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

描述(由申请人提供)：本申请旨在识别导致肥胖和饮食诱导的胰岛素抵抗的起始分子和细胞事件。我们以前的研究发现，炎症是胰岛素抵抗的一个基本特征，炎症特别是由IKK和NF-β介导的。我们发现：(A)肥胖和西方饮食可以激活脂肪和肝脏中的核因子-βB，但不能激活肌肉，(B)这会导致促炎细胞因子的产生(例如IL-6、抵抗素、 IL-1β、肿瘤坏死因子-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、PAI-1等)，(C)在脂肪或肝脏中转基因激活的核因子？B模拟这些事件，并在没有肥胖的情况下导致全身性胰岛素抵抗，(D)胰岛素抵抗可通过移植受影响的脂肪传递，(E)胰岛素抵抗可通过中和脂肪或肝脏中由核因子-？B刺激的细胞因子而可逆，以及(F)最重要的可能是从遗传或药物上抑制IKK和核因子-？B，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 包括活性氧(ROS)、内质网应激、PKC酶或促炎细胞因子。虽然在某些情况下，这些受体中的任何一个或全部都可以激活核因子-βB并导致胰岛素抵抗，但我们的注意力已经集中在Toll受体(Toll Receptor，TLR)上。TLR家族的13名成员(包括 IL-1R和IL-18R)通过共同的信号通路介导其对核因子-β的影响。尤其是MyD88、IRAK4和IRAK-M，通过只操纵三个关键蛋白质，为研究这一大领域提供了机会。对MyD88-/-、MyD88+/-和IRAK4+/-小鼠的初步结果表明，TLR信号的减少逆转了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、T2D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和更具选择性的靶点。

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.