TLR4 links innate immunity and fatty acid-induced insulin resistance
TLR4 links innate immunity and fatty acid-induced insulin resistance
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DOI：
10.1172/jci28898
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发表时间：
2006-11-01
影响因子：
15.9
通讯作者：
Flier, Jeffrey S.
中科院分区：
文献类型：
--
作者：
Shi, Hang;Kokoeva, Maia V.;Flier, Jeffrey S.
TLR 4是LPS的受体，在先天免疫中起关键作用。TLR 4的刺激激活促炎途径并诱导多种细胞类型中的细胞因子表达。炎症途径在肥胖动物和人的组织中被激活，并在肥胖相关的胰岛素抵抗中起重要作用。在这里，我们表明，营养脂肪酸，其循环水平往往增加肥胖症，激活TLR 4信号在脂肪细胞和巨噬细胞和脂肪酸诱导炎症信号在脂肪细胞或组织和巨噬细胞的能力是钝化在TLR 4的情况下。此外，基本上保护缺乏TLR 4的小鼠免于全身脂质输注的能力，以（a）抑制肌肉中的胰岛素信号传导和（B）减少全身葡萄糖代谢中胰岛素介导的变化。最后，缺乏TLR 4的雌性C57 BL/6小鼠肥胖增加，但部分保护免受高脂肪饮食诱导的胰岛素抵抗，这可能是由于肝脏和脂肪中炎症基因表达减少。总之，这些数据表明，TLR 4是营养，脂质和炎症之间的分子联系，先天免疫系统参与调节能量平衡和胰岛素抵抗，以响应营养环境的变化。
TLR4 is the receptor for LPS and plays a critical role in innate immunity. Stimulation of TLR4 activates proinflammatory pathways and induces cytokine expression in a variety of cell types. inflammatory pathways are activated in tissues of obese animals and humans and play an important role in obesity-associated insulin resistance. Here we show that nutritional fatty acids, whose circulating levels are often increased in obesity, activate TLR4 signaling in adipocytes and macrophages and that the capacity of fatty acids to induce inflammatory signaling in adipose cells or tissue and macrophages is blunted in the absence of TLR4. Moreover, mice lacking TLR4 are substantially protected from the ability of systemic lipid infusion to (a) suppress insulin signaling in muscle and (b) reduce insulin-mediated changes in systemic glucose metabolism. Finally, female C57BL/6 mice lacking TLR4 have increased obesity but are partially protected against high fat diet-induced insulin resistance, possibly due to reduced inflammatory gene expression in liver and fat. Taken together, these data suggest that TLR4 is a molecular link among nutrition, lipids, and inflammation and that the innate immune system participates in the regulation of energy balance and insulin resistance in response to changes in the nutritional environment.