Dissecting the thermogenic adipose niche

项目摘要/摘要 脂肪组织在调节全身能量代谢和脂肪功能障碍中起着关键作用。 直接与几种常见代谢性疾病的病因学有关，如2型糖尿病 和心血管疾病。人体内有几个不同的脂肪储存库。白色 脂肪组织(WAT)是甘油三酯储存库的主要部位。相比之下，发热性脂肪，它 由经典的棕色脂肪组织(BAT)和诱导性米色/褐褐色脂肪组成，专门用于产热 能源支出。在人类中，携带可检测到的蝙蝠的人患上BAT的几率明显较低 心脏代谢性疾病，指出了BAT的新陈代谢益处和治疗前景。生热 脂肪组织可以通过调节细胞组成和细胞- 细胞间的相互作用。这种适应是维持新陈代谢健康的关键。内部的细胞间通信 生热脂肪生态位协调脂肪组织的发育，并在脂肪中发挥重要作用 组织更新、扩张和重塑对外界刺激的反应。解剖复杂的细胞 我们进行了BAT的单细胞RNA测序分析，这些BAT来自于 不同的温度。结果表明，生热脂肪生态位具有高度的异质性。 显示了冷暴露引起蝙蝠细胞成分的动态变化。重要的是，我们确定了一个 血管平滑肌来源的脂肪前体细胞的新群体 (VSM)谱系及其独有表达的TRPV1(瞬时受体电位阳离子通道V亚家族成员 1)。谱系追踪研究表明，表达TRPV1的VSM-APC可以增殖并 在冷刺激下分化为高产热脂肪细胞。正在进行的工作表明， 表达TRPV1的APC成脂分化受阻导致生热基因表达减少 BAT和WAT中的基因，表明这些细胞在体温调节中起着重要作用。额外的初步报告 数据表明，表达TRPV1的APC能够对局部信号做出反应，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信的模型 APC和诱导信号之间的相互作用决定了脂肪细胞的分化和功能。在这 建议，我们将通过确定TRPV1表达的APC在 代谢调节，识别TRPV1阳性APC的内源性和外源性刺激，并定位 利用计算工具和空间转录技术研究生热脂肪生态位的细胞互动组 分析。拟议研究的成功完成将为细胞间的作用提供新的见解 在调节脂肪组织发育和功能方面的通讯。

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.