Inhibition of insulin sensitivity by free fatty acids requires activation of multiple serine kinases in 3T3-L1 adipocytes
Inhibition of insulin sensitivity by free fatty acids requires activation of multiple serine kinases in 3T3-L1 adipocytes
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DOI：
10.1210/me.2003-0383
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发表时间：
2004-08-01
影响因子：
--
通讯作者：
Ye, JP
中科院分区：
文献类型：
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作者：
Gao, ZG;Zhang, XY;Ye, JP
胰岛素受体底物（IRS）被认为是游离脂肪酸（FFA）作用于胰岛素抵抗的分子靶点。然而，信号转导途径，其中FFA导致抑制IRS功能仍有待建立。在这项研究中，我们探讨了FFA信号通路，有助于丝氨酸磷酸化和IRS-1在脂肪细胞和饮食肥胖小鼠的降解。亚油酸，FFA在这项研究中使用，导致胰岛素诱导的葡萄糖摄取在3 T3-L1脂肪细胞减少。这模拟了C57 BL/6 J小鼠中由高脂饮食诱导的胰岛素抵抗。葡萄糖摄取的减少与IRS-1的减少有关，但与IRS-2或GLUT 4蛋白丰度无关。IRS-1蛋白的减少是通过IRS-1（丝氨酸307）磷酸化进行的，该磷酸化由丝氨酸激酶抑制剂kappaB激酶（IKK）和c-JUN NH 2-末端激酶（JNK）催化。IKK和JNK被亚油酸激活，抑制这两种激酶导致IRS-1减少的预防。我们证明，蛋白激酶C（PKC）θ在脂肪细胞中表达。在3 T3-L1脂肪细胞和脂肪组织中，PKC θ被脂肪酸激活，分别由其磷酸化状态和其蛋白水平指示。PKC θ的激活有助于IKK和JNK的激活，因为通过钙磷蛋白C抑制PKC θ阻断了后者激酶的激活。通过化学抑制剂抑制PKC θ或IKK加JNK导致3 T3-L1脂肪细胞中IRS-1功能和胰岛素敏感性的保护。这些数据表明：1）PKC θ的激活通过FFA促进IKK和JNK的激活; 2）IKK和JNK介导IRS-1丝氨酸磷酸化和降解的PKC θ信号; 3）这种分子机制可能是与高脂血症相关的胰岛素抵抗的原因。
Insulin receptor substrate (IRS) has been suggested as a molecular target of free fatty acids (FFAs) for insulin resistance. However, the signaling pathways by which FFAs lead to the inhibition of IRS function remain to be established. In this study, we explored the FFA-signaling pathway that contributes to serine phosphorylation and degradation of IRS-1 in adipocytes and in dietary obese mice. Linoleic acid, an FFA used in this study, resulted in a reduction in insulin-induced glucose uptake in 3T3-L1 adipocytes. This mimics insulin resistance induced by high-fat diet in C57BL/6J mice. The reduction in glucose uptake is associated with a decrease in IRS-1, but not IRS-2 or GLUT4 protein abundance. Decrease in IRS-1 protein was proceeded by IRS-1 (serine 307) phosphorylation that was catalyzed by serine kinases inhibitor kappaB kinase (IKK) and c-JUN NH2-terminal kinase (JNK). IKK and JNK were activated by linoleic acid and inhibition of the two kinases led to prevention of IRS-1 reduction. We demonstrate that protein kinase C (PKC)theta is expressed in adipocytes. In 3T3-L1 adipocytes and fat tissue, PKCtheta was activated by fatty acids as indicated by its phosphorylation status, and by its protein level, respectively. Activation of PKCtheta contributes to IKK and JNK activation as inhibition of PKCtheta by calphostin C blocked activation of the latter kinases. Inhibition of either PKCtheta or IKK plus JNK by chemical inhibitors resulted in protection of IRS-1 function and insulin sensitivity in 3T3-L1 adipocytes. These data suggest that: 1) activation of PKCtheta contributes to IKK and JNK activation by FFAs; 2) IKK and JNK mediate PKCtheta signals for IRS-1 serine phosphorylation and degradation; and 3) this molecular mechanism may be responsible for insulin resistance associated with hyperlipidemia.