Beige Adipocyte Development: lineage analysis and molecular characterization

项目总结/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。 有益于肥胖和糖尿病。我们的总体目标是阐明控制 米色脂肪细胞的形成，并确定这些过程是否以及如何被利用， 治疗代谢性疾病，占流行病的比例。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。 对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，减少肥胖和葡萄糖水平。这个过程在老化过程中失败， 与能量消耗减少、肥胖和糖尿病发病率增加一致。新 米色脂肪细胞的形式，至少在年轻的成年人，表明存在一个假定的冷诱导 米色成脂干细胞/祖细胞。然而，解开这种冷诱导米色脂肪的主要障碍是， 祖细胞室包括缺乏试剂，工具和方法来研究和操纵祖细胞室。 祖细胞，以及缺乏对年龄依赖性功能障碍的理解，这是一个主要的临床障碍。 我们发表的工作表明，我们解决了其中的一些问题，并确定了冷诱导 通过设计、工程化和研究表达分子报告基因的小鼠， 和米色祖细胞隔室中的可诱导基因开关。这些工具使我们能够可视化 冷诱导的米色脂肪祖细胞在体内，跟随他们的后代，因为他们分裂，迁移， 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 在这个关键的祖先群体中发挥作用。通过这些方法，我们发现衰老导致 年龄依赖性的失败，以诱导米色细胞在寒冷中，我们可以扭转这一进程， 通过创新的遗传方法使年老的祖细胞恢复活力，产生米色脂肪细胞， 毒品 该提案的中心焦点是使用我们的新工具来描绘体内功能， 冷诱导米色脂肪祖细胞的分子特征及其年龄依赖性衰竭 我们的初步研究确定了新的控制机制。我们将定义这些机械 基础，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 研究旨在阐明脂肪生物学和代谢控制的新方面，强调 那些与肥胖症和糖尿病的新疗法特别相关的研究。

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.