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.

棕色脂肪组织是由异质脂肪细胞群组成的，它们的共存证明了这一点