Transcriptional Control of High-thermogenic Adipocyte Development

高产热脂肪细胞发育的转录控制

基本信息

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
项目类别：
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

项目摘要

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.

棕色脂肪组织由异质脂肪细胞群组成，其共存证明低产热脂肪细胞（线粒体含量低且解偶联蛋白 1 (UCP1) 低）和高产热脂肪细胞组织内的产热脂肪细胞，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代谢中的意义疾病的定义仍然不明确。在我们的初步研究中，我们发现了富含 JunB 的群体棕色脂肪库内的脂肪细胞（JunB+脂肪细胞）表现出较低的产热能力和较少的脂肪细胞与高产热脂肪细胞相比，脂滴。 JunB+脂肪细胞的丰度增加肥胖期间。通过 snRNA-seq 和功能测定，我们观察到脂肪细胞中 JunB 的失活增加了表现出高线粒体含量和产热能力的脂肪细胞的比例。重要的是，UCP1+脂肪细胞中的 JunB 消融导致基础能量和冷诱导能量增强支出并保护小鼠免受饮食引起的肥胖。基于这些新颖的发现，我们假设 JunB 在控制脂肪细胞异质性和全身能量方面发挥关键作用和葡萄糖稳态。我们将阐明 JunB 抑制高产热的机制细胞分化并通过检查 JunB+ 脂肪细胞的身份、起源、以及这个独特亚群的命运。我们还将使用白喉毒素基因A链（DTA）- 介导的方法消融脂肪组织内的 JunB+ 脂肪细胞以确定其生理作用调节能量和葡萄糖代谢的亚群。 JunB 调节脂肪细胞的特性异质性和可塑性将为棕色脂肪细胞的生物学和固体提供新的知识基金会旨在帮助开发肥胖及其相关疾病的治疗干预措施。