Lipids, Inflammation and Insulin Action

肥胖、胰岛素抵抗、糖尿病、心血管疾病和 其他相关的病理学尚未完全揭示。在过去的十年里，许多团体的研究， 包括我们的研究，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，并提示巨噬细胞及其相互作用的潜在参与 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.在这个项目中，我们建议关注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功能， 导致与肥胖相关的代谢疾病。两种脂肪细胞/巨噬细胞FABP，aP 2 和mal 1，协调调节脂肪细胞和巨噬细胞的反应， 这些基因的突变表现出对胰岛素抵抗、2型糖尿病、脂肪肝和糖尿病的显著保护作用。 肝病、动脉粥样硬化和哮喘。最近，我们的实验室和其他小组证明，aP 2 通过发现aP 2基因的遗传变异与人类疾病之间的联系， 2型糖尿病和心血管疾病的风险。令人兴奋的新兴数据 在我们的小组和其他地方也证明了这些FABP是分泌蛋白， 全身aP 2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调节来自脂肪的额外蛋白质的分泌， 组织，并在介导靶细胞中的脂毒性反应中发挥重要作用，包括 巨噬细胞在本提案计划的研究中，我们将讨论 可溶性FABP，主要集中在aP 2，检查其他分泌的功能后果， 研究脂肪组织中由这些FABP调控的产物，并探索其分子机制。 FABPs介导脂毒性，重点是脂质诱导的内质网应激， 相关的信令网络。在这些研究中，我们还将利用新开发的化学工具， 抑制aP 2，其可以模拟细胞中FABP遗传缺陷的代谢结果， 在整个动物中，并探索新发现的翻译后的功能意义， aP 2在其亚细胞运输和功能中的修饰。研究的生物学和机制 脂肪细胞/巨噬细胞FABP的作用将有助于建立模型，以了解如何 代谢疾病聚集在肥胖周围，并在机械上相互联系并携带这种疾病 了解人类疾病，以获得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.