ADIPOSE TISSUE MACROPHAGE PHENOTYPE AND FUNCTION

脂肪组织巨噬细胞表型和功能

基本信息

批准号：
9924516
负责人：
Anthony W Ferrante
金额：
$ 48.08万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-15 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9924516
关键词：
Acid Lipase Adipocytes Adipose tissue Affect Apoptotic Biogenesis Biological Assay Biological Response Modifiers Catabolism Catecholamines Cells Clinical Data Development Dyslipidemias Fatty acid glycerol esters Functional disorder Funding Glycerol Goals Grant Health Heart Hematopoietic Homeostasis Human Hydrolysis Immune Immune system Impairment In Vitro Inflammation Inflammatory Insulin Lead Link Lipase Lipids Lipoatrophy Lipolysis Liver Lysosomes Maintenance Mediating Metabolism Modeling Mus Mutation Non-Insulin-Dependent Diabetes Mellitus Nonesterified Fatty Acids Obese Mice Obesity Obesity associated disease Pancreas Pathway interactions Phenotype Play Production Publishing Rodent Role Signal Transduction Skeletal Muscle Source Techniques Testing Therapeutic Thermogenesis Thinness Tissue Differentiation Tissues Triglycerides Vascularization Work base carbohydrate metabolism combat exosome immune function immunoregulation in vivo insulin sensitivity insulin signaling lipid biosynthesis lipid metabolism macrophage non-alcoholic fatty liver disease novel precursor cell preservation prevent public health relevance recruit restoration uptake

项目摘要

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.

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功能受到干扰，脂质在非脂肪细胞中积聚，损害全身代谢并改变关键组织的功能，包括肝脏、心脏、骨骼肌和胰腺。尽管我们了解调节脂肪细胞中脂肪分解和脂肪生成的典型途径，但这些因素有助于脂肪组织脂质稳态的因素尚未完全确定。在我们努力了解非脂肪组织中免疫细胞的炎症功能，我们最近发现除了典型的通过中性脂肪酶释放脂质，脂肪细胞在富含甘油三酯的外泌体中释放脂质，这些脂质被脂肪组织巨噬细胞（ATM）并在溶酶体中分解代谢。这笔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，对脂肪细胞功能做出反应并做出贡献。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发挥作用损害胰岛素信号传导，从而扰乱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性功能，事实上，其他人也具有研究表明，ATM 参与脂肪组织分化、产热和血管化。在当前的资助周期中，我们发现肥胖不仅增加了 ATM 的数量，而且增加了它们的数量。中性脂质的摄取和溶酶体依赖性分解代谢。当我们调查 ATM 脂质的来源时，我们毫不意外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，ATM 中的脂质积累不需要中性脂肪酶介导的经典脂肪分解途径。相反，脂肪细胞释放富含甘油三酯的外泌体既可以为 ATM 提供脂质，又可以诱导 ATM 的分化。这就建立了外泌体作为脂肪组织脂质代谢的组成部分和免疫功能的调节剂。基于我们的根据初步数据和之前的临床和小鼠研究，我们提出脂肪细胞衍生的外泌体和 ATM 是正常脂肪组织维持和功能所需的脂质循环的必要组成部分。本申请中提出的工作将描述这些外泌体的特征，它们如何影响 ATM 招募和分化，以及 ATM 是否需要局部溶酶体水解脂质来预防脂肪萎缩。