Molecular control of beige fat heterogeneity

项目总结 新出现的证据表明了米色脂肪的生物学意义，米色脂肪是一种可诱导的生热脂肪细胞， 在调节新陈代谢健康方面。米色脂肪生物生成最著名的刺激因素是冷适应和 随后激活β3-肾上腺素受体(β3-AR)信号通路；然而，最近的研究发现 刺激米色脂肪生物生成的各种外部刺激，如组织损伤和间歇性禁食 通过β3-AR非依赖通路。此外，我们最近的研究发现了一种以前没有特征的 米色脂肪的群体，称为糖酵解米色脂肪细胞(或g-米色脂肪)，其发育 与β3-AR诱导的米色脂肪不同，其调节和来源也不同。 这些结果使我们假设米色脂肪是由发育不同的细胞群体组成的，并且 根据外部线索的性质(例如，寒冷与组织)，每个种群扮演着独特的生物角色 受伤)。然而，检验这一假说的一个技术障碍是缺乏使我们能够靶向 特定的脂肪细胞祖细胞群体。因此，我们采用了单细胞RNA(ScRNA)分析并鉴定了 两种不同的脂肪细胞前体细胞(APC)，它们可以产生冷诱导的米色脂肪细胞(CD81 APC)和 肌源性G-米色脂肪(MyoD APC)。因此，本建议旨在检验上述假设。 通过确定米色脂肪细胞的发育调节、分子机制和生物学功能 来源于CD81 APC和MyoD APC。我们在这项提议中的贡献是提供一个基本的 理解异质性米色脂肪细胞群体如何受生理和免疫调节 病理线索，以及它们如何有助于调节代谢组织的动态平衡，如燃料 氧化、血管生成、神经支配、组织纤维化和炎症。

PROJECT SUMMARY Emerging evidence illuminates the biological significance of beige fat, an inducible form of thermogenic fat cells, in the regulation of metabolic health. The best-known stimulus of beige fat biogenesis is cold acclimation and subsequent activation of the β3-adrenoceptor (β3-AR) signaling pathway; however, recent studies identified a variety of external stimuli, such as tissue injury and intermittent fasting, that stimulate beige fat biogenesis through β3-AR independent pathways. Furthermore, our recent study identified a previously uncharacterized population of beige fat, referred to as glycolytic beige adipocytes (or g-beige fat), whose developmental regulation and origin are distinct from β3-AR-induced beige fat. These results lead us to hypothesize that beige fat is composed of developmentally diverse cell populations, and that each population plays unique biological roles depending on the nature of external cues (e.g., cold vs. tissue injury). A technical hurdle to test the hypothesis, however, is the lack of genetic tools that enable us to target particular adipocyte progenitor populations. Thus, we employed single-cell RNA (scRNA) analysis and identified two distinct adipocyte progenitor cells (APCs) that give rise to cold-induced beige adipocytes (CD81+ APCs) and g-beige fat from a myogenic lineage (MyoD+ APCs). Accordingly, this proposal aims to test the above hypothesis by determining the developmental regulation, molecular mechanisms, and biological function of beige adipocytes stem from CD81+ APCs and MyoD+ APCs. Our contribution in this proposal is to provide a fundamental understanding as to how heterogeneous beige adipocyte populations are regulated by physiological and pathological cues, and how they contribute to the regulation of metabolic tissue homeostasis, such as fuel oxidation, angiogenesis, innervation, tissue fibrosis, and inflammation.