Aging-Dependent Changes in Adipose Tissue

脂肪组织的衰老依赖性变化

• 批准号: 10536237
• 负责人: Frances Lin
• 金额: $ 4.29万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10536237
• 关键词: ATAC-seq; Ablation; Adipocytes; Adipose tissue; Adolescence; Age; Aging; Area; Automobile Driving; Binding; Binding Sites; Biological Assay; Blood Vessels; Cardiovascular Diseases; Cell Count; Cell Proliferation; Cell Size; Cells; ChIP-seq; Chromatin; Defect; Deposition; Development; Disease; Disease Progression; Equilibrium; Exhibits; Family; Fatty acid glycerol esters; Fibroblasts; Future; Gene Expression; Generations; Genetic Transcription; Glucose tolerance test; Health; Hematopoietic; Human; Hyperphagia; Hyperplasia; Hypertrophy; Impairment; Insulin Resistance; Knockout Mice; Lead; Lipids; Longevity; Luciferases; Lymphoid; Measures; Mediating; Metabolic; Metabolic Diseases; Metabolism; Mus; Myelogenous; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organ; Pathogenesis; Pathologic; Population; Promoter Regions; Proteins; Reporting; Research; Role; Site; Stromal Change; Structure; T-Lymphocyte; Testing; Therapeutic; Tissues; Visceral; adipocyte differentiation; aged; cell type; chromatin remodeling; conditional knockout; cytokine; energy balance; granulocyte; in vivo; in vivo evaluation; insulin tolerance; lipid biosynthesis; macrophage; novel therapeutics; precursor cell; programs; promoter; recruit; single-cell RNA sequencing; stem cells; subcutaneous; transcription factor; transcriptome

Abstract White adipose tissue (WAT) is a metabolically active organ that is adaptive and undergoes changes throughout the human lifespan. While adipocyte number can increase via recruitment of precursors in the stromal vascular fraction (SVF) of WAT to differentiate into adipocytes, the total number of adipocytes in WAT is set mainly during adolescence, and thus changes in WAT mass, adiposity, mostly reflect alterations in lipid storage. In obesity, WAT may become severely dysfunctional and does not expand properly to store the excess energy, resulting in ectopic fat deposition and lipotoxicity in other tissues. Unhealthy expansion of WAT by adipocyte hypertrophy (increasing cell size) may also result in deleterious effects, such as insulin resistance and type 2 diabetes. In addition, SVF populations may drastically change and be contributing factors towards disease progression. Hence, maintaining white adipose tissue with balance between adipocyte hypertrophy and hyperplasia (increasing cell number) is important for whole-body metabolism and energy balance. In general, WAT is categorized as either subcutaneous (SAT) or visceral (VAT) adipose tissue. SAT provides insulation and cushioning and serves as a long-term energy storage depot. VAT cushions and maintains distance between organs and is critical for lipid storage during hyperphagia. While VAT is associated with pathological conditions, such as insulin resistance and cardiovascular disease, SAT is protective against these diseases. During aging, VAT tends to increase while SAT decreases significantly. VAT expansion occurs as lipid storage is shifted from SAT to VAT and visceral adipocyte hypertrophy increases. However, the explanation behind the decrease in metabolically protective SAT mass during aging has been more elusive. Although the developmental origin and function of VAT and SAT are known to differ, in general, the proliferation and differentiation capacities of adipose precursor cells (APCs) in each depot are believed to drastically decline during aging. I have recently reported that aging-dependent regulatory cells (ARCs) emerge and accumulate as a unique subpopulation of SAT during aging. ARCs arise from APCs but exhibit impaired differentiation capacity and express high levels of proinflammatory cytokines. By secreting cytokines, such as Ccl6, ARCs inhibit the proliferation and differentiation of neighboring bona fide APCs. Thus, the emergence of ARCs is responsible for the drastic decrease in adipose precursors and defects in adipogenesis, resulting in the loss of SAT during aging. Interestingly, the transcription factor PU.1 is the driver for the development of ARCs in SAT during aging. Though I have shown PU.1 to be responsible for the development of ARCs, the exact mechanism by which PU.1 alters the transcriptome of ARCs is currently unknown. Therefore, the objective of the proposed study will be to 1) identify the mechanism by which PU.1 alters gene expression in ARCs and to 2) characterize the role of PU.1 on SAT function in vivo.

抽象的 白色脂肪组织（WAT）是一种代谢活跃的器官，具有适应性并在整个过程中经历变化 人类的寿命。虽然脂肪细胞数量可以通过基质血管中前体细胞的募集来增加 WAT分化为脂肪细胞的分数(SVF)，主要设定WAT中脂肪细胞的总数 青春期期间，WAT 质量和肥胖的变化主要反映了脂质储存的变化。在 肥胖，WAT 可能会严重失调，无法正常扩张以储存多余的能量， 导致其他组织异位脂肪沉积和脂毒性。脂肪细胞 WAT 的不健康扩张 肥大（细胞大小增加）也可能导致有害影响，例如胰岛素抵抗和 2 型糖尿病 糖尿病。此外，SVF 种群可能会发生巨大变化，并成为导致疾病的因素 进展。因此，维持白色脂肪组织与脂肪细胞肥大和脂肪细胞肥大之间的平衡 增生（细胞数量增加）对于全身新陈代谢和能量平衡很重要。一般来说， WAT 分为皮下 (SAT) 或内脏 (VAT) 脂肪组织。 SAT 提供绝缘 和缓冲，并作为长期能量储存库。增值税缓冲并保持距离 器官之间的相互作用，对于进食过多期间的脂质储存至关重要。虽然增值税与病理相关 SAT 可以预防这些疾病。 在老化过程中，VAT 趋于增加，而 SAT 则显着下降。脂质储存导致增值税扩大 从SAT转向VAT，内脏脂肪细胞肥大增加。然而，背后的解释 衰老过程中代谢保护性 SAT 质量的减少更加难以捉摸。虽然 众所周知，VAT 和 SAT 的发育起源和功能是不同的，一般而言，增殖和 人们认为每个储存库中的脂肪前体细胞（APC）的分化能力急剧下降 老化期间。我最近报道了衰老依赖性调节细胞（ARC）的出现和积累 作为衰老过程中 SAT 的一个独特亚群。 ARC 源自 APC，但表现出分化受损 能力并表达高水平的促炎细胞因子。 通过分泌细胞因子，如Ccl6、ARCs 抑制邻近真正 APC 的增殖和分化。因此，ARC的出现 导致脂肪前体急剧减少和脂肪生成缺陷，导致脂肪损失 老化期间的SAT。有趣的是，转录因子 PU.1 是 SAT 中 ARC 发展的驱动力 老化期间。虽然我已经证明 PU.1 负责 ARC 的开发，但确切的 PU.1 改变 ARC 转录组的机制目前尚不清楚。因此，目标是 拟议的研究将是 1) 确定 PU.1 改变 ARC 基因表达的机制并 2)表征PU.1对体内SAT功能的作用。