Toll-like receptor 2 deficiency improves insulin sensitivity and hepatic insulin signalling in the mouse
Toll-like receptor 2 deficiency improves insulin sensitivity and hepatic insulin signalling in the mouse
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DOI：
10.1007/s00125-010-1931-5
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发表时间：
2011-01-01
期刊：
影响因子：
8.2
通讯作者：
Tsai, Y. -S.
中科院分区：
文献类型：
--
作者：
Kuo, L. -H.;Tsai, P. -J.;Tsai, Y. -S.
大量证据表明炎症升高与胰岛素抵抗的发展之间存在联系。 Toll 样受体 2 (TLR2) 可识别大量含脂质分子并在多种细胞类型（包括胰岛素反应细胞）中转导炎症信号传导。考虑到脂肪酸组成在TLR2依赖性信号传导中的贡献，我们假设TLR2转导的炎症信号有助于胰岛素抵抗。使用TLR2缺陷的小鼠来研究TLR2在启动和维持炎症相关的胰岛素抵抗和能量稳态中的体内作用。我们首先概括了ob/ob小鼠白色脂肪组织和肝脏中TLR2和炎症细胞因子表达升高的观察结果。与野生型小鼠相比，老年或高脂肪喂养的 TLR2 缺陷小鼠可以免受肥胖和脂肪细胞肥大的影响。此外，缺乏TLR2的小鼠无论喂食普通食物还是高脂肪饮食，都表现出改善的葡萄糖耐量和胰岛素敏感性。伴随着炎症细胞因子表达的减少和细胞外信号调节激酶（ERK）以肝脏特异性方式的激活。在 TLR2 缺陷小鼠中，肝脏炎症细胞因子表达和相关信号传导的减弱与肝脏中胰岛素作用的增加相关，这反映在胰岛素刺激蛋白激酶 B (Akt) 磷酸化和 IRS1 酪氨酸磷酸化增加以及胰岛素抑制的肝细胞葡萄糖产生增加。TLR2 的缺失会减弱局部炎症细胞因子表达和相关信号传导，并增加肝脏中的胰岛素作用。因此，我们的工作已确定 TLR2 是肝脏炎症相关信号传导和胰岛素抵抗的关键介质。
Substantial evidence suggests a link between elevated inflammation and development of insulin resistance. Toll-like receptor 2 (TLR2) recognises a large number of lipid-containing molecules and transduces inflammatory signalling in a variety of cell types, including insulin-responsive cells. Considering the contribution of the fatty acid composition in TLR2-depedent signalling, we hypothesised that the inflammatory signals transduced by TLR2 contribute to insulin resistance.Mice deficient in TLR2 were used to investigate the in vivo roles of TLR2 in initiating and maintaining inflammation-associated insulin resistance and energy homeostasis.We first recapitulated the observation with elevated expression of TLR2 and inflammatory cytokines in white adipose tissue and liver of ob/ob mice. Aged or high-fat-fed TLR2-deficient mice were protected from obesity and adipocyte hypertrophy compared with wild-type mice. Moreover, mice lacking TLR2 exhibited improved glucose tolerance and insulin sensitivity regardless of feeding them regular chow or a high-fat diet. This is accompanied by reductions in expression of inflammatory cytokines and activation of extracellular signal-regulated kinase (ERK) in a liver-specific manner. The attenuated hepatic inflammatory cytokine expression and related signalling are correlated with increased insulin action specifically in the liver in TLR2-deficient mice, reflected by increased insulin-stimulated protein kinase B (Akt) phosphorylation and IRS1 tyrosine phosphorylation and increased insulin-suppressed hepatocyte glucose production.The absence of TLR2 attenuates local inflammatory cytokine expression and related signalling and increases insulin action specifically in the liver. Thus, our work has identified TLR2 as a key mediator of hepatic inflammation-related signalling and insulin resistance.