Unitat de Farmacologia. Facultat de Farmàcia, Diagonal 643, E-08028 Barcelona, Spain.
Endocrinology. 2010 Apr;151(4):1560-9. doi: 10.1210/en.2009-1211. Epub 2010 Feb 25.
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)-kappaB activation as a result of diacylglycerol (DAG) accumulation and subsequent protein kinase Ctheta (PKCtheta) phosphorylation. At present, it is unknown whether peroxisome proliferator-activated receptor-delta (PPARdelta) activation prevents fatty acid-induced inflammation and insulin resistance in skeletal muscle cells. In C2C12 skeletal muscle cells, the PPARdelta 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 PPARdelta antagonist GSK0660. Treatment with the PPARdelta agonist enhanced the expression of two well known PPARdelta 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 PKCtheta 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, PPARdelta activation by GW501516 blocked palmitate-induced NF-kappaB 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 PPARdelta attenuates fatty acid-induced NF-kappaB activation and the subsequent development of insulin resistance in skeletal muscle cells by reducing DAG accumulation. Our results point to PPARdelta activation as a pharmacological target to prevent insulin resistance.
升高的血浆游离脂肪酸通过激活慢性炎症过程导致骨骼肌胰岛素抵抗。这个过程涉及核因子（NF）-κB 的激活，这是由于二酰基甘油（DAG）的积累和随后的蛋白激酶 Cθ（PKCθ）磷酸化。目前，尚不清楚过氧化物酶体增殖物激活受体-δ（PPARδ）的激活是否可以防止脂肪酸诱导的骨骼肌细胞炎症和胰岛素抵抗。在 C2C12 骨骼肌细胞中，PPARδ激动剂 GW501516 可防止胰岛素受体底物-1在丝氨酸（307）处的磷酸化，以及饱和脂肪酸棕榈酸暴露引起的胰岛素刺激的 Akt 磷酸化的抑制。后一种作用被 PPARδ拮抗剂 GSK0660 逆转。PPARδ激动剂的处理增强了两个与脂肪酸氧化有关的众所周知的 PPARδ靶基因的表达，即肉毒碱棕榈酰转移酶-1 和丙酮酸脱氢酶激酶 4，并增加了 AMP 激活蛋白激酶的磷酸化，防止了棕榈酸暴露引起的脂肪酸氧化减少。与这些变化一致，GW501516 处理逆转了棕榈酸引起的 DAG 和 PKCθ激活的增加。在肉毒碱棕榈酰转移酶-1 抑制剂 etomoxir 的存在下，这些作用被消除，从而表明增加的脂肪酸氧化参与了观察到的变化。与这些发现一致，GW501516 通过 PPARδ 的激活阻断了棕榈酸诱导的 NF-κB DNA 结合活性。同样，药物处理抑制了棕榈酸在 C2C12 和人骨骼肌细胞中引起的 IL-6 表达的增加以及该细胞因子的蛋白分泌。这些发现表明，PPARδ 通过减少 DAG 积累来减轻脂肪酸诱导的 NF-κB 激活和随后的骨骼肌细胞胰岛素抵抗。我们的研究结果表明，激活 PPARδ 可作为预防胰岛素抵抗的药理学靶点。
