JNK and tumor necrosis factor-α mediate free fatty acid-induced insulin resistance in 3T3-L1 adipocytes
JNK and tumor necrosis factor-α mediate free fatty acid-induced insulin resistance in 3T3-L1 adipocytes
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DOI：
10.1074/jbc.m504611200
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发表时间：
2005-10-21
影响因子：
4.8
通讯作者：
Olefsky, JM
中科院分区：
文献类型：
--
作者：
Nguyen, MTA;Satoh, H;Olefsky, JM
脂肪输注和高脂喂养是全身性和脂肪组织胰岛素抵抗的既定原因。在这项研究中，我们用一种混合的游离脂肪酸(FFA)处理3T3-L1脂肪细胞，以探讨脂肪诱导胰岛素抵抗的分子机制。FFA治疗可损害胰岛素受体介导的信号转导，减少胰岛素刺激的GLUT4转位和葡萄糖转运。FFAs激活应激/炎性蛋白激酶c-jun氨基末端激酶(JNK)和IKKβ，以及细胞因子信号蛋白3的抑制因子，增加炎性细胞因子肿瘤坏死因子-α的分泌，减少脂联素的分泌。RNA干扰介导的JNK下调阻断了JNK的激活，并阻止了FFA诱导的大部分胰岛素作用缺陷。用抗肿瘤坏死因子-α及其受体的中和性抗体或以显性负性肿瘤坏死因子-α多肽阻断肿瘤坏死因子-α信号转导通路，对FFA诱导的细胞胰岛素抵抗有部分抑制作用。我们发现，FFA对JNK的激活不能通过阻断TNF-α信号来抑制，而FFA诱导的分泌增加可以被RNA干扰介导的JNK基因敲除所抑制。综上所述，这些结果表明：1)JNK可通过非依赖于肿瘤坏死因子的机制被FFA激活，2)激活的JNK是FFA诱导的细胞胰岛素抵抗的主要贡献者，3)TNF-α是激活的JNK的自分泌/旁分泌下游效应者，也可以介导胰岛素抵抗。
Lipid infusion and high fat feeding are established causes of systemic and adipose tissue insulin resistance. In this study, we treated 3T3- L1 adipocytes with a mixture of free fatty acids ( FFAs) to investigate the molecular mechanisms underlying fat- induced insulin resistance. FFA treatment impaired insulin receptor- mediated signal transduction and decreased insulin- stimulated GLUT4 translocation and glucose transport. FFAs activated the stress/ inflammatory kinases c- Jun N- terminal kinase ( JNK) and IKK beta, and the suppressor of cytokine signaling protein 3, increased secretion of the inflammatory cytokine tumor necrosis factor ( TNF)-alpha, and decreased secretion of adiponectin into the medium. RNA interference-mediated down- regulation of JNK blocked JNK activation and prevented most of the FFA- induced defects in insulin action. Blockade of TNF-alpha signaling with neutralizing antibodies to TNF-alpha or its receptors or with a dominant negative TNF-alpha peptide had a partial effect to inhibit FFA- induced cellular insulin resistance. We found that JNK activation by FFAs was not inhibited by blocking TNF-alpha signaling, whereas the FFA- induced increase in TNF-alpha secretion was inhibited by RNA interference- mediated JNK knockdown. Together, these results indicate that 1) JNK can be activated by FFAs through TNF-alpha- independent mechanisms, 2) activated JNK is a major contributor to FFA- induced cellular insulin resistance, and 3) TNF-alpha is an autocrine/ paracrine downstream effector of activated JNK that can also mediate insulin resistance.