Hepatocyte Toll-like receptor 4 regulates obesity-induced inflammation and insulin resistance.
Hepatocyte Toll-like receptor 4 regulates obesity-induced inflammation and insulin resistance.
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DOI：
10.1038/ncomms4878
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发表时间：
2014-05-12
影响因子：
16.6
通讯作者：
Elmquist, Joel K.
中科院分区：
文献类型：
--
作者：
Jia, Lin;Vianna, Claudia R.;Fukuda, Makoto;Berglund, Eric D.;Liu, Chen;Tao, Caroline;Sun, Kai;Liu, Tiemin;Harper, Matthew J.;Lee, Charlotte E.;Lee, Syann;Scherer, Philipp E.;Elmquist, Joel K.
慢性低度炎症是肥胖的标志，并被认为有助于肥胖相关胰岛素抵抗的发展。Toll样受体4（Tlr 4）是促炎反应的关键介质。缺乏Tlr 4的小鼠受到保护，免受饮食诱导的胰岛素抵抗和炎症的影响;然而，表达Tlr 4的细胞介导这种效应是未知的。在这里，我们表明，缺乏肝细胞Tlr 4（Tlr 4LKO）的小鼠表现出改善的葡萄糖耐量，增强胰岛素敏感性，并改善肝脏脂肪变性，尽管肥胖的发展后，高脂肪饮食（HFD）的挑战。此外，Tlr 4 LKO小鼠在白色脂肪组织中具有减少的巨噬细胞含量，以及减少的组织和循环炎性标志物。相反，髓样细胞中Tlr 4活性的丧失对胰岛素敏感性几乎没有影响。总的来说，这些数据表明肝细胞上Tlr 4的活化有助于肥胖相关的炎症和胰岛素抵抗，并表明靶向肝细胞Tlr 4可能是治疗2型糖尿病的有用的治疗策略。
Chronic low-grade inflammation is a hallmark of obesity and thought to contribute to the development of obesity-related insulin resistance. Toll-like receptor 4 (Tlr4) is a key mediator of pro-inflammatory responses. Mice lacking Tlr4s are protected from diet-induced insulin resistance and inflammation; however which Tlr4 expressing cells mediate this effect is unknown. Here we show that mice deficient in hepatocyte Tlr4 (Tlr4LKO) exhibit improved glucose tolerance, enhanced insulin sensitivity, and ameliorated hepatic steatosis despite the development of obesity after a high fat diet (HFD) challenge. Furthermore, Tlr4LKO mice have reduced macrophage content in white adipose tissue, as well as decreased tissue and circulating inflammatory markers. In contrast, the loss of Tlr4 activity in myeloid cells has little effect on insulin sensitivity. Collectively, these data indicate that the activation of Tlr4 on hepatocytes contributes to obesity-associated inflammation and insulin resistance, and suggest that targeting hepatocyte Tlr4 might be a useful therapeutic strategy for the treatment of type 2 diabetes.
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