Ubiquitin-dependent regulation of inflammation and insulin resistance

描述（由申请人提供）：肥胖相关炎症被认为是胰岛素抵抗发展的关键因素，导致2型糖尿病和其他代谢紊乱。然而，抑制炎症是否是治疗胰岛素抵抗的好方法这一关键问题仍然悬而未决。我们的长期目标是研究内源性调节机制，以预防脂肪组织中炎症反应的过度激活，并了解钝化炎症是否在维持胰岛素敏感性方面可能部分适得其反。其基本原理是，虽然促炎细胞因子的有害影响是众所周知的，但炎症的有益影响可能通常被忽视。g蛋白通路抑制因子2 （GPS2）是一种转录辅助因子和泛素信号的抑制剂，在脂肪组织中起重要的抗炎作用。本提案旨在：i)利用aP2-GPS2小鼠模型来解剖肥胖诱导的胰岛素抵抗背景下抑制炎症的相反作用；ii)揭示GPS2作为一种新型PPARγ共激活因子的转录作用的分子机制。为了解决这些问题，我们提出了三个目的：特异性目的1将表征aP2-GPS2转基因小鼠的代谢和炎症表型，并研究GPS2介导的脂肪细胞和巨噬细胞炎症反应抑制损害脂肪组织的储存能力并诱导异位脂肪沉积的假设。特异性目标2将剖析GPS2介导的脂肪因子基因抵抗素转录调控的分子机制，并广泛评估GPS2作为脂肪细胞转录共激活因子的相关性。Specific Aim 3将阐明gps2通过抑制特定泛素机制介导的炎症反应调节的结构基础。总的来说，这些研究将有助于了解抑制炎症反应对脂肪组织稳态和异位脂肪积累的调节作用，并将确定GPS2作为核受体PPARγ的新型共激活因子的转录作用的分子和结构基础。

DESCRIPTION (provided by applicant): Obesity-associated inflammation is recognized as a critical factor in the development of insulin resistance leading to Type 2 diabetes and other metabolic disorders. However, the critical question of whether inhibiting inflammation is a good approach in the attempt to treat insulin resistance remains open. Our long-term goal is to investigate the endogenous regulatory mechanisms geared toward prevention of hyper-activation of inflammatory responses in the adipose tissue and to understand whether blunting inflammation may be partially counterproductive in maintaining insulin sensitivity. The rationale being that while the detrimental effects of pro-inflammatory cytokines are well known, there may be beneficial effects of inflammation that have been generally overlooked. G-protein Pathway Suppressor 2 (GPS2) is a transcriptional cofactor and an inhibitor of ubiquitin signaling playing an important anti-inflammatory role in the adipose tissue. This proposal is designed to: i) take advantage of the aP2-GPS2 mouse model to dissect the opposing effects of inhibiting inflammation in the context of obesity-induced insulin resistance; ii) uncover the molecular mechanism of GPS2 transcriptional actions as a novel coactivator of PPARγ. To address these questions, we propose three Aims: Specific Aim 1 will characterize the metabolic and inflammatory phenotype of the aP2-GPS2 transgenic mice and investigate the hypothesis that GPS2- mediated inhibition of inflammatory responses in adipocytes and macrophages impairs the storage capacity of the adipose tissue and induce ectopic fat deposition. Specific Aim 2 will dissect the molecular mechanism of GPS2-mediated transcriptional regulation of the adipokine gene resistin and broadly assess the relevance of GPS2 as a transcriptional coactivator in adipocytes. Specific Aim 3 will elucidate the structural basis of GPS2-mediated regulation of inflammatory responses via inhibition of specific ubiquitin machineries. Overall, the proposed studies will contribute significantly to the general understanding of the effects of inhibiting inflammatory responses on the regulation of the adipose tissue homeostasis and ectopic fat accumulation, and will define the molecular and structural basis of GPS2 transcriptional actions as a novel coactivator for the nuclear receptor PPARγ.