ADIPOSE TISSUE MACROPHAGE PHENOTYPE AND FUNCTION

脂肪组织中的脂质稳态是全身代谢的关键决定因素。当效率 脂肪细胞储存或释放甘油三酯的机制受到干扰，脂质在非脂肪细胞中积累， 系统代谢和改变关键组织的功能，包括肝脏、心脏、骨骼肌和胰腺。 尽管我们了解脂肪细胞中调节脂解和脂肪生成的典型途径， 对脂肪组织中脂质稳态有贡献。在我们努力了解非- 我们最近发现，除了典型的脂肪组织中的免疫细胞的炎症功能， 通过中性脂肪酶释放脂质，脂肪细胞在富含磷脂酰胆碱的外泌体中释放脂质， 脂肪组织巨噬细胞（ATM）和分解代谢的溶酶体。 这项资助支持的研究最初确定了免疫细胞，特别是巨噬细胞， 脂肪组织的重要组成部分，对脂肪细胞的功能作出反应和贡献。由于这些 最初的观察大多数研究都集中在免疫细胞的炎症作用以及它们如何 损害胰岛素信号传导，从而干扰全身脂质和碳水化合物代谢。我们假设 ATM具有正常脂肪组织代谢所必需的适应功能，事实上，其他ATM具有 表明ATM参与脂肪组织分化、产热和血管化。 在当前的资金周期中，我们发现肥胖不仅增加了自动取款机的数量， 中性脂质的摄取和溶酶体依赖性catalysis。当我们调查ATM脂质的来源时，我们 不出意料地发现几乎所有的脂质都是脂肪细胞衍生的。然而，令人惊讶的是， 不需要中性脂肪酶介导的典型脂肪分解途径。相反，脂肪细胞释放 富含磷脂酰肌醇的外泌体，既为ATM提供脂质又诱导ATM分化。这建立 外泌体作为脂肪组织脂质代谢的组分和免疫功能的调节剂。基于我们 根据初步数据和先前的临床和鼠研究，我们提出脂肪细胞来源的外泌体和 ATM是正常脂肪组织维持和功能所需的脂质循环中的必要组分。 本申请中提出的工作将表征这些外泌体，它们如何影响ATM募集， 分化，以及是否需要ATM对脂质的局部溶酶体水解来防止脂肪萎缩。

Lipid homeostasis in adipose tissue is a critical determinant of whole body metabolism. When the efficiency with which adipocytes store or release triglycerides is perturbed, lipids accumulate in non-adipocytes, impairing systemic metabolism and altering the function of key tissues, including liver, heart, skeletal muscle and pancreas. Despite our understanding of canonical pathways that regulate lipolysis and lipogenesis in adipocytes, the factors that contribute to lipid homeostasis in adipose tissue are incompletely defined. In our efforts to understand non- inflammatory function of immune cells in adipose tissue, we have recently discovered that in addition to canonical release of lipids via neutral lipases, adipocytes release lipid in triglyceride-rich exosomes which are taken up by adipose tissue macrophages (ATMs) and catabolized in lysosomes. Studies supported by this grant originally identified immune cells, and in particular macrophages, as important components of adipose tissue that respond to and contribute to adipocyte function. Since these original observations most studies have focused on the inflammatory roles of immune cells and how they can impair insulin signaling, and thereby perturb systemic lipid and carbohydrate metabolism. We have hypothesized that ATMs have adaptive functions necessary for normal adipose tissue metabolism and indeed, others have shown that ATMs participate in adipose tissue differentiation, thermogenesis and vascularization. During the current funding cycle we found that obesity increases not only the number of ATMs but their uptake and lysosomal-dependent catabolism of neutral lipid. As we investigated the source of ATM lipid, we found not unexpectedly nearly all the lipid is adipocyte derived. However, surprisingly lipid accumulation in ATMs does not require the canonical lipolytic pathway mediated by neutral lipases. Instead, adipocytes release triglyceride-rich exosomes that both provide lipid to and induce differentiation of ATMs. This establishes exosomes as components of adipose tissue lipid metabolism and regulators of immune function. Based on our preliminary data and previous clinical and murine studies, we propose that adipocyte-derived exosomes and ATMs are necessary components in a lipid cycle required for normal adipose tissue maintenance and function. The work proposed in this application will characterize these exosomes, how they affect ATM recruitment and differentiation, and whether local lysosomal hydrolysis of lipid by ATMs is required to prevent lipoatrophy.