Lipids, Inflammation and Insulin Action

描述（由申请人提供）：与肥胖、胰岛素抵抗、糖尿病、心血管疾病和其他相关病理相关的分子机制尚未完全了解。在过去的十年中，包括我们在内的许多小组的研究已经说明了炎症在代谢疾病中的重要性，特别是在肥胖脂肪组织中。巨噬细胞及其与脂肪组织中脂肪细胞的相互作用可能通过脂质信号与炎症网络的整合参与这一过程。在这个项目中，我们建议重点研究脂肪酸结合蛋白（FABP）的功能和作用机制，该蛋白整合巨噬细胞和脂肪细胞功能，并显着促进与肥胖相关的代谢疾病。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，这些基因发生靶向突变的小鼠表现出对胰岛素抵抗、2 型糖尿病、脂肪肝疾病、动脉粥样硬化和哮喘的显着保护作用。最近，我们的实验室和其他团队通过发现 aP2 位点的遗传变异与 2 型糖尿病和心血管疾病风险之间的联系，证明了 aP2 功能与人类疾病高度相关。我们小组和其他地方出现的令人兴奋的新数据也表明，aP2 由脂肪细胞分泌，全身 aP2 水平与人类肥胖、2 型糖尿病和心血管疾病密切相关。此外，这些 FABP 调节脂肪组织中其他蛋白质的分泌，并在介导靶细胞（包括巨噬细胞）的脂毒性反应中发挥重要作用。在本提案计划的研究中，我们将解决可溶性FABP的生物学功能，主要关注aP2，表征脂肪组织中其他FABP调节的分泌产物，并探索aP2介导脂毒性的分子机制，重点关注脂质诱导的内质网应激以及相关的信号传导和转录网络。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，它可以模拟细胞和整个动物中 FABP 遗传缺陷的代谢后果。研究脂肪细胞/巨噬细胞 FABP 的生物学和作用机制将有助于构建模型，以了解代谢疾病如何围绕肥胖聚集并在机制上相互关联，并将这些知识应用于人类疾病的预防和治疗应用。公共健康相关性：研究脂肪细胞/巨噬细胞 FABP 的生物学和作用机制将有助于建立模型，以了解代谢疾病如何围绕肥胖聚集并在机制上相互联系，并将这些知识应用于人类疾病，以获得独特的预防和治疗机会。

DESCRIPTION (provided by applicant): The molecular mechanisms linking obesity, insulin resistance, diabetes, cardiovascular diseases and other associated pathologies are not fully understood. In the past decade, studies in many groups, including ours, have illustrated the importance of inflammation in metabolic disease, particularly in obese adipose tissue. Macrophages and their interactions with adipocytes in the adipose tissue are potentially involved in this process in this process 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. 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 aP2 is secreted from adipocytes 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 FABP, focusing primarily on aP2, characterize other FABP-regulated secreted products in adipose tissue and explore the molecular mechanisms by which aP2 mediate lipotoxicity, with a focus on lipid-induced endoplasmic reticulum stress and related signaling and transcriptional 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. 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 linked to each other and carry this knowledge to human disease for preventive and therapeutic applications. PUBLIC HEALTH RELEVANCE: 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 preventative and therapeutic opportunities.