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

本申请旨在鉴定导致肥胖诱导的起始分子和细胞事件， 饮食诱导的胰岛素抵抗我们以前的研究确定了炎症，特别是由IKKP介导的 和NF-κ B作为胰岛素抵抗的潜在特征。我们已经发现（A）NF-κ B被激活， 肥胖和西方饮食中的脂肪和肝脏，但不是肌肉，（B）这导致了促炎的产生 细胞因子（例如IL-6、IL-10、FL-lp、TNF-α）和其它标志物和潜在的炎症介质 与代谢综合征相关（如CRP、PAI-1等），(C)脂肪或脂肪组织中NF-κ B的转基因活化 肝脏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 通过移植受影响的脂肪传播，（E）胰岛素抵抗通过中和细胞因子是可逆的 受脂肪或肝脏中NF-κ B刺激，和（F），也许最重要的，IKKP和NF-κ B的抑制， 在基因上或非基因上逆转动物和人类的胰岛素抵抗。为了确定西方 饮食和肥胖刺激了这种亚急性炎症级联反应，我们已经检测了已知的NF-κ B激活剂， 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 在某些情况下，这些可能激活NF-κ B并导致胰岛素抵抗，我们的注意力已经被吸引到 Toll受体（TLR）。TLR家族的13个成员（包括IL-1R和IL-18 R）介导它们的免疫应答。 通过共同的信号传导途径对NF-κ B的影响。MyD88、IRAK4和IRAK-M特别提供了一种新的免疫调节剂。 我们有机会通过操纵三种关键蛋白质来研究这个大领域。初步结果与 MyD88-/-、MyD88 +/-和IRAK4 +/-小鼠显示TLR信号传导的减少逆转饮食诱导的胰岛素 阻力提出的实验使用这些和其他遗传模型来确定组织特异性作用， TLR信号在胰岛素抵抗中的作用这一发现将提高我们对亚急性胰腺炎的认识。 “炎症”在胰岛素抵抗，T2D和代谢综合征，并可能确定新的和更多的 治疗干预的选择性目标。

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 IKKP and NF-KB, as an underlying feature of insulin resistance. We have found that (A) NF-KB 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, FL-lp, 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-KB in fat or liver mimics these events and causes systemic insulinresistance 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-KB in fat or liver, and (F), perhaps most importantly, inhibition of IKKP and NF-KB, 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-KB, including reactive oxygen (ROS), ER stress, PKC enzymes or proinflammatory cytokines. While any or all of these may activate NF-KB 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-KB 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.