Turnover of Adipose Tissue Macrophages

脂肪组织巨噬细胞的周转

• 批准号: 8907658
• 负责人: Alyssa H Hasty
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8907658
• 关键词: Address; Adipose tissue; Apoptosis; Apoptotic; Biological Models; Blood Vessels; Body Weight decreased; Bone Marrow Transplantation; Cardiovascular Diseases; Cell Death; Cells; Cleaved cell; Contracts; Country; Data; Defect; Development; Diabetes Mellitus; Diet; Employee Strikes; Environment; Eosinophilia; Equilibrium; Event; Excision; Health; Hematopoietic; Homeostasis; Human; Immune; Immune system; Immunofluorescence Immunologic; In Vitro; Inflammation; Inflammatory; Insulin Resistance; Laboratories; Maintenance; Mediating; Metabolic; Metabolic Diseases; Metabolic stress; Modeling; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Pathway interactions; Peptide Hydrolases; Peripheral; Peroxidases; Phenotype; Physiological; Plastics; Prevalence; Process; Proteins; Publishing; Regulation; Reporting; Research Personnel; Resolution; Rodent; Signal Pathway; Staining method; Stains; Technology; Testing; Time; Tissues; Veterans; Weight Gain; Western Blotting; Woman; cardiovascular risk factor; caspase-3; energy balance; eosinophil; glucose tolerance; human subject; improved; in vivo Model; insulin sensitivity; interest; macrophage; men; monocyte; mouse model; novel; nuclease; pro-apoptotic protein; research study; sex; subcutaneous; trend

DESCRIPTION (provided by applicant): The progressive recruitment of macrophages to adipose tissue (AT) is a hallmark of diet-induced obesity and is thought to be key for the development of insulin resistance both in AT and peripheral tissues. Because of the importance of AT macrophage (ATM) accumulation most investigators in the field have focused almost exclusively on the molecular mechanisms mediating their recruitment. However, AT is one of the most plastic tissues in the body, with the capacity to expand and contract dramatically during positive and negative energy balance. It was therefore reasoned that ATM accumulation is likely to be a dynamic event reflecting a balance of ATM recruitment, retention, and removal. This led to the consideration that the accelerated accumulation of macrophages in AT during its expansion might in fact primarily reflect a defect in ATM removal rather than simply reflecting increased recruitment. In this application exciting new preliminary data is presented showing that ATM cell death may be an important physiological mechanism mediating ATM turnover and contributing to AT homeostasis during weight loss. First, Western blot analysis shows that apoptosis markers are lower in macrophage-enriched SVFs of AT from obese compared to lean mice. Second, immunofluorescence staining demonstrates decreased TUNELpos;F4/80pos (apoptotic macrophages) in obese compared to lean AT. The higher levels of apoptosis in lean ATMs suggest that ATM cell death may be a physiologically regulated process in lean AT that becomes impaired during obesity. In support of the concept that ATM turnover is regulated, our data demonstrate that ATM apoptosis is "restored" during weight loss. These novel observations have led us to consider the possibility that apoptosis is essential to ATM turnover and removal to maintain healthy AT. Thus, the hypothesis to be tested in this application is: apoptosis contributes to the homeostatic maintenance of macrophage numbers in AT. Implicit within this hypothesis is that a decrease in ATM turnover during weight gain occurs in parallel with increased recruitment of new macrophages and may contribute to the retention of macrophages within AT during obesity. This hypothesis is striking in that it focuses on recruitment-independent mechanisms for ATM accrual in obesity. Our studies will address a critical void in the current understanding of mechanisms by which the immune system responds to the metabolic stresses incurred during weight gain and loss. Our hypothesis will be tested in the following aims: Specific Aim 1: To determine the temporal and spatial regulation of ATM apoptosis. We hypothesize that ATM apoptosis is impaired during positive energy balance and restored during negative energy balance. Specific Aim 2: To determine whether eosinophils regulate ATM apoptosis. We hypothesize that eosinophils regulate the apoptosis and turnover of ATMs. Specific Aim 3: To determine the physiological consequences of impaired ATM apoptosis. We hypothesize that inhibition of macrophage apoptosis will result in increased ATM content as well as local and systemic IR.

描述（由申请人提供）： 巨噬细胞逐渐募集至脂肪组织 (AT) 是饮食引起的肥胖的标志，并且被认为是 AT 和外周组织中胰岛素抵抗发展的关键。由于 AT 巨噬细胞 (ATM) 积累的重要性，该领域的大多数研究人员几乎完全专注于介导其募集的分子机制。然而，AT 是体内可塑性最强的组织之一，在正能量和负能量平衡期间能够急剧膨胀和收缩。因此，ATM 积累可能是一个动态事件，反映了 ATM 招募、保留和移除的平衡。这导致人们认为，AT 扩张过程中巨噬细胞的加速积累实际上可能主要反映了 ATM 去除的缺陷，而不是简单地反映了招募的增加。在本申请中，提出了令人兴奋的新初步数据，表明 ATM 细胞死亡可能是介导 ATM 周转并有助于减肥过程中 AT 稳态的重要生理机制。首先，蛋白质印迹分析表明，与瘦小鼠相比，肥胖小鼠 AT 中富含巨噬细胞的 SVF 的凋亡标记物较低。其次，免疫荧光染色表明，与瘦 AT 相比，肥胖者的 TUNELpos;F4/80pos（凋亡巨噬细胞）减少。瘦 ATM 中较高水平的细胞凋亡表明，ATM 细胞死亡可能是瘦 AT 中的一个生理调节过程，在肥胖期间会受到损害。为了支持 ATM 周转受到调节的概念，我们的数据表明 ATM 细胞凋亡在减肥过程中“恢复”。这些新的观察结果使我们考虑细胞凋亡对于 ATM 周转和清除以维持健康的 AT 至关重要的可能性。因此，本申请中要测试的假设是：细胞凋亡有助于AT中巨噬细胞数量的稳态维持。这一假设隐含的是，体重增加期间 ATM 周转率的减少与新巨噬细胞招募的增加同时发生，并且可能有助于肥胖期间巨噬细胞在 AT 内的保留。这一假设引人注目，因为它关注肥胖中 ATM 累积的独立于招募的机制。我们的研究将解决目前对免疫系统对体重增加和减少期间产生的代谢应激作出反应的机制的理解中的一个关键空白。我们的假设将在以下目标中得到检验： 具体目标 1：确定 ATM 细胞凋亡的时间和空间调节。我们假设 ATM 细胞凋亡在正能量平衡期间受损，并在负能量平衡期间恢复。具体目标 2：确定嗜酸性粒细胞是否调节 ATM 细胞凋亡。我们假设嗜酸性粒细胞调节 ATM 的凋亡和周转。具体目标 3：确定 ATM 细胞凋亡受损的生理后果。我们假设抑制巨噬细胞凋亡将导致 ATM 含量以及局部和全身 IR 增加。