Thiazolidinediones block tumor necrosis factor-alpha-induced inhibition of insulin signaling
Thiazolidinediones block tumor necrosis factor-alpha-induced inhibition of insulin signaling
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DOI：
10.1172/jci119715
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发表时间：
1997-10-01
影响因子：
15.9
通讯作者：
Spiegelman, BM
中科院分区：
文献类型：
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作者：
Peraldi, P;Xu, M;Spiegelman, BM
TNF-α 已被证明是与肥胖相关的胰岛素抵抗的重要介质。该细胞因子至少部分通过抑制胰岛素受体的酪氨酸激酶活性来诱导胰岛素抵抗。最近，一类新的抗糖尿病化合物噻唑烷二酮 (TZD) 已被证明可以改善啮齿动物和人类肥胖和非胰岛素依赖性糖尿病的胰岛素抵抗。在此，我们表明 TZD 对 TNF-α 改变胰岛素信号传导最近步骤的能力具有强大的影响，包括胰岛素受体及其主要底物 IRS-1 的酪氨酸磷酸化和 PI3 激酶的激活。曲格列酮或吡格列酮基本上消除了脂肪细胞中由 TNF-α 引起的 IR 和 IRS-1 酪氨酸磷酸化的减少，即使在相对较高的剂量（25 ng/ml）下也是如此。 TZD 的这种作用是通过激活核受体 PPAR gamma/RXR 复合物来发挥作用，这一事实通过其他 PPAR gamma/RXR 配体（例如 15 脱氧 Delta(12,14)PGJ2 和 LG268）观察到类似作用的事实表明。 TZD 不会抑制所有 TNF-α 信号转导，因为转录因子 NF-kB 仍能被良好诱导。这些数据表明，TZD 可以特异性阻断与胰岛素抵抗相关的 TNF-α 的某些作用，表明这种阻断可能有助于其抗糖尿病作用。
TNF-alpha has been shown to be an important mediator of insulin resistance linked to obesity, This cytokine induces insulin resistance, at least in part, through inhibition of the tyrosine kinase activity of the insulin receptor. Recently, a new class of compounds, the antidiabetic thiazolidinediones (TZDs), has been shown to improve insulin resistance in obesity and non-insulin-dependent diabetes mellitus in both rodents and man, Here we show that TZDs have powerful effects on the ability of TNF-alpha to alter the most proximal steps of insulin signaling, including tyrosine phosphorylation of the insulin receptor and its major substrate, IRS-1, and activation of PI3-kinase. Troglitazone or pioglitazone essentially eliminate the reduction in tyrosine phosphorylation of IR and IRS-1 caused by TNF-alpha in fat cells, even at relatively high doses (25 ng/ml). That this effect of TZDs operates through activation of the nuclear receptor PPAR gamma/RXR complex is shown by the fact that similar effects are observed with other PPAR gamma/RXR ligands such as 15 deoxy Delta(12,14)PGJ2 and LG268. The TZDs do not inhibit all TNF-alpha signaling in that the transcription factor NF-kB is still induced well. These data indicate that TZDs can specifically block certain actions of TNF-alpha related to insulin resistance, suggesting that this block may contribute to their antidiabetic actions.