Adipose Tissue Macrophage Phenotype and Function

脂肪组织有效储存和释放脂肪的能力对哺乳动物维持新陈代谢至关重要 健康。在脂肪细胞储存甘油三酯受到损害的情况下，脂质在非脂肪细胞中异位聚集 脂肪细胞，与常见的全身疾病有关，包括2型糖尿病、非酒精性脂肪肝 疾病、感染易感性、动脉粥样硬化、痴呆症和自身免疫性疾病。尽管 通过脂肪分解和脂肪酸和碳水化合物的摄取调节全身脂类释放的途径 脂肪生成由来已久，并得到了很好的研究，我们对脂肪局部脂肪动态平衡的理解是 很大程度上是未被开发的。最初由该基金资助的研究发现，巨噬细胞和其他免疫细胞 脂肪组织中蓄积对代谢状态变化的反应以及脂肪组织巨噬细胞 具有独特的表型和处理和代谢脂质的能力。在研究脂肪中脂肪的来源 组织巨噬细胞，我们发现了脂肪细胞释放脂肪的不依赖于脂肪酶的途径，在该途径中，酰基- 甘油三酯被结合到细胞外小泡(AdExos)中，并以较高的速度释放，这与 脂肪组织巨噬细胞含量和脂解作用。在当前的资金周期中，我们公布了这些发现 并描述了AdExos生物学的基本方面，包括它们在脂肪细胞中的释放速度和通过 肥胖，ATM通过巨噬细胞吞噬而摄取，诱导骨髓趋化的能力 并激活正宗自动取款机典型的脂类代谢程序。根据这些发现，我们 假设AdExos是脂肪和中枢神经系统代谢和免疫系统之间的关键接口 脂肪组织中脂质动态平衡的成分。在目前的提案中，我们着手确定是否 AdExos调节单核细胞来源和常驻ATM的募集、分化和增殖 单核细胞来源的ATM和常驻ATM对AdExo的不同反应是否解释了 炎症和营养表型，确定脂解本身是否驱动AdExo的产生，并测试 AdExos中脂类的ATM水解有助于脂肪组织中的脂类循环。

The ability of adipose tissue to efficiently store and release lipid is critical for mammals to maintain metabolic health. In conditions when triglyceride storage by adipocytes is impaired lipid accumulates ectopically in non- adipocytes and is associated with common systemic disorders including type 2 diabetes, non-alcoholic fatty liver disease, susceptibility to infections, atherosclerosis, dementia and autoimmune disorders. Although the pathways that regulate systemic release of lipids via lipolysis and the uptake of fatty acids and carbohydrates for lipogenesis have long been known and are well studied, our understanding of local lipid homeostasis in fat is largely unexplored. Studies originally funded by the grant found that macrophages and other immune cells accumulate in adipose tissue in response to changes in metabolic state and that the adipose tissue macrophages have a unique phenotype and ability to handle and metabolism lipid. In studying the source of lipid in adipose tissue macrophages, we discovered a lipase-independent pathway of lipid release by adipocytes, in which acyl- glycerides are incorporated into extracellular vesicles (AdExos) and released at a high rate that correlates with adipose tissue macrophage content and lipolysis. During the current funding cycle we published these findings and described basic aspects of AdExos biology including their rate of release by adipocytes and regulation by adiposity, uptake by ATMs via macropinocytosis, ability to induce chemotaxis in bone marrow derived macrophages and to activate a program of lipid metabolism typical of authentic ATMs. From these findings we hypothesize AdExos are the key interface between the metabolic and immune systems in fat and a central component of lipid homeostasis in adipose tissue. In the current proposal, we set out to determine whether AdExos regulate the recruitment, differentiation and proliferation of monocyte-derived and resident ATMs, test whether the differential response to AdExo of monocyte derived and resident ATMs account for differences in inflammatory and trophic phenotypes, determine whether a lipolysis per se drives AdExo production and test if ATM hydrolysis of lipids in AdExos contribute to a lipid cycle in adipose tissue.