Thursday, December 26, 2024
12/26/2024
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.
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