Saturated Fatty Acid and TLR Signaling Link β Cell Dysfunction and Islet Inflammation
Saturated Fatty Acid and TLR Signaling Link β Cell Dysfunction and Islet Inflammation
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DOI：
10.1016/j.cmet.2012.01.023
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发表时间：
2012-04-04
期刊：
影响因子：
29
通讯作者：
Nagai, Ryozo
中科院分区：
文献类型：
--
作者：
Eguchi, Kosei;Manabe, Ichiro;Nagai, Ryozo
摄入富含饱和脂肪酸（FAs）的食物以及循环游离FAs水平升高与T2D有关。尽管先前的研究表明炎症在胰岛素抵抗的发展中起着至关重要的作用，但炎症如何导致β细胞功能障碍仍不清楚。我们在这里报道饱和FA棕榈酸盐通过激活胰岛内的炎症过程诱导体内β细胞功能障碍。通过体内和体外研究的结合，我们发现β细胞通过TLR4/MyD88途径对棕榈酸酯产生反应，并产生趋化因子，将CD11b(+)Ly-6C(+) m1型促炎单核细胞/巨噬细胞招募到胰岛。耗尽m1型细胞可保护小鼠免受棕榈酸盐诱导的β细胞功能障碍。胰岛炎症在T2D小鼠模型中β细胞功能障碍中也起重要作用。总的来说，这些结果表明β细胞功能障碍和炎症之间存在明确的机制联系，至少部分是通过FFA-TLR4/MyD88途径介导的。
Consumption of foods high in saturated fatty acids (FAs) as well as elevated levels of circulating free FAs are known to be associated with T2D. Though previous studies showed inflammation is crucially involved in the development of insulin resistance, how inflammation contributes to beta cell dysfunction has remained unclear. We report here the saturated FA palmitate induces beta cell dysfunction in vivo by activating inflammatory processes within islets. Through a combination of in vivo and in vitro studies, we show beta cells respond to palmitate via the TLR4/MyD88 pathway and produce chemokines that recruit CD11b(+)Ly-6C(+) M1-type proinflammatory monocytes/macrophages to the islets. Depletion of M1-type cells protected mice from palmitate-induced beta cell dysfunction. Islet inflammation also plays an essential role in beta cell dysfunction in T2D mouse models. Collectively, these results demonstrate a clear mechanistic link between beta cell dysfunction and inflammation mediated at least in part via the FFA-TLR4/MyD88 pathway.