the protein components thought to be involved in insulin-stimulated glucose transport in adipocytes, namely the insulin receptor, its major substrate IRS-1, and the insulin responsive glucose transporter GLUT4. Prolonged exposure (72-96 h) of 3T3-L1 adipocytes to TNF-alpha causes a substantial reduction (>80%) in IRS-1 and GLUT4 mRNA and protein as well as a lesser reduction (>50%) in the amount of the insulin receptor, Nevertheless, the remaining proteins appear to be biochemically indistinguishable from those in untreated adipocytes. Both the insulin receptor and IRS-1 are tyrosine-phosphorylated to the same extent in response to acute insulin stimulation following cellular TNF-alpha exposure. Furthermore, the ability of the insulin receptor to phosphorylate exogenous substrate in the test tube is also normal following its isolation from TNF-alpha-treated cells. These results are confirmed by the reduced but obvious level of insulin-dependent glucose transport and GLUT4 translocation observed in TNF-alpha-treated adipocytes. We conclude that the insulin resistance of glucose transport in 3T3-L1 adipocytes exposed to TNF-alpha for 72-96 h results from a reduced amount in requisite proteins involved in insulin action, These results are consistent with earlier studies indicating that TNF-alpha reduces the transcriptional activity of the GLUT4 gene in murine adipocytes, and reduced mRNA transcription of a number of relevant genes may be the general mechanism by which TNF-alpha causes insulin resistance in adipocytes.