Myeloid Cell Functions in Obesity and Diabetes.

骨髓细胞在肥胖和糖尿病中发挥作用。

• 批准号: 8899057
• 负责人: Ajay Chawla
• 金额: $ 35.63万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8899057
• 关键词: Address; Adipocytes; Adipose tissue; Antigens; Applications Grants; Area; Back; Body mass index; CD8B1 gene; Cardiovascular Diseases; Cell physiology; Cells; Chronic; Coronary Arteriosclerosis; Cytokine Activation; Dental crowns; Development; Diabetes Mellitus; Diet; Fatty acid glycerol esters; Functional disorder; Genetic; Human; ITGAX gene; Immune; Immunology; Individual; Inflammation; Inflammatory; Inflammatory Response; Insulin Resistance; Intrinsic factor; Knowledge; Link; Lipids; Lysosomes; Maintenance; Malignant Neoplasms; Mediating; Metabolic; Metabolic Diseases; Metabolism; Molecular; Molecular Target; Molecular and Cellular Biology; Mus; Myeloid Cells; Natural Immunity; Neurodegenerative Disorders; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Obesity associated disease; PPAR gamma; Pathogenesis; Pathway interactions; Predisposition; Process; Property; Regulatory Pathway; Resistance; Risk Factors; Role; Signal Transduction; Structure; Supplementation; T-Lymphocyte; Testing; Therapeutic Intervention; Tissues; Visceral; Work; adaptive immunity; arm; base; cell type; cellular targeting; chemokine; cytokine; high risk; insulin sensitivity; interdisciplinary approach; macrophage; mortality; novel; programs; public health relevance; sensor; subcutaneous

 DESCRIPTION (provided by applicant): In both mice and humans, low-grade chronic inflammation has emerged as a potential link between obesity, insulin resistance and cardiovascular disease. For instance, obesity results in a gradual increase (2-4-fold) in various inflammatory cytokines and chemokines in white adipose tissue (WAT). This increase in tissue inflammation, which is primarily observed in visceral WAT (epididymal WAT (eWAT) in mice), results from the recruitment and activation of innate and adaptive immune cells. In contrast, obese subcutaneous WAT (scWAT) seems to be resistant to the development of tissue inflammation. Although this resistance of scWAT to diet-induced inflammation is observed in both mice and humans, the cellular and molecular pathways that limit the inflammatory response in scWAT or exacerbate it in eWAT remain incompletely understood. This is an important question to address because studies dating back half a century have demonstrated that increases in visceral, but not subcutaneous, fat mass is associated with a higher risk of metabolic disease in humans. Although a number of cell types and molecules that contribute to adipose tissue inflammation have been identified, three fundamental questions remain unanswered. First, is the susceptibility of eWAT or the resistance of scWAT to developing obesity-associated inflammation an intrinsic property of adipocytes or do adipocyte extrinsic factors also contribute to depot specific inflammatory responses? Second, what factors restrain or limit the recruitment of inflammatory cells into obese scWAT? Third, what controls the susceptibility of eWAT to developing metabolic inflammation? In this application, we will elucidate adipocyte extrinsic factors that regulate susceptibility or resistance of eWAT or scWAT, respectively, to diet-induced inflammation, and the mechanisms by which these pathways contribute to the pathogenesis of obesity-induced metabolic dysfunction. This will be accomplished by employing an interdisciplinary approach that encompasses mouse genetics, molecular and cellular biology, immunology, and metabolism. The completion of these studies will address a central question in the area of type 2 diabetes, fill an important gap in our knowledge, and significantly advance our understanding of how depot-specific functions of WAT are regulated during obesity.

 描述（由适用提供）：在小鼠和人类中，低度慢性炎症已成为肥胖，胰岛素抵抗和心血管疾病之间的潜在联系。例如，在白色脂肪组织（WAT）的各种炎症细胞因子和趋化因子中，肥胖会导致肥胖升高（2-4倍）。组织炎症的这种增加，主要是在募集和激活先天和适应性免疫球的募集和激活中，主要在内脏WAT（小鼠的附属WAT（EWAT））中观察到的。相反，肥胖的皮下WAT（SCWAT）似乎对组织感染的发展具有抵抗力。尽管在小鼠和人类中都观察到SCWAT对饮食诱导的感染的这种抗性，但限制SCWAT或EWAT中炎症反应的细胞和分子途径仍未完全理解。这是一个重要的问题要解决的问题，因为可以追溯到半个世纪的研究表明，内脏（但不是皮下）的增加，脂肪质量与人类代谢疾病的风险更高有关。尽管已经确定了有助于脂肪组织注射的许多细胞类型和分子，但仍未解决三个基本问题。首先，EWAT的敏感性或SCWAT对发展肥胖相关感染的抗性是脂肪细胞的内在特性还是脂肪细胞外在因素也有助于沉积特定的炎症反应？第二，哪些因素限制或限制炎症细胞募集到肥胖的SCWAT中？第三，是什么控制EWAT对发展代谢感染的敏感性？在此应用中，我们将阐明分别调节EWAT或SCWAT易感性或耐药性的脂肪细胞外部因素，对饮食诱发的炎症以及这些途径有助于肥胖诱导的代谢功能障碍的发病机理的机制。这将通过采用跨学科方法来实现，该方法包括小鼠遗传学，分子和细胞生物学，免疫学和代谢。这些研究的完成将解决2型糖尿病领域的一个核心问题，填补我们所知的重要空白，并显着促进我们对肥胖期间如何调节WAT功能的理解。