Beige Adipocyte Development: lineage analysis and molecular characterization

米色脂肪细胞发育：谱系分析和分子表征

• 批准号: 9214159
• 负责人: JONATHAN M GRAFF
• 金额: $ 48.6万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-12 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9214159
• 关键词: Address; Adipocytes; Adipose tissue; Adrenergic Agents; Adrenergic Agonists; Aging; Biology; Brown Fat; Cell Aging; Cells; Characteristics; Clinical; Clinical Trials; Communication; Development; Diabetes Mellitus; Drug Targeting; Elderly; Energy Metabolism; Engineering; Epidemic; Failure; Fatty acid glycerol esters; Food; Functional disorder; Genes; Genetic; Glucose; Goals; Healthcare; Histologic; Human; Incidence; Insulin; Lead; Maintenance; Metabolic; Metabolic Control; Metabolic Diseases; Metabolism; Methods; Modeling; Molecular; Mouse Strains; Mus; Nature; Obesity; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Pharmacology; Physiological; Placebos; Population; Positron-Emission Tomography; Process; Publishing; Reagent; Reporter; Reporting; Role; Signal Transduction; Stem cells; Stimulus; Switch Genes; System; Testing; Therapeutic; Transgenes; Translations; Work; adipocyte biology; adipocyte differentiation; age related; base; blood glucose regulation; clinical practice; cold temperature; design; falls; gene function; genetic approach; genetic manipulation; genetic strain; in vivo; inhibitor/antagonist; innovation; insight; insulin sensitivity; mouse development; new therapeutic target; novel; novel therapeutics; premature; progenitor; response; senescence; tool; young adult

Project Summary/Abstract Beige (brown) adipocytes convert energy (food, fat, glucose) to heat, a feature of potential therapeutic benefit for obesity and diabetes. Our overall objective is to elucidate the mechanisms that control formation of beige adipocytes and to determine whether and how these processes might be harnessed to treat metabolic diseases, which are at epidemic proportion. Thus there is an urgent need to better understand the mechanisms and molecules that control adiposity and glucose homeostasis. Clinical trials studying young adults show that daily cold exposure induces beige adipocyte formation, increases energy expenditure, and reduces adiposity and glucose levels. This process fails during aging, in concert with decreasing energy expenditure, increasing adiposity and diabetes incidence. That new beige adipocytes form, at least in younger adults, indicates the presence of a putative cold-inducible beige adipogenic stem cell/progenitor. Yet major barriers to unraveling this cold-inducible beige adipose progenitor compartment include lack of reagents, tools, and methods to study and manipulate the progenitor, and the lack of understanding of age-dependent dysfunction, a major clinical impediment. Our published work indicate that we addressed some of these issues, and identified cold-inducible beige adipose progenitors by designing, engineering, and studying mice that express molecular reporters and inducible gene switches in the beige progenitor compartment. These tools enable us to visualize cold-inducible beige adipose progenitors in vivo, to follow their descendants as they divide, migrate and develop into mature beige adipocytes. The tools also allow us to interrogate and manipulate gene function within this key progenitor population. With such approaches, we found that senescence causes the age-dependent failure to induce beige cells in the cold, and that we could reverse the process and rejuvenate old progenitors to produce beige adipocytes through innovative genetic approaches and with drugs. The central focus of this proposal is to use our new tools to delineate the in vivo functions and molecular characteristics of cold-inducible beige adipocyte progenitors, and their age-dependent failure to function; our Preliminary Studies identify novel control mechanisms. We will define these mechanistic underpinnings, we will understand how physiological and pharmacological stimuli regulate the progenitor population, energy expenditure, and adiposity, and we will exploit these insights to therapeutic ends. Our studies are designed to elucidate new aspects of adipose biology and metabolic control, highlighting those that are particularly relevant to new therapies for obesity and diabetes.

项目概要/摘要 米色（棕色）脂肪细胞将能量（食物、脂肪、葡萄糖）转化为热量，这是潜在治疗的一个特征 对肥胖和糖尿病有益。我们的总体目标是阐明控制机制 米色脂肪细胞的形成，并确定是否以及如何利用这些过程来 治疗流行病的代谢性疾病。因此迫切需要更好地 了解控制肥胖和葡萄糖稳态的机制和分子。 研究年轻人的临床试验表明，每天的寒冷暴露会诱导米色脂肪细胞的形成， 增加能量消耗，降低肥胖和血糖水平。这个过程在老化过程中失败， 与减少能量消耗、增加肥胖和糖尿病发病率相一致。那个新的 米色脂肪细胞的形成，至少在年轻人中，表明存在假定的寒冷诱导细胞 米色脂肪干细胞/祖细胞。然而，解开这种寒冷诱导的米色脂肪的主要障碍 祖室包括缺乏试剂、工具和方法来研究和操纵 祖细胞，以及缺乏对年龄依赖性功能障碍的了解，这是一个主要的临床障碍。 我们发表的工作表明我们解决了其中一些问题，并确定了冷诱导 通过设计、改造和研究表达分子报告基因的小鼠，产生米色脂肪祖细胞 和米色祖细胞室中的诱导基因开关。这些工具使我们能够可视化 体内冷诱导的米色脂肪祖细胞，跟随它们的后代分裂、迁移和 发育成成熟的米色脂肪细胞。这些工具还允许我们询问和操纵基因 在这个关键祖细胞群中发挥功能。通过这些方法，我们发现衰老会导致 与年龄相关的在寒冷条件下无法诱导米色细胞的失败，我们可以逆转这个过程 通过创新的遗传方法和 药物。 该提案的中心重点是使用我们的新工具来描述体内功能和 冷诱导米色脂肪细胞祖细胞的分子特征及其年龄依赖性衰竭 发挥作用；我们的初步研究确定了新颖的控制机制。我们将定义这些机制 在此基础上，我们将了解生理和药理刺激如何调节祖细胞 人口、能量消耗和肥胖，我们将利用这些见解来达到治疗目的。我们的 研究旨在阐明脂肪生物学和代谢控制的新方面，强调 那些与肥胖和糖尿病新疗法特别相关的。