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

描述（由申请人提供）：本申请旨在确定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。我们之前的研究确定了炎症，特别是由IKK¿和NF-？B，作为胰岛素抵抗的潜在特征。我们发现(A) NF-？B被肥胖和西方饮食在脂肪和肝脏中激活，而不是在肌肉中，这导致促炎细胞因子的产生(例如IL-6，抵抗素，

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.