Adipocyte-derived exosomes in macrophage regulation

项目摘要 肥胖是一种常见的疾病，与不良的健康结果有关， 这些病理是由脂肪组织在细胞和分子水平上的功能障碍和失调介导的， 水平脂肪组织含有独特的巨噬细胞群（脂肪组织巨噬细胞，或ATM）。 这些ATM在肥胖中积累并介导脂肪组织中的许多关键过程和病理， 包括脂质处理、炎症和胰岛素抵抗。存在多种ATM人群：一种组织- 常驻的抗炎群体是卵黄囊胚胎造血祖细胞的后代， 在任何时候都存在;促炎群体来源于成人中循环的单核细胞前体 并且在代谢应激如肥胖的条件下被招募。外泌体很小，分泌， 内体衍生的膜结合的细胞外囊泡。脂肪细胞组成性地释放含脂质的 外泌体（脂肪细胞来源的外泌体，或AdExos），并且它们的分泌速率在状态期间增加 ATM积累增加，包括肥胖和急性禁食。AdExos也可以充当巨噬细胞 趋化因子和驱动骨髓源性巨噬细胞向ATM样细胞重编程 转录和表型同一性。然而，许多问题涉及的全面范围和影响， AdExos仍然没有解决。我们假设AdExos调节了细胞内蛋白质的积累和分化， 巨噬细胞在脂肪组织中通过规范已知的调节ATM的途径。鉴于AdExo 在单核细胞募集和ATM募集发生的条件下， AdExos直接作为巨噬细胞趋化因子，并驱动单核细胞趋化因子的产生。 我们认为AdExos调节单核细胞向脂肪组织的募集。要求1 试图通过监测直接AdExo注射对 单核细胞的化学吸引和积聚。之前的工作研究了AdExos对 骨髓源性巨噬细胞的鉴别，但不是更相关的前体，如卵黄囊 造血祖细胞和外周单核细胞。目标2旨在测试祖细胞之间的关系 细胞身份和AdExo暴露对细胞命运的影响。虽然我们已经确定AdExos可以发挥作用， 在ATM招募和ATM身份中的作用，我们不知道管理这些行为的机制。 目的3旨在测试已知的途径是否规范地调节ATM分化和身份，如 CCR 2轴和PPARG也分别负责AdExo介导的这些调节。 在ATM机上。

Project Summary Obesity is a common condition that is associated with poor health outcomes, and a significant portion of these pathologies are mediated by dysfunction and dysregulation of adipose tissue at a cellular and molecular level. Adipose tissue contains a unique population of macrophages (adipose tissue macrophages, or ATMs). These ATMs accumulate in obesity and mediate a number of key processes and pathologies in adipose tissue, including lipid handling, inflammation, and insulin resistance. Multiple populations of ATMs exist: a tissue- resident, anti-inflammatory population is descended from yolk sac embryonic hematopoietic progenitors and is present at all times; a pro-inflammatory population is derived from circulating monocyte precursors in adults and is recruited under conditions of metabolic stress such as obesity. Exosomes are small, secreted, endosome-derived, membrane-bound extracellular vesicles. Adipocytes constitutively release lipid-containing exosomes (adipocyte-derived exosomes, or AdExos), and the rate of their secretion is increased during states of increased ATM accumulation, including obesity and acute fasting. AdExos can also act as macrophage chemoattractants and drive reprogramming of bone marrow-derived macrophages toward an ATM-like transcriptional and phenotypic identity. However, many questions regarding the full scope and effects of AdExos remain unaddressed. We hypothesize that AdExos regulate the accumulation and differentiation of macrophages in adipose tissue via pathways canonically known to regulate ATMs. Given that AdExo production is increased in conditions during which monocyte recruitment and ATM recruitment occurs, and that AdExos both act directly as macrophage chemoattractants and drive production of monocyte chemoattractant factors in adipose tissue, we believe that AdExos regulate monocyte recruitment to adipose tissue. Aim 1 seeks to establish this role in an in vivo setting by monitoring the effect of direct AdExo injection on chemoattraction and accumulation of monocytes. Previous work has examined the effect of AdExos on the identity of bone marrow-derived macrophages, but not more relevant precursors such as yolk sac hematopoietic progenitors and peripheral monocytes. Aim 2 seeks to test the relationship between progenitor cell identity and the effect of AdExo exposure on cell fate. While we have established that AdExos may play a role in both ATM recruitment and ATM identity, we do not know the mechanisms that govern these actions. Aim 3 seeks to test whether pathways known to canonically regulate ATM differentiation and identity, like the CCR2 axis and PPARG, respectively, are also responsible for the AdExo-mediated regulation of these processes in ATMs.