Molecular control of beige fat heterogeneity

项目摘要 新出现的证据阐明了米色脂肪的生物学意义，米色脂肪是产热脂肪细胞的一种诱导形式， 代谢健康的调节。米色脂肪生物合成的最著名的刺激是冷驯化， 随后激活β 3-肾上腺素受体（β 3-AR）信号通路;然而，最近的研究发现， 各种外部刺激，如组织损伤和间歇性禁食，刺激米色脂肪生物合成 通过β 3-AR非依赖性途径。此外，我们最近的研究发现了一种以前没有特征的 一群米色脂肪，称为糖酵解米色脂肪细胞（或g-米色脂肪），其发育 调节和起源与β 3-AR诱导的米色脂肪不同。 这些结果使我们假设米色脂肪是由发育不同的细胞群组成的， 每个种群根据外部线索的性质发挥独特的生物学作用（例如，冷与组织 伤害）。然而，测试这一假设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。因此，我们采用单细胞RNA（scRNA）分析并鉴定了 两种不同的脂肪细胞祖细胞（APC），产生冷诱导的米色脂肪细胞（CD81 + APC）， 来自肌源性谱系的g-米色脂肪（MyoD + APC）。因此，本提案旨在检验上述假设 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。我们在这一建议中的贡献是提供一个基本的 了解异源米色脂肪细胞群是如何被生理和 病理线索，以及它们如何有助于调节代谢组织稳态，例如燃料 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.