Activation of Peroxisome Proliferator-Activated Receptor-δ by GW501516 Prevents Fatty Acid-Induced Nuclear Factor-κB Activation and Insulin Resistance in Skeletal Muscle Cells
Activation of Peroxisome Proliferator-Activated Receptor-δ by GW501516 Prevents Fatty Acid-Induced Nuclear Factor-κB Activation and Insulin Resistance in Skeletal Muscle Cells
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DOI：
10.1210/en.2009-1211
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发表时间：
2010-04-01
期刊：
影响因子：
4.8
通讯作者：
Vazquez-Carrera, Manuel
中科院分区：
文献类型：
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作者：
Coll, Teresa;Alvarez-Guardia, David;Vazquez-Carrera, Manuel
血浆游离脂肪酸升高通过激活慢性炎症过程导致骨骼肌胰岛素抵抗。该过程涉及由于二酰基甘油 (DAG) 积累和随后的蛋白激酶 C theta (PKC theta) 磷酸化而导致的核因子 (NF)-kappa B 激活。目前，尚不清楚过氧化物酶体增殖物激活受体-δ（PPAR δ）激活是否可以预防骨骼肌细胞中脂肪酸诱导的炎症和胰岛素抵抗。在 C2C12 骨骼肌细胞中，PPAR δ 激动剂 GW501516 可阻止胰岛素受体底物 1 Ser(307) 的磷酸化，并抑制因暴露于饱和脂肪酸棕榈酸酯而引起的胰岛素刺激的 Akt 磷酸化。 PPAR δ 拮抗剂 GSK0660 可逆转后一种效应。使用 PPAR δ 激动剂治疗可增强参与脂肪酸氧化的两个众所周知的 PPAR δ 靶基因（肉毒碱棕榈酰转移酶-1 和丙酮酸脱氢酶激酶 4）的表达，并增加 AMP 激活蛋白激酶的磷酸化，从而防止棕榈酸盐暴露引起的脂肪酸氧化减少。与这些变化一致，GW501516 治疗逆转了棕榈酸酯引起的 DAG 和 PKC theta 激活的增加。在存在肉碱棕榈酰转移酶 1 抑制剂依托莫昔尔的情况下，这些效应被消除，从而表明观察到的变化涉及脂肪酸氧化的增加。与这些发现一致，GW501516 激活 PPAR δ 阻断了棕榈酸诱导的 NF-kappa B DNA 结合活性。同样，药物治疗抑制了 C2C12 和人骨骼肌细胞中棕榈酸酯引起的 IL-6 表达增加以及该细胞因子的蛋白质分泌。这些发现表明，PPAR δ 通过减少 DAG 积累来减弱脂肪酸诱导的 NF-κ B 激活以及随后骨骼肌细胞中胰岛素抵抗的发展。我们的结果表明 PPAR δ 激活是预防胰岛素抵抗的药理学靶点。 （内分泌学151：1560-1569，2010）
Elevated plasma free fatty acids cause insulin resistance in skeletal muscle through the activation of a chronic inflammatory process. This process involves nuclear factor (NF)-kappa B activation as a result of diacylglycerol (DAG) accumulation and subsequent protein kinase C theta (PKC theta) phosphorylation. At present, it is unknown whether peroxisome proliferator-activated receptor-delta (PPAR delta) activation prevents fatty acid-induced inflammation and insulin resistance in skeletal muscle cells. In C2C12 skeletal muscle cells, the PPAR delta agonist GW501516 prevented phosphorylation of insulin receptor substrate-1 at Ser(307) and the inhibition of insulin-stimulated Akt phosphorylation caused by exposure to the saturated fatty acid palmitate. This latter effect was reversed by the PPAR delta antagonist GSK0660. Treatment with the PPAR delta agonist enhanced the expression of two well known PPAR delta target genes involved in fatty acid oxidation, carnitine palmitoyltransferase-1 and pyruvate dehydrogenase kinase 4 and increased the phosphorylation of AMP-activated protein kinase, preventing the reduction in fatty acid oxidation caused by palmitate exposure. In agreement with these changes, GW501516 treatment reversed the increase in DAG and PKC theta activation caused by palmitate. These effects were abolished in the presence of the carnitine palmitoyltransferase-1 inhibitor etomoxir, thereby indicating that increased fatty acid oxidation was involved in the changes observed. Consistent with these findings, PPAR delta activation by GW501516 blocked palmitate-induced NF-kappa B DNA-binding activity. Likewise, drug treatment inhibited the increase in IL-6 expression caused by palmitate in C2C12 and human skeletal muscle cells as well as the protein secretion of this cytokine. These findings indicate that PPAR delta attenuates fatty acid-induced NF-kappa B activation and the subsequent development of insulin resistance in skeletal muscle cells by reducing DAG accumulation. Our results point to PPAR delta activation as a pharmacological target to prevent insulin resistance. (Endocrinology 151: 1560-1569, 2010)