Beige Adipocyte Development: lineage analysis and molecular characterization

项目摘要/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，这是潜在的治疗特征 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，并确定是否以及如何利用这些过程来 治疗流行比例高的代谢性疾病。因此，迫切需要更好地 了解控制肥胖和葡萄糖动态平衡的机制和分子。 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。该过程在老化期间失败， 在减少能量消耗的同时，肥胖和糖尿病的发病率也在增加。那是新的 至少在年轻人中，米色脂肪细胞的形态表明存在一种可能的冷诱导 米色成脂干细胞/祖细胞。然而，拆解这种冷诱导的米色脂肪的主要障碍 祖细胞隔间包括缺乏试剂、工具和方法来研究和操作 缺乏对年龄依赖性功能障碍的认识，这是一个主要的临床障碍。 我们发表的研究表明，我们解决了其中一些问题，并确定了冷诱导 通过设计、设计和研究表达分子记者的小鼠，使脂肪祖细胞变成米色 以及米色祖细胞隔间中的可诱导基因开关。这些工具使我们能够可视化 体内可冷诱导的米色脂肪前体细胞，在其后代分裂、迁移和 发育成成熟的米色脂肪细胞。这些工具还允许我们审问和操纵基因 在这个关键的祖先群体中发挥作用。通过这样的方法，我们发现衰老导致 在寒冷中诱导米色细胞的年龄依赖性失败，我们可以逆转这一过程， 通过创新的遗传方法使年老的祖细胞再生为米色脂肪细胞 毒品。 这项提议的中心焦点是使用我们的新工具来描绘体内功能和 冷诱导米色脂肪细胞前体细胞的分子特征及其年龄相关性衰竭 发挥作用；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论 在此基础上，我们将了解生理和药物刺激是如何调节祖细胞的 人口、能量消耗和肥胖症，我们将利用这些洞察力来达到治疗目的。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 那些与肥胖症和糖尿病的新疗法特别相关的。

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.