TOLL RECEPTOR ACTIVATION OF NF-kB IN INSULIN RESISTANCE AND T2DM

描述（由申请人提供）：本申请旨在鉴定导致诱导肥胖和饮食诱导的胰岛素抵抗的起始分子和细胞事件。我们以前的研究确定炎症，特别是介导的IKK和NF-？B作为胰岛素抵抗的一个潜在特征。我们发现（A）NF-？B在脂肪和肝脏中被肥胖和西方饮食激活，但在肌肉中不被激活，（B）这导致促炎细胞因子（例如IL-6，β-内酰胺酶， IL-1、TNF-α）和其他与代谢综合征相关的炎症标志物和潜在介质（如CRP、派-1等），(C)NF-？脂肪或肝脏中的B模拟这些事件，并在没有肥胖的情况下引起全身性胰岛素抵抗，（D）胰岛素抵抗可通过移植受影响的脂肪传播，（E）胰岛素抵抗可通过中和NF-？脂肪或肝脏中的B，和（F），也许最重要的是，抑制IKK和NF-？B，无论是遗传还是非遗传，都能逆转动物和人类的胰岛素抵抗。为了确定西方饮食和肥胖是如何刺激这种亚急性炎症级联反应的，我们研究了已知的炎症因子， NF-？B，包括活性氧（ROS）、ER应激、PKC酶或促炎细胞因子。虽然任何或所有这些可能激活NF-？B并在一定条件下引起胰岛素抵抗，我们的注意力已被吸引到Toll受体（TLR）。TLR家族的13个成员（包括 IL-1 R和IL-18 R介导NF-？B通过共同的信号通路。特别是MyD 88、IRAK 4和IRAK-M提供了一个机会，通过仅操纵三个关键蛋白来研究这个大领域。MyD 88-/-、MyD 88 +/-和IRAK 4 +/-小鼠的初步结果显示TLR信号传导的减少逆转饮食诱导的胰岛素抵抗。拟议的实验使用这些和其他遗传模型来确定TLR信号传导在胰岛素抵抗中的组织特异性作用。这些发现将提高我们对亚急性“炎症”在胰岛素抵抗，T2 D和代谢综合征中的作用的理解，并可能为治疗干预确定新的更具选择性的靶点。

DESCRIPTION (provided by applicant): This application aims to identify initiating molecular and cellular events leading to the induction of obesity- and diet-induced insulin resistance. Our previous studies identified inflammation, specifically mediated by IKK¿ and NF-?B, as an underlying feature of insulin resistance. We have found that (A) NF-?B is activated by obesity and Western diet in fat and liver, but not muscle, (B) this leads to the production of proinflammatory cytokines (e.g. IL-6, resistin, IL-1¿, TNF-a) and other markers and potential mediators of inflammation associated with the metabolic syndrome (e.g. CRP, PAI-1, etc.), (C) transgenic activation of NF-?B in fat or liver mimics these events and causes systemic insulin resistance in the absence of obesity, (D) insulin resistance is transmissible by transplanting affected fat, (E) insulin resistance is reversible by neutralizing cytokines stimulated by NF-?B in fat or liver, and (F), perhaps most importantly, inhibition of IKK¿ and NF-?B, either genetically or pharmacologically, reverses insulin resistance in animals and humans. To identify how Western diet and obesity incite this subacute inflammatory cascade, we have examined the known activators of NF-?B, including reactive oxygen (ROS), ER stress, PKC enzymes or proinflammatory cytokines. While any or all of these may activate NF-?B and cause insulin resistance under certain conditions, our attention has been drawn to the toll receptors (TLRs). The 13 members of the TLR family (including IL-1R and IL-18R) mediate their effects on NF-?B through common signaling pathways. MyD88, IRAK4 and IRAK-M in particular provide an opportunity to investigate this large field by manipulating only three key proteins. Preliminary results with MyD88-/-, MyD88+/- and IRAK4+/- mice show that decreases in TLR signaling reverse diet-induced insulin resistance. Proposed experiments use these and other genetic models to determine the tissue specific roles of TLR signaling in insulin resistance. The findings will improve our understanding of the role of subacute 'inflammation' in insulin resistance, T2D and the metabolic syndrome, and may identify new and more selective targets for therapeutic intervention.