Dissecting the thermogenic adipose niche

项目概要/摘要 脂肪组织在调节全身能量代谢中起着关键作用， 与几种常见的代谢性疾病的病因直接相关，如2型糖尿病 和心血管疾病。有几个不同的脂肪库分散在整个身体。白色 脂肪组织（WAT）是甘油三酯储存的主要部位。相反，产热脂肪， 由经典的棕色脂肪组织（BAT）和可诱导的米色/棕色脂肪组成，专门用于产热 能量消耗在人类中，具有可检测到的BAT的个体具有显著较低的 心脏代谢疾病，指出BAT的代谢益处和治疗前景。产热 脂肪组织可以通过调节细胞组成和细胞- 与细胞的相互作用这种适应是维持代谢健康的关键。细胞间通讯 产热脂肪生态位协调脂肪组织发育并在脂肪发育中起重要作用 组织更新、扩张和重塑以响应外部刺激。解剖复杂的细胞 组成的产热脂肪，我们进行了单细胞RNA测序分析BAT从小鼠圈养在 不同温度结果显示，产热脂肪生态位的高度异质性， 冷暴露引起BAT细胞组成的动态变化。重要的是，我们发现了一个 来源于血管平滑肌的新型脂肪祖细胞（APC）群体 (VSM)谱系和独特表达的Trpv 1（瞬时受体电位阳离子通道亚家族V成员 1）。谱系追踪研究表明，表达Trpv 1的VSM-APCs可以增殖， 对冷刺激作出反应，分化成高度产热的脂肪细胞。正在进行的工作表明， 表达Trpv 1的APC的脂肪形成分化受损导致产热因子表达减少。 BAT和WAT中的基因，表明这些细胞在体温调节中的重要作用。补充初步 结果表明，表达Trpv 1的APC能对局部信号作出反应，并分化为产热细胞， 脂肪细胞这些令人兴奋的发现使我们提出了一个涉及细胞间通讯的模型， APC和诱导信号之间的相互作用塑造了脂肪细胞的分化和功能。在这 我们将通过确定表达Trpv 1的APC的生理作用来检验这一假设， 代谢调节，鉴定Trpv 1阳性APC的内源性和外源性刺激，以及作图 使用计算工具和空间转录组学研究生热脂肪生态位的细胞相互作用组 分析.成功完成拟议的研究将提供新的见解细胞间的作用， 在调节脂肪组织发育和功能的通讯。

Project Summary/Abstract Adipose tissue plays a critical role in the regulation of whole-body energy metabolism, and adipose dysfunction directly links to the etiology of several commonly seen metabolic diseases, such as type 2 diabetes mellitus and cardiovascular diseases. There are several different adipose depots dispersed throughout the body. White adipose tissue (WAT) is the primary site of the triglyceride storehouse. In contrast, thermogenic fat, which consists of classical brown adipose tissue (BAT) and inducible beige/brite fat, is specialized for thermogenic energy expenditure. In humans, individuals with detectable BAT have a significantly lower prevalence of cardiometabolic diseases, pointing to the metabolic benefits and therapeutic promise of BAT. Thermogenic adipose tissue can rapidly respond to environmental challenges by modulating cellular compositions and cell- to-cell interactions. Such adaptation is key to maintaining metabolic health. Intercellular communications within the thermogenic adipose niche orchestrate adipose tissue development and play an essential role in adipose tissue turnover, expansion, and remodeling in response to external stimuli. To dissect the complex cellular makeup of thermogenic fat, we performed single-cell RNA-sequencing analysis of BAT from mice housed at different temperatures. The results revealed a high degree of heterogeneity of thermogenic adipose niche and showed cold exposure induced dynamic changes of cellular composition in BAT. Importantly, we identified a novel population of adipose progenitor cells (APCs), which was derived from the vascular smooth muscle (VSM) lineage and uniquely expressed Trpv1 (transient receptor potential cation channel subfamily V member 1). Lineage tracing studies demonstrated that the Trpv1-expressing VSM-APCs could proliferate and differentiate into highly thermogenic adipocytes in response to cold stimulation. Work in progress showed that impaired adipogenic differentiation of Trpv1-expressing APCs resulted in reduced expression of thermogenic genes in BAT and WAT, suggesting an important role of these cells in thermoregulation. Additional preliminary data showed that the Trpv1-expressing APCs could respond to local signals and differentiate into thermogenic adipocytes. These exciting findings have led us to propose a model involving intercellular communications in which interplays between the APCs and inductive signals shapes adipocyte differentiation and function. In this proposal, we will test this hypothesis by determining the physiological role of the Trpv1-expressing APCs in metabolic regulation, identifying the endogenous and exogenous stimuli of Trpv1-positive APCs, and mapping the cellular interactome of the thermogenic adipose niche using computational tools and spatial transcriptomic analysis. Successful completion of the proposed studies will provide new insight into the role of intercellular communications in the regulation of adipose tissue development and function.