Lipids, Inflammation and Insulin Action

脂质、炎症和胰岛素作用

• 批准号: 7583753
• 负责人: GOKHAN S HOTAMISLIGIL
• 金额: $ 37.59万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7583753
• 关键词: Address; Adipocytes; Adipose tissue; Animals; Asthma; Atherosclerosis; Biochemical; Biological; Biological Process; Biology; Blood Circulation; Bone Marrow Transplantation; Cardiovascular Diseases; Cells; Chemicals; Cyclophilin A; Cytoplasmic Protein; Data; Diabetes Mellitus; Disease; Disease Clusterings; Endoplasmic Reticulum; Event; Exhibits; Experimental Models; Fatty Liver; Genes; Genetic; Genetic Variation; Heterogeneous-Nuclear Ribonucleoproteins; Human; Inflammation; Inflammatory; Insulin; Insulin Resistance; Knowledge; LXRalpha protein; Link; Lipids; Liver diseases; Mediating; Mediator of activation protein; Metabolic; Metabolic Diseases; Metabolism; Modeling; Molecular; Mus; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Obesity; Pathogenesis; Pathology; Pathway interactions; Play; Preventive; Process; Protein Isoforms; Proteins; Proteomics; Regulation; Risk; Role; Signal Transduction; Stress; System; Testing; Therapeutic; Work; base; cell type; endoplasmic reticulum stress; fatty acid-binding proteins; glucose metabolism; hnRNP A2-B1; human FRAP1 protein; human disease; inhibitor/antagonist; insight; insulin sensitivity; interest; lipid metabolism; loss of function; macrophage; mouse model; novel; novel therapeutics; p23 translationally controlled tumor protein; public health relevance; research study; response; small molecule; tool

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.

描述（由申请人提供）：连接肥胖，胰岛素抵抗，糖尿病，心血管疾病和其他相关病理的分子机制尚不完全了解。在过去的十年中，包括我们在内的许多小组的研究都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在这一过程中通过将脂质信号与炎症网络的整合结合在一起，有可能参与此过程。在这个项目中，我们建议专注于整合巨噬细胞和脂肪细胞功能的脂肪酸结合蛋白（FABP）的作用和机制，并显着促进与肥胖相关的代谢疾病。脂肪细胞/巨噬细胞Fabps，AP2和MAL1协调调节这些基因中具有靶向突变的脂肪细胞和巨噬细胞反应和小鼠具有明显的保护，可针对胰岛素抵抗，2型糖尿病，脂肪肝病，动脉粥样硬化和哮喘具有明显的保护。最近，我们的实验室和其他小组表明，通过发现AP2基因座的遗传变异与2型糖尿病和心血管疾病的风险之间的联系，AP2功能与人类疾病高度相关。我们小组和其他地方的新的和令人兴奋的新兴数据也表明，AP2是从脂肪细胞中分泌的，系统性AP2水平与肥胖，2型糖尿病和人类的心血管疾病密切相关。此外，这些Fabps调节了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）的脂肪毒性反应中起重要作用。在该提案中计划的研究中，我们将解决可溶性FABP的生物学功能，主要集中在AP2上，以脂肪组织中的其他FABP调节的产品进行了特征，并探索AP2介导脂毒性的分子机制，重点是脂质诱导的脂质诱导的内质性网状网络应力和转录网络。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，该工具可以模仿细胞和整个动物中FABPS遗传缺乏的代谢后果。研究脂肪细胞/巨噬细胞Fabps的生物学和作用机制将对建立模型有见地，以了解肥胖周围的代谢疾病聚类如何以及机械机械地彼此相关，并将这些知识带到人类疾病中，以进行预防和治疗应用。公共卫生相关性：研究脂肪细胞/巨噬细胞Fabps的生物学和作用机制将对建筑模型有见地，以了解肥胖周围的代谢疾病聚类以及机械机械上的彼此之间如何联系，并将这种知识与人类疾病相互联系，以获得独特的预防和治疗机会。