The c-Jun N-Terminal Kinase Mediates the Induction of Oxidative Stress and Insulin Resistance by Palmitate and Toll-like Receptor 2 and 4 Ligands in 3T3-L1 Adipocytes
The c-Jun N-Terminal Kinase Mediates the Induction of Oxidative Stress and Insulin Resistance by Palmitate and Toll-like Receptor 2 and 4 Ligands in 3T3-L1 Adipocytes
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DOI：
10.1055/s-0029-1202852
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发表时间：
2009-07-01
影响因子：
2.2
通讯作者：
Spurlock, M. E.
中科院分区：
文献类型：
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作者：
Davis, J. E.;Gabler, N. K.;Spurlock, M. E.
已知饱和脂肪酸（SFA）通过Toll样受体-4（Tlr 4）信号转导诱导脂肪细胞中的炎症和胰岛素抵抗，但其机制尚未被很好地描述。此外，Tlr 2和c-Jun N-末端激酶（JNK）在脂肪细胞炎症中的潜在作用尚未研究。我们证明，棕榈酸酯，脂多糖（LPS），和Toll样受体-2（Tlr 2）激动剂，酵母聚糖A（ZymA），诱导胰岛素抵抗的时间和剂量依赖性的方式在3 T3-L1脂肪细胞。与胰岛素敏感性降低相对应的是IL-6的表达增加，以及促炎性转录因子、核因子κ B和激活蛋白-1的激活。在棕榈酸酯和Tlr激动剂处理的脂肪细胞中也观察到活性氧（ROS）积累。JNK抑制剂SP 600125减弱了SFA和Tlr激动剂介导的胰岛素抵抗，这与减少的促炎反应和减少的ROS积累相对应。总的来说，这些结果表明Tlr 2参与脂肪细胞炎症，因此暗示受体作为SFA的潜在靶点。此外，JNK的激活似乎也是必需的Tlr 2-，以及Tlr 4-诱导的胰岛素抵抗和氧化应激。
Saturated fatty acids (SFAs) are known to induce inflammation and insulin resistance in adipocytes through toll-like receptor-4 (Tlr4) signaling, but the mechanisms are not well delineated. Furthermore, the potential roles of Tlr2 and the c-Jun N-terminal kinase (JNK) in inflammation in adipocytes have not been investigated. We demonstrated that palmitate, lipopolysaccharide (LPS), and the toll-like receptor-2 (Tlr2) agonist, zymosan A (ZymA), induced insulin resistance in a time- and dose-dependent manner in 3T3-L1 adipocytes. Corresponding with the reduction of insulin sensitivity was an increased expression of IL-6, as well as activation of the proinflammatory transcription factors, nuclear factor kappa B, and activator protein-1. Reactive oxygen species (ROS) accumulation was also observed in palmitate and Tlr agonist treated adipocytes. The JNK inhibitor, SP600125, attenuated insulin resistance mediated by SFA and Tlr agonists, which corresponded with a diminished proinflammatory response and reduced ROS accumulation. Collectively, these results demonstrated Tlr2 involvement in adipocyte inflammation and therefore implicated the receptor as a potential target for SFA. Moreover, activation of JNK also appeared to be essential to Tlr2-, as well as Tlr4-induced insulin resistance and oxidative stress.