Senn Joseph J
Department of Pediatrics, Charles P. Darby Children's Research Institute, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
J Biol Chem. 2006 Sep 15;281(37):26865-75. doi: 10.1074/jbc.M513304200. Epub 2006 Jun 22.
Fatty acids can activate proinflammatory pathways leading to the development of insulin resistance, but the mechanism is undiscovered. Toll like receptor 2 (TLR2) recognizes lipids, activates proinflammatory pathways, and is genetically associated with inflammatory diseases. This study aimed to examine the role of TLR2 in palmitate-induced insulin resistance in C2C12 myotubes. Treatment with palmitate rapidly induced the association of myeloid differentiation factor 88 (MyD88) with the TLR2 receptor, activated the stress-linked kinases p38, JNK, and protein kinase C, induced degradation of IkappaBalpha, and increased NF-kappaB DNA binding. The activation of these pathways by palmitate was sensitive and temporally regulated and occurred within the upper physiologic range of saturated fatty acid concentrations in vivo, suggesting a receptor-mediated event and not simple lipotoxicity. When compared with an equimolar concentration of palmitate, fibroblast-stimulating lipopeptide-1, a known TLR2 ligand, was a slightly more potent activator of signal transduction and interleukin (IL)-6 production. Palmitate inhibited insulin signal transduction in C2C12 cells beginning 1-2 h after exposure and reached a maximum at 12-16 h. An antagonist TLR2 antibody, mAb 2.5, led to a 50-60% decrease in palmitate-induced IL-6 production and partially restored insulin signal transduction, whereas an isotype-matched control antibody had no effect. RNA interference-mediated inhibition of TLR2 and MyD88 expression in C2C12 muscle cells resulted in a near complete inhibition of palmitate-induced insulin resistance and IL-6 production. This study provides strong evidence that TLR2 mediates the initial events of fatty acid-induced insulin resistance in muscle.
脂肪酸可激活促炎途径，导致胰岛素抵抗的发生，但其机制尚不清楚。Toll样受体2（TLR2）可识别脂质，激活促炎途径，且在基因上与炎症性疾病相关。本研究旨在探讨TLR2在棕榈酸酯诱导的C2C12肌管胰岛素抵抗中的作用。用棕榈酸酯处理可迅速诱导髓样分化因子88（MyD88）与TLR2受体结合，激活应激相关激酶p38、JNK和蛋白激酶C，诱导IkappaBalpha降解，并增加NF-kappaB与DNA的结合。棕榈酸酯对这些途径的激活具有敏感性且受时间调控，发生在体内饱和脂肪酸浓度的生理上限范围内，提示这是一个受体介导的事件，而非简单的脂毒性。与等摩尔浓度的棕榈酸酯相比，成纤维细胞刺激脂肽-1（一种已知的TLR2配体）是信号转导和白细胞介素（IL）-6产生的稍强激活剂。棕榈酸酯在暴露后1-2小时开始抑制C2C12细胞中的胰岛素信号转导，并在12-16小时达到最大值。抗TLR2抗体mAb 2.5可使棕榈酸酯诱导的IL-6产生减少50-60%，并部分恢复胰岛素信号转导，而异型对照抗体则无作用。RNA干扰介导的C2C12肌肉细胞中TLR2和MyD88表达的抑制导致棕榈酸酯诱导的胰岛素抵抗和IL-6产生几乎完全受到抑制。本研究提供了强有力的证据，表明TLR2介导了脂肪酸诱导的肌肉胰岛素抵抗的初始事件。
