Regulation of adipose lineage plasticity in obesity

肥胖症中脂肪谱系可塑性的调节

• 批准号: 10352438
• 负责人: Yuwei Jiang
• 金额: $ 11.99万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-15 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10352438
• 关键词: AKT Signaling Pathway; Address; Adipocytes; Adipose tissue; Adult; Age; Animals; Appearance; Area; Biological Assay; Blood; Blood Vessels; Burn injury; Cardiovascular Diseases; Cell Lineage; Cell physiology; Cellular biology; Chronic; Consumption; Cues; Data; Development; Diabetes Mellitus; Diet; Diet therapy; Disease; Energy Metabolism; Epidemic; Event; Experimental Models; Fatty acid glycerol esters; Fibroblasts; Fibrosis; Future; Generations; Genetic; Glucose; Goals; Health; High Fat Diet; Homeostasis; Imatinib; In Vitro; Inflammation; Inflammatory; Light; Longevity; Maintenance; Mentored Research Scientist Development Award; Metabolic; Metabolic Diseases; Metabolism; Mission; Mitochondria; Molecular; Molecular Profiling; Molecular Target; Mus; Mutant Strains Mice; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Nutrient; Obese Mice; Obesity; Obesity Epidemic; Obesity associated disease; Overweight; PDGFRB gene; Persons; Pharmacology; Phenotype; Physiological; Platelet-Derived Growth Factor alpha Receptor; Population; Prevention; Process; Proteins; Receptor Protein-Tyrosine Kinases; Regulation; Research; Resistance; Risk; Risk Factors; Role; Signal Pathway; Signal Transduction; Smooth Muscle Actin Staining Method; Source; Testing; Therapeutic; Tissue Expansion; Weight; Weight Gain; Work; base; design; diet-induced obesity; feeding; fighting; glucose metabolism; improved; in vivo; inhibitor; innovation; insulin sensitivity; lipid biosynthesis; metabolic fitness; novel; novel strategies; obesity treatment; obesogenic; preservation; prevent; progenitor; recruit; response; stem cells; sugar; targeted treatment; therapeutic target; tool; transcriptome sequencing

Title: “Regulation of adipose lineage plasticity in obesity” Project Summary/Abstract A potential therapeutic target to curb the global obesity and diabetes epidemic is thermogenic beige fat within white adipose tissue. Unlike white adipocyte which stores fat, beige adipocyte absorbs sugar and fat from the blood and then burns it. Recent studies indicate that beige adipocytes are present in adult human, and their activities are correlated with a metabolically healthy phenotype. Due to its promise to reduce adiposity and improve insulin sensitivity, various molecular cues to induce beige adipocyte lineage have been extensively investigated. However, most of these studies focus on young and healthy adult. Relatively little work has been done investigating the white and beige adipocyte plasticity and their regulation in obese and old subjects, who constitutes a large percentage of the obesity-diabetes epidemic. Our long-term goal is to understand adipose lineage development and their plasticity in health and disease. During the K01 award period, we identified a perivascular smooth muscle actin (Sma) positive adipocyte progenitor cells (APCs) that is capable of generating both white and beige adipocytes. Mechanistically, we identified a platelet-derived growth factor receptor α (Pdgfrα) as a novel regulator of white and beige adipocyte switch, the deletion of which leads to beige lineage maintenance in high fat diet induced obesity. We observed that mutant mice with the perdurance of beige adipocytes were resistant to weight gain, improved glucose metabolism, and had better overall energy expenditure. We hypothesize that this would be a novel approach to utilize white-to-beige fat switch as a therapy for diet-induced and age-associated obesity. We will test the hypothesis that modulating APC Pdgfrα activity will alter adipose lineage plasticity in obesity with the following 2 aims: 1: Determine the APC-intrinsic role of Pdgfrα in diet-induced obesity; and 2: Determine the mechanisms by which Pdgfrα controls beiging potential in obese and old mice. In this proposal, we plan to leverage our innovative experimental models to understand how Pdgfrα controls the fate of white and beige APCs, and how this increased beige life span regulates adiposity and metabolism in obese and old animals. It is hoped that the results of this proposal will shed light on novel molecular targets and cellular processes that can be therapeutically exploited to improve energy expenditure for the prevention and treatment of obesity and its associated metabolic disorders, including diabetes. This R03 application's proposed aims are based on strong preliminary data generated from the ongoing K01, will allow developing the rationale and provide additional preliminary data for an R01 application in this area.

标题：“肥胖症中脂肪谱系可塑性的调节” 项目总结/摘要 一个潜在的治疗目标，以遏制全球肥胖和糖尿病的流行是产热米色脂肪内 白色脂肪组织。与储存脂肪的白色脂肪细胞不同，米色脂肪细胞从 最近的研究表明，米色脂肪细胞存在于成年人中，其 活性与代谢健康表型相关。由于其减少肥胖的承诺， 改善胰岛素敏感性，诱导米色脂肪细胞谱系各种分子线索已经被广泛地 研究了然而，这些研究大多集中在年轻和健康的成年人身上。相对来说， 研究肥胖和老年受试者的白色和米色脂肪细胞可塑性及其调节， 占肥胖糖尿病流行病的很大比例。我们的长期目标是了解脂肪 谱系发展及其在健康和疾病中的可塑性。在K 01授予期间，我们确定了一个 血管周围平滑肌肌动蛋白（Sma）阳性脂肪祖细胞（APC），其能够产生 白色和米色脂肪细胞。从机制上讲，我们鉴定了一种血小板衍生生长因子受体α， （Pdgfrα）作为白色和米色脂肪细胞转换的新调节因子，其缺失导致米色谱系 维持高脂饮食诱导的肥胖。我们观察到， 脂肪细胞抵抗体重增加，改善葡萄糖代谢，并具有更好的整体能量 支出我们假设这将是一种利用白色至米色脂肪转换作为治疗的新方法 饮食引起的和年龄相关的肥胖症。我们将检验调节APC Pdgfrα活性将 改变肥胖症的脂肪谱系可塑性，有以下2个目的：1：确定Pdgfrα的APC内在作用 2：确定Pdgfrα控制肥胖患者beiging潜力的机制 老老鼠在这项提案中，我们计划利用我们的创新实验模型来了解Pdgfrα 控制白色和米色APC的命运，以及这种增加的米色寿命如何调节肥胖， 肥胖和老年动物的新陈代谢。我们希望这一建议的结果将有助于揭示新的分子 靶点和细胞过程，可以在治疗上利用这些靶点和细胞过程来改善患者的能量消耗。 预防和治疗肥胖及其相关的代谢紊乱，包括糖尿病。R03 应用程序的拟议目标是基于正在进行的K 01产生的强大的初步数据，将允许 为R 01在这一领域的应用提供更多的初步数据。

项目成果

Differential roles of insulin receptor in adipocyte progenitor cells in mice.

胰岛素受体在小鼠脂肪细胞祖细胞中的不同作用。

• DOI: 10.1016/j.mce.2023.111968
• 发表时间: 2023
• 期刊: Molecular and cellular endocrinology
• 影响因子: 4.1
• 作者: Yuan,Yexian;Shi,Zuoxiao;Xiong,Shaolei;Hu,Ruoci;Song,Qing;Song,Zhenyuan;Ong,Sang-Ging;Jiang,Yuwei
• 通讯作者: Jiang,Yuwei