Transcriptional Control of High-thermogenic Adipocyte Development

高产热脂肪细胞发育的转录控制

• 批准号: 10612098
• 负责人: Meilian Liu
• 金额: $ 37.34万
• 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/10612098
• 关键词: Ablation; Adipocytes; Adipose tissue; Adult; Aging; Amino Acids; Area; Biogenesis; Biological; Biological Assay; Biology; Brown Fat; Cell Differentiation process; Cell Proliferation; Cell Separation; Cells; Development; Diphtheria Toxin; Disease; ERR1 protein; 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; Solid; Stimulus; Testing; Thermogenesis; Tissues; Transcription Factor AP-1; Transcriptional Regulation; Vascularization; adipocyte differentiation; blood glucose regulation; cardiometabolism; diet-induced obesity; glucose metabolism; improved; insight; lipid biosynthesis; member; mouse model; novel; obesity treatment; precursor cell; response; single nucleus RNA-sequencing; 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.

棕色脂肪组织由共存证明的异源脂肪细胞组成 低热脂肪细胞（线粒体含量低和解偶联蛋白1（UCP1）低）和高 - 组织内的热脂肪细胞，这是脂肪细胞异质性和可塑性的基本特征。 但是，脂肪细胞异质性的基础机制及其在代谢生理学和 疾病的定义较差。在我们的初步研究中，我们发现了一群富含Junb的人群 棕色脂肪仓库中的脂肪细胞（JUNB+脂肪细胞），其热能能力较低，较少 与高热的脂肪细胞相比，脂质液滴。 Junb+脂肪细胞的丰度增加 在肥胖期间。通过snRNA-seq和功能分析，我们观察到脂肪细胞中的junb失活 增加了表现出高线粒体含量和热能能力的脂肪细胞的比例。 重要的是，UCP1+脂肪细胞中的JUNB消融导致基底和冷诱导的能量增强 支出和保护小鼠免受饮食引起的肥胖症的影响。根据这些新颖的发现，我们 假设JUNB在管理脂肪细胞异质性和系统能量中起着至关重要的作用 和葡萄糖稳态。我们将阐明JUNB抑制高热量的机制 细胞分化并探索JunB+脂肪细胞发育的调节，通过检查身份，起源， 和这种独特的亚群的命运。我们还将使用白喉毒素基因链（DTA） - 在脂肪组织中浸泡Junb+脂肪细胞的介导方法，以确定这一点的生理作用 调节能量和葡萄糖代谢的亚群。 JUNB在调节脂肪细胞中的表征 异质性和可塑性将为棕色脂肪细胞和固体的生物学提供新颖的知识 帮助开发肥胖及其相关疾病的治疗干预措施。