Activation of peroxisome proliferator-activated receptor-β/-δ (PPAR-β/-δ) ameliorates insulin signaling and reduces SOCS3 levels by inhibiting STAT3 in interleukin-6-stimulated adipocytes.
Activation of peroxisome proliferator-activated receptor-β/-δ (PPAR-β/-δ) ameliorates insulin signaling and reduces SOCS3 levels by inhibiting STAT3 in interleukin-6-stimulated adipocytes.
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DOI：
10.2337/db10-0704
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发表时间：
2011-07
期刊：
影响因子：
7.7
通讯作者：
Vázquez-Carrera M
中科院分区：
文献类型：
--
作者：
Serrano-Marco L;Rodríguez-Calvo R;El Kochairi I;Palomer X;Michalik L;Wahli W;Vázquez-Carrera M
已有研究表明，IL-6是通过激活STAT3，进而上调细胞因子信号转导抑制因子3(SOCS3)，将肥胖所致的慢性炎症与胰岛素抵抗联系起来的介质之一。我们评估了过氧化物酶体增殖物激活受体(PPAR-β/-δ)是否能阻止IL-6-STAT3-SOCS3途径的激活和脂肪细胞的胰岛素抵抗。利用野生型和pPAR-β/-δ基因敲除小鼠的脂肪细胞和白色脂肪组织，观察pPAR-β/-δ对IL-6-STAT3-SOCS3途径的影响。首先，我们观察到PPAR-β/-δ激动剂GW501516阻止了IL-6依赖的胰岛素刺激的Akt磷酸化和脂肪细胞葡萄糖摄取的减少。此外，该药物治疗取消了IL-6诱导分化的3T3-L1脂肪细胞SOCS3的表达。这一作用与药物在体内外阻止IL-6诱导的Tyr705和Ser727残基上的STAT3磷酸化有关。此外，GW501516阻止了IL-6依赖的细胞外信号相关激酶(ERK)1/2的诱导，ERK是一种参与丝氨酸STAT3磷酸化的丝氨酸-苏氨酸蛋白激酶。此外，在PPARβ/-δ缺失小鼠的白色脂肪组织中，STAT3磷酸化(Tyr705和Ser727)、STAT3DNA结合活性和SOCS3蛋白水平高于野生型小鼠。STAT3激活的几个步骤需要它与热休克蛋白90(Hsp90)结合，免疫沉淀研究表明GW501516可以阻止热休克蛋白90的表达。与这一发现一致的是，与野生型小鼠相比，PPAR-β/-δ缺失小鼠的白色脂肪组织中STAT3-Hsp90的关联性得到了增强。总之，我们的发现表明，PPAR-β/-δ的激活通过抑制ERK1/2和阻止STAT3-Hsp90的结合来阻止IL-6诱导的STAT3的激活，这一效应可能有助于预防细胞因子诱导的脂肪细胞的胰岛素抵抗。
It has been suggested that interleukin (IL)-6 is one of the mediators linking obesity-derived chronic inflammation with insulin resistance through activation of STAT3, with subsequent upregulation of suppressor of cytokine signaling 3 (SOCS3). We evaluated whether peroxisome proliferator–activated receptor (PPAR)-β/-δ prevented activation of the IL-6-STAT3-SOCS3 pathway and insulin resistance in adipocytes. Adipocytes and white adipose tissue from wild-type and PPAR-β/-δ-null mice were used to evaluate the effect of PPAR-β/-δ on the IL-6-STAT3-SOCS3 pathway. First, we observed that the PPAR-β/-δ agonist GW501516 prevented both IL-6–dependent reduction in insulin-stimulated Akt phosphorylation and glucose uptake in adipocytes. In addition, this drug treatment abolished IL-6–induced SOCS3 expression in differentiated 3T3-L1 adipocytes. This effect was associated with the capacity of the drug to prevent IL-6–induced STAT3 phosphorylation on Tyr705 and Ser727 residues in vitro and in vivo. Moreover, GW501516 prevented IL-6–dependent induction of extracellular signal–related kinase (ERK)1/2, a serine-threonine-protein kinase involved in serine STAT3 phosphorylation. Furthermore, in white adipose tissue from PPAR-β/-δ–null mice, STAT3 phosphorylation (Tyr705 and Ser727), STAT3 DNA-binding activity, and SOCS3 protein levels were higher than in wild-type mice. Several steps in STAT3 activation require its association with heat shock protein 90 (Hsp90), which was prevented by GW501516 as revealed in immunoprecipitation studies. Consistent with this finding, the STAT3-Hsp90 association was enhanced in white adipose tissue from PPAR-β/-δ–null mice compared with wild-type mice. Collectively, our findings indicate that PPAR-β/-δ activation prevents IL-6–induced STAT3 activation by inhibiting ERK1/2 and preventing the STAT3-Hsp90 association, an effect that may contribute to the prevention of cytokine-induced insulin resistance in adipocytes.