Suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 cause insulin resistance through inhibition of tyrosine phosphorylation of insulin receptor substrate proteins by discrete mechanisms
Suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 cause insulin resistance through inhibition of tyrosine phosphorylation of insulin receptor substrate proteins by discrete mechanisms
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DOI：
10.1128/mcb.24.12.5434-5446.2004
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发表时间：
2004-06-01
影响因子：
5.3
通讯作者：
Kahn, CR
中科院分区：
文献类型：
--
作者：
Ueki, K;Kondo, T;Kahn, CR
胰岛素抵抗是2型糖尿病和肥胖症的病理生理学组成部分，也发生在与细胞因子上调相关的应激、感染和炎症状态中。在这里，我们表明，在肥胖和脂多糖（LPS）诱导的内毒素血症有一个增加抑制细胞因子信号（SOCS）蛋白，SOCS-1和SOCS-3，在肝脏，肌肉，并在较小程度上，脂肪。与LPS引起的这些增加一致，胰岛素受体（IR）的酪氨酸磷酸化部分受损，胰岛素受体底物（IRS）蛋白的磷酸化几乎完全受到抑制。通过腺病毒介导的基因转移在肝脏中直接过表达SOCS-3显著降低IRS-1和IRS-2的酪氨酸磷酸化，而SOCS-1过表达优先抑制IRS-2磷酸化。两者都不影响IR磷酸化，尽管SOCS-1和SOCS-3在体内以胰岛素依赖性方式与胰岛素受体结合。用表达突变胰岛素受体的培养细胞进行的实验表明，SOCS-3与IR的Tyr 960结合，这是识别IRS-1和IRS-2的关键残基，而SOCS-1与体外IRS-2识别所必需的催化环中的结构域结合。此外，SOCS-1或SOCS-3的过表达减弱了胰岛素诱导的L 6肌管糖原合成和3 T3 L1脂肪细胞葡萄糖摄取的激活。相比之下，通过反义处理减少SOCS-1或SOCS-3部分恢复了肿瘤坏死因子α诱导的3 T3 L1脂肪细胞中IRS蛋白酪氨酸磷酸化的下调。这些数据表明，SOCS-1和SOCS-3在胰岛素信号传导中起负调节剂的作用，并作为胰岛素抵抗和细胞因子信号传导之间的缺失环节之一。
Insulin resistance is a pathophysiological component of type 2 diabetes and obesity and also occurs in states of stress, infection, and inflammation associated with an upregulation of cytokines. Here we show that in both obesity and lipopolysaccharide (LPS)-induced endotoxemia there is an increase in suppressor of cytokine signaling (SOCS) proteins, SOCS-1 and SOCS-3, in liver, muscle, and, to a lesser extent, fat. In concordance with these increases by LPS, tyrosine phosphorylation of the insulin receptor (IR) is partially impaired and phosphorylation of the insulin receptor substrate (IRS) proteins is almost completely suppressed. Direct overexpression of SOCS-3 in liver by adenoviral-mediated gene transfer markedly decreases tyrosine phosphorylation of both IRS-1 and IRS-2, while SOCS-1 overexpression preferentially inhibits IRS-2 phosphorylation. Neither affects IR phosphorylation, although both SOCS-1 and SOCS-3 bind to the insulin receptor in vivo in an insulin-dependent fashion. Experiments with cultured cells expressing mutant insulin receptors reveal that SOCS-3 binds to Tyr960 of IR, a key residue for the recognition of IRS-1 and IRS-2, whereas SOCS-1 binds to the domain in the catalytic loop essential for IRS-2 recognition in vitro. Moreover, overexpression of either SOCS-1 or SOCS-3 attenuates insulin-induced glycogen synthesis in L6 myotubes and activation of glucose uptake in 3T3L1 adipocytes. By contrast, a reduction of SOCS-1 or SOCS-3 by antisense treatment partially restores tumor necrosis factor alpha-induced downregulation of tyrosine phosphorylation of IRS proteins in 3T3L1 adipocytes. These data indicate that SOCS-1 and SOCS-3 act as negative regulators in insulin signaling and serve as one of the missing links between insulin resistance and cytokine signaling.