Aging-Dependent Changes in Adipose Tissue

摘要 白色脂肪组织（WAT）是一种代谢活性器官，具有适应性，并在整个过程中发生变化 人类的寿命而脂肪细胞的数量可以通过在基质血管中募集前体细胞而增加， 为了确定WAT的SVF分数（SVF）以分化成脂肪细胞，WAT中脂肪细胞的总数主要设定为 在青春期，因此WAT质量的变化，肥胖，主要反映了脂质储存的变化。在 肥胖，WAT可能变得严重功能失调，不能适当地膨胀以储存多余的能量， 导致其它组织中的异位脂肪沉积和脂毒性。脂肪细胞WAT的不健康扩张 肥大（增加细胞大小）也可能导致有害的影响，如胰岛素抵抗和2型糖尿病。 糖尿病此外，SVF群体可能会发生急剧变化，并成为疾病的促成因素 进展因此，保持白色脂肪组织与脂肪细胞肥大和 增生（细胞数量增加）对全身代谢和能量平衡很重要。总的来说， WAT分为皮下（SAT）或内脏（VAT）脂肪组织。SAT提供绝缘 和缓冲，并作为一个长期的能量储存库。增值税缓冲和保持距离 在器官之间，并且在摄食过多期间对脂质储存至关重要。虽然VAT与病理性 在某些疾病中，如胰岛素抵抗和心血管疾病，SAT可以预防这些疾病。 在老龄化过程中，增值税趋于增加，而SAT显着下降。增值税扩张发生在脂质储存 从SAT转移到VAT，内脏脂肪细胞肥大增加。然而， 衰老过程中代谢保护性SAT质量的减少更加难以捉摸。虽然 VAT和SAT的发育起源和功能是不同的，一般来说，增殖和 每个贮库中的脂肪前体细胞（APC）的分化能力被认为急剧下降 在老化过程中。我最近报道了衰老依赖性调节细胞（ARC）的出现和积累， 作为一个独特的亚群SAT在老化过程中。ARC来源于APC，但分化受损 并表达高水平的促炎细胞因子。 通过分泌细胞因子，如Ccl6、ARC 抑制邻近真正的APC的增殖和分化。因此，ARC的出现是 负责脂肪前体的急剧减少和脂肪形成的缺陷，导致损失的脂肪， 在老化过程中。有趣的是，转录因子PU.1是SAT中ARC发展的驱动因素 在老化过程中。虽然我已经表明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， 拟议的研究将是：1）确定PU.1改变ARC中基因表达的机制， 2)表征PU.1对体内SAT功能的作用。

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.