Ribosome biogenesis regulates adipocyte function

项目摘要 功能性白色脂肪组织(WAT)在代谢紊乱的病因学中起着核心作用 包括糖尿病和代谢综合征。然而，并不是所有肥胖的脂肪组织都是 与病理变化相关的。个人似乎有一个功能设定的限制，超过这个限制 无法正常运行。识别这种控制设定点的机制或因素是非常重要的 利息。鉴于动态平衡蛋白质合成作为一种基本细胞功能的重要性，我们假设 健康脂肪细胞的功能调节也应该包括蛋白质的变态适应 合成的目的是尽可能长时间地维持更大的细胞体和脂肪因子的分泌需求， 特别是在新陈代谢具有挑战性的条件下。在这项提议中，假设 适应性核糖体的生物发生可能决定脂肪细胞功能稳态的最大限度。 PTRF(Cavin-1)最初被克隆为“聚合酶I和转录释放因子”。初步数据 这里显示了PTRF在功能上定位于细胞核，并在调节 核糖体DNA转录效率。为了研究分子机制的细节，提出了3个目标： Aim-1，定义PTRF、核糖体生物发生和脂肪细胞功能调节途径；Aim-2，至 了解该通路如何调节PTRF的细胞定位；以及Aim-3，探索 这些观察结果的生理学相关性。通过使用全面的细胞培养和小鼠模型， 对这一提议的研究不仅将阐明这种调控的分子机制细节 途径，也为改善脂肪细胞的动态平衡和质量提供了潜在的治疗靶点 控制人类肥胖和糖尿病。

Project Summary Dysfunctional white adipose tissue (WAT) plays a central role in the etiology of metabolic disorders including diabetes and metabolic syndromes. However, not all obese adipose tissue is necessarily associated with pathological changes. Individuals seem to have a functional set limit beyond which WAT fails to function properly. Identification of such mechanisms or factors that control the set point is of great interest. Given the importance of a homeostatic protein synthesis as a basic cellular function, it is postulated that the healthy adipocyte's functional regulation should also incorporate allostatic adaptions of protein synthesis aiming to maintain larger cellular body and adipokine secretion demands as long as possible, particularly under metabolically challenging conditions. In this proposal it is hypothesized that the capacity of adaptational ribosome biogenesis may determine the maximal limit of adipocyte functional homeostasis. PTRF (Cavin-1) was original cloned as "polymerase I and transcription release factor". The preliminary data here show PTRF functionally localizing in the nucleus and playing a critical role on the regulation of ribosomal DNA transcription efficiency. To study the details of molecular mechanisms, 3 aims are proposed: Aim-1, to define the PTRF, ribosome biogenesis and adipocyte function regulatory pathway; Aim-2, to understand how this pathway regulates the cellular localization of PTRF; and Aim-3, to explore the physiological relevance of these observations. By using comprehensive cell culture and mouse models, the studies from this proposal will not only shed light on the molecular mechanistic details of this regulatory pathway but also provide potential therapeutic targets for improving adipocyte homeostasis and quality control in human obesity and diabetes.