Lipids, Inflammation and Insulin Action

肥胖、胰岛素抵抗、糖尿病、心血管疾病和 其他相关的病理还没有完全被发现。在过去的十年里，许多小组的研究， 包括我们在内，都说明了炎症在代谢性疾病中的重要性，特别是在 肥胖的脂肪组织，并提示巨噬细胞的潜在参与及其相互作用 与脂肪细胞在这一过程中，可能通过整合脂质信号与炎症 网络。在本项目中，我们建议重点研究脂肪酸的功能和作用机制。 结合蛋白(FABP)整合巨噬细胞和脂肪细胞的功能，并显著 导致与肥胖相关的代谢性疾病。两种脂肪细胞/巨噬细胞FABP，aP2 和Mal1，协调调节脂肪细胞和巨噬细胞的反应，并靶向地与小鼠 这些基因的突变对胰岛素抵抗、2型糖尿病、肥胖症有显著的保护作用 肝病、动脉粥样硬化和哮喘。最近，我们的实验室和其他研究小组证明了aP2 通过发现aP2基因变异之间的联系，功能与人类疾病高度相关 基因座与2型糖尿病和心血管疾病的风险。新出现的令人振奋的数据 我们组和其他地方的人也证明了这些FABP是分泌蛋白，并且 全身aP2水平与肥胖、2型糖尿病和心血管疾病密切相关 在人类身上。此外，这些FABP调节脂肪分泌额外的蛋白质。 并在介导靶细胞的脂毒反应中发挥重要作用，包括 巨噬细胞。在这项建议计划的研究中，我们将探讨细胞的生物学功能。 可溶性FABP，主要集中在aP2，检查其他分泌的功能后果 脂肪组织中受这些FABP调控的产物，并探讨其分子机制 哪些FABP介导脂毒性，重点是脂质诱导的内质网应激和 相关信令网络。在这些研究中，我们还将利用一种新开发的化学工具来 抑制aP2，它可以模拟FABP遗传缺陷在细胞和细胞中的代谢后果 并探索新发现的翻译后基因的功能意义 修饰aP2的亚细胞转运和功能。研究其生物学特性和发病机制 脂肪细胞/巨噬细胞FABP的作用将有助于建立模型以了解 代谢性疾病围绕肥胖聚集，相互机械地联系在一起，携带着 为人类疾病提供独特的预防和治疗机会。

The molecular mechanisms linking obesity, insulin resistance, diabetes, cardiovascular diseases and other associated pathologies are not fully uncovered. In the past decade, studies in many groups, including ours, have illustrated the importance of inflammation in metabolic disease, particularly in obese adipose tissue, and suggested potential involvement of macrophages and their interactions with adipocytes in this process, potentially through the integration of lipid signals with inflammatory networks. In this project, we propose to focus on the function and mechanisms of action of fatty acid binding proteins (FABPs) that integrate macrophage and adipocyte function and significantly contribute to metabolic diseases associated with obesity. Two adipocyte/macrophage FABPs, aP2 and mal1, coordinately regulate adipocyte and macrophage responses and mice with targeted mutations in these genes exhibit marked protection against insulin resistance, type 2 diabetes, fatty liver disease, atherosclerosis, and asthma. Recently, our lab and other groups demonstrated that aP2 function is highly relevant to human disease by discovering the links between genetic variation at aP2 locus and the risk for type 2 diabetes and cardiovascular disease. New and exciting emerging data both in our group and elsewhere also demonstrated that these FABPs are secreted proteins, and systemic aP2 levels are strongly associated with obesity, type 2 diabetes and cardiovascular disease in humans. Furthermore, these FABPs regulate the secretion of additional proteins from the adipose tissue and play a significant role in mediating lipotoxic responses in target cells, including macrophages. In the studies planned in this proposal, we will address the biological functions of the soluble FABPs, focusing primarily on aP2, examine the functional consequences of other secreted products regulated by these FABPs in adipose tissue and explore the molecular mechanisms by which FABPs mediate lipotoxicity, with a focus on lipid-induced endoplasmic reticulum stress and related signaling networks. In these studies we will also utilize a newly developed chemical tool to inhibit aP2 which can mimic the metabolic consequences of genetic deficiency of FABPs in cells and in whole animals and explore the functional significance of newly identified posttranslational modification of aP2 in its subcellular trafficking and function. Studying the biology and mechanisms of action of adipocyte/macrophage FABPs will be insightful in building models to understand how metabolic disease cluster around obesity and mechanistically link to each other and carry this knowledge to human disease for unique preventive and therapeutic opportunities.