Transcriptional Control of High-thermogenic Adipocyte Development

高产热脂肪细胞发育的转录控制

• 批准号: 10435752
• 负责人: Meilian Liu
• 金额: $ 36.98万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-20 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10435752
• 关键词: Ablation; Adipocytes; Adipose tissue; Adult; Amino Acids; Area; Biogenesis; Biological; Biological Assay; Biology; Brown Fat; Cell Differentiation process; Cell Proliferation; Cells; Development; Diphtheria Toxin; Disease; Energy Metabolism; Exhibits; Family; Fatty Acids; Foundations; Futile Cycling; Genes; Glucose; Health; Heterogeneity; Homeostasis; Human; Immune response; Insulin Resistance; Knowledge; Link; Lipids; Lipolysis; Maintenance; Mediating; Metabolic; Metabolic Diseases; Metabolism; Mitochondria; Modeling; Mus; Obesity; Oxidative Phosphorylation; Pathway interactions; Physiological; Physiology; Play; Population; Regulation; Research; Research Subjects; Rodent; Role; Small Nuclear RNA; Solid; Testing; Thermogenesis; Tissues; Transcription Factor AP-1; Transcriptional Regulation; Vascularization; adipocyte differentiation; base; blood glucose regulation; cardiometabolism; diet-induced obesity; estrogen-related receptor; glucose metabolism; improved; insight; lipid biosynthesis; member; mouse model; novel; obesity treatment; precursor cell; response; stem cells; therapeutic development; therapeutic target; transcription factor; uncoupling protein 1

Brown adipose tissue is composed of heterogenous adipocyte populations evidenced by the coexistence of low-thermogenic adipocytes (mitochondria content low and uncoupling protein 1 (UCP1) low) and high- thermogenic adipocytes within the tissue, a fundamental feature of adipocyte heterogeneity and plasticity. However, the mechanisms underlying adipocyte heterogeneity and its significance in metabolic physiology and disease remain poorly defined. In our preliminary study, we discovered a population of JunB-enriched adipocytes (JunB+ adipocytes) within the brown fat depot that exhibits lower thermogenic capacity and less lipid droplets compared to high-thermogenic adipocytes. The abundance of JunB+ adipocytes is increased during obesity. Through snRNA-seq and functional assays, we observed that inactivation of JunB in adipocytes increased the fraction of adipocytes exhibiting high mitochondrial content and thermogenic capacity. Importantly, JunB ablation in UCP1+ adipocytes resulted in enhanced basal and cold-induced energy expenditure and protected mice against diet-induced obesity. Based upon these novel findings, we hypothesize that JunB serves a critical role in governing adipocyte heterogeneity and systemic energy and glucose homeostasis. We will elucidate the mechanisms by which JunB suppresses high-thermogenic cell differentiation and explore the regulation of JunB+ adipocyte development by examining the identity, origin, and fate of this distinct subpopulation. We will also use Diphtheria toxin gene A chain (DTA)- mediated approach to ablate JunB+ adipocytes within adipose tissue to determine the physiological role of this subpopulation in regulating energy and glucose metabolism. Characterization of JunB in regulating adipocyte heterogeneity and plasticity will provide novel knowledge to the biology of brown adipocyte and a solid foundation to aid in the development of therapeutic interventions for obesity and its associated disorders.

棕色脂肪组织由异种脂肪细胞群组成，这是共存的证据 低温性脂肪细胞(线粒体含量低，解偶联蛋白1(UCP1)低)和高 组织内的生热脂肪细胞是脂肪细胞异质性和可塑性的基本特征。 然而，脂肪细胞异质性的机制及其在代谢生理学和生物学中的意义 疾病的定义仍然很模糊。在我们的初步研究中，我们发现了一个富含JunB的种群 棕色脂肪库中的脂肪细胞(JunB+脂肪细胞)，表现出较低的生热能力和较少的 脂滴与高热脂肪细胞的比较。JunB+脂肪细胞丰度增加 在肥胖期间。通过SNRNA-seq和功能分析，我们观察到在脂肪细胞中JunB的失活 增加了表现出高线粒体含量和生热能力的脂肪细胞的比例。 重要的是，JunB消融UCP1+脂肪细胞导致基础能量和冷诱导能量增加 支出和保护小鼠免受饮食诱导的肥胖。基于这些新发现，我们 假设JunB在调节脂肪细胞异质性和全身能量方面起关键作用 和葡萄糖动态平衡。我们将阐明JunB抑制高产热的机制 通过对JunB+脂肪细胞的特性、起源、分化和发育的研究，探讨JunB+脂肪细胞的发育规律 以及这一独特亚群的命运。我们还将使用白喉毒素基因A链(DTA)- 消融脂肪组织内JunB+脂肪细胞以确定其生理作用的介导法 调节能量和葡萄糖代谢的亚群。JunB对脂肪细胞调节作用的研究 异质性和可塑性将为棕色脂肪细胞的生物学和固体 基金会协助开发针对肥胖及其相关疾病的治疗干预措施。