Department of Internal Medicine (L.A.V., F.F., M.J.S.), University of Campinas, 13084-970 Campinas SP, Brazil; and Department of Medicine (F.F.), Division of Diabetes, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229.
Endocr Rev. 2015 Jun;36(3):245-71. doi: 10.1210/er.2014-1100. Epub 2015 Mar 26.
Obesity is accompanied by the activation of low-grade inflammatory activity in metabolically relevant tissues. Studies have shown that obesity-associated insulin resistance results from the inflammatory targeting and inhibition of key proteins of the insulin-signaling pathway. At least three apparently distinct mechanisms-endoplasmic reticulum stress, toll-like receptor (TLR) 4 activation, and changes in gut microbiota-have been identified as triggers of obesity-associated metabolic inflammation; thus, they are expected to represent potential targets for the treatment of obesity and its comorbidities. Here, we review the data that place TLR4 in the center of the events that connect the consumption of dietary fats with metabolic inflammation and insulin resistance. Changes in the gut microbiota can lead to reduced integrity of the intestinal barrier, leading to increased leakage of lipopolysaccharides and fatty acids, which can act upon TLR4 to activate systemic inflammation. Fatty acids can also trigger endoplasmic reticulum stress, which can be further stimulated by cross talk with active TLR4. Thus, the current data support a connection among the three main triggers of metabolic inflammation, and TLR4 emerges as a link among all of these mechanisms.
肥胖伴随着代谢相关组织中低度炎症活动的激活。研究表明，与肥胖相关的胰岛素抵抗是由于胰岛素信号通路的关键蛋白受到炎症靶向和抑制所致。至少有三种明显不同的机制——内质网应激、Toll 样受体 4（TLR4）激活和肠道微生物群的变化——被认为是肥胖相关代谢炎症的触发因素；因此，它们有望成为肥胖及其合并症治疗的潜在靶点。在这里，我们回顾了将 TLR4 置于连接饮食脂肪与代谢炎症和胰岛素抵抗的事件中心的数据。肠道微生物群的变化会导致肠道屏障完整性降低，导致内毒素和脂肪酸的泄漏增加，这些物质可以作用于 TLR4 激活全身炎症。脂肪酸也可以引发内质网应激，而内质网应激可以通过与活跃的 TLR4 的相互作用进一步被刺激。因此，目前的数据支持代谢炎症的三个主要触发因素之间存在联系，而 TLR4 则是所有这些机制之间的联系。
