Department of Immunobiology and Pharmacological Genetics, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama, Japan.
Diabetes. 2012 May;61(5):1199-209. doi: 10.2337/db11-1182. Epub 2012 Mar 6.
Recent accumulating evidence suggests that innate immunity is associated with obesity-induced chronic inflammation and metabolic disorders. Here, we show that a Toll-like receptor (TLR) protein, radioprotective 105 (RP105)/myeloid differentiation protein (MD)-1 complex, contributes to high-fat diet (HFD)-induced obesity, adipose tissue inflammation, and insulin resistance. An HFD dramatically increased RP105 mRNA and protein expression in stromal vascular fraction of epididymal white adipose tissue (eWAT) in wild-type (WT) mice. RP105 mRNA expression also was significantly increased in the visceral adipose tissue of obese human subjects relative to nonobese subjects. The RP105/MD-1 complex was expressed by most adipose tissue macrophages (ATMs). An HFD increased RP105/MD-1 expression on the M1 subset of ATMs that accumulate in eWAT. Macrophages also acquired this characteristic in coculture with 3T3-L1 adipocytes. RP105 knockout (KO) and MD-1 KO mice had less HFD-induced adipose tissue inflammation, hepatic steatosis, and insulin resistance compared with wild-type (WT) and TLR4 KO mice. Finally, the saturated fatty acids, palmitic and stearic acids, are endogenous ligands for TLR4, but they did not activate RP105/MD-1. Thus, the RP105/MD-1 complex is a major mediator of adipose tissue inflammation independent of TLR4 signaling and may represent a novel therapeutic target for obesity-associated metabolic disorders.
最近越来越多的证据表明，先天免疫与肥胖引起的慢性炎症和代谢紊乱有关。在这里，我们表明 Toll 样受体（TLR）蛋白，辐射保护 105（RP105）/髓样分化蛋白（MD）-1 复合物，有助于高脂肪饮食（HFD）诱导的肥胖、脂肪组织炎症和胰岛素抵抗。高脂肪饮食（HFD）在野生型（WT）小鼠的附睾白色脂肪组织（eWAT）基质血管部分显著增加 RP105 mRNA 和蛋白表达。肥胖人类受试者内脏脂肪组织中 RP105 mRNA 的表达也明显高于非肥胖受试者。RP105/MD-1 复合物由大多数脂肪组织巨噬细胞（ATMs）表达。高脂肪饮食（HFD）增加了 eWAT 中积累的 M1 亚群 ATMs 上的 RP105/MD-1 表达。巨噬细胞在与 3T3-L1 脂肪细胞共培养时也获得了这种特征。与野生型（WT）和 TLR4 KO 小鼠相比，RP105 敲除（KO）和 MD-1 KO 小鼠的高脂肪饮食（HFD）诱导的脂肪组织炎症、肝脂肪变性和胰岛素抵抗较少。最后，饱和脂肪酸，棕榈酸和硬脂酸，是 TLR4 的内源性配体，但它们不能激活 RP105/MD-1。因此，RP105/MD-1 复合物是一种独立于 TLR4 信号的主要脂肪组织炎症介质，可能是肥胖相关代谢紊乱的新的治疗靶点。
