Molecular control of beige fat heterogeneity

米色脂肪异质性的分子控制

• 批准号: 10453783
• 负责人: Shingo Kajimura
• 金额: $ 48.13万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-20 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10453783
• 关键词: Acclimatization; Adipocytes; Adipose tissue; Adrenergic Receptor; Adult; Agonist; Biogenesis; Biological; Biological Process; Brown Fat; CD81 gene; CRISPR interference; Cell Differentiation process; Cells; Chronic; Crista ampullaris; Cues; Data; Development; Exercise; Fatty acid glycerol esters; Fibrosis; Genetic; Genetic Transcription; Glucose; Glucose Intolerance; Health; Heterogeneity; Homeostasis; Hormonal; Inflammation; Insulin Resistance; Intermittent fasting; Label; Lead; Lipids; Mediator of activation protein; Metabolic; Mitochondria; Molecular; Mus; Nature; Pathologic; Pathway interactions; Physiological; Play; Population; RNA analysis; Regulation; Reporter; Research; Role; Signal Pathway; Signal Transduction; Stimulus; Technology; Testing; Thermogenesis; Tissues; adipocyte differentiation; angiogenesis; autocrine; improved; in vivo; insulin sensitivity; lipid biosynthesis; nerve supply; oxidation; paracrine; progenitor; recruit; stem; stem cell proliferation; stem cells; tissue injury; tissue repair; tool

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.

项目概要 新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， 米色脂肪生物发生的最著名的刺激因素是冷驯化和 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 各种外部刺激，例如组织损伤和间歇性禁食，都会刺激米色脂肪的生物合成 此外，我们最近的研究发现了一个以前未表征的途径。 米色脂肪群体，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β3-AR诱导的米色脂肪不同。 这些结果使我们认识到米色脂肪是由发育多样化的细胞群组成的，并且 每个种群根据外部线索的性质（例如寒冷与组织）发挥独特的生物学作用 然而，检验这一假设的一个技术障碍是缺乏使我们能够瞄准的遗传工具。 因此，我们采用单细胞 RNA (scRNA) 分析并鉴定。 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) 和 来自生肌谱系的 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控、分子机制和生物学功能 源于 CD81+ APC 和 MyoD+ APC，我们在此提案中的贡献是提供一个基本的。 了解异质米色脂肪细胞群如何受到生理和 病理线索，以及它们如何促进代谢组织稳态的调节，例如燃料 氧化、血管生成、神经支配、组织纤维化和炎症。