Deconstructing the brown neogenic zone in classic brown adipose tissue

项目总结/摘要 2型糖尿病（T2D）的全球发病率已达到流行病的比例，越来越多的证据表明， 表明功能失调的脂肪组织是T2D发病机制的重要贡献者。扩大 通过肾上腺素能激活脂肪组织内的分解代谢脂肪细胞表型改善能量平衡 和胰岛素敏感性。为了利用这种脂肪组织的重塑来获得治疗益处，我们需要 了解肾上腺素能信号扩大分解代谢脂肪细胞群体的机制， vivo. 棕色脂肪组织（BAT）是啮齿类动物的一种产热器官，也是BAT的实验性激活 改善T2D模型的代谢特征。BAT也存在于成年人中，其中冷诱导的活动 与代谢健康有关。然而，人类BAT的量是高度可变的，并且具有低的 产热活动因此，为了扩大BAT在人体内的产热活性， 了解新的棕色脂肪细胞的来源，以及它们是如何在成年人中招募和维持的。 哺乳动物 BAT新生是冷暴露扩大产热能力的主要手段， 因此，冷诱导的新生提供了体内棕色脂肪形成的生理学相关模型。 我们实验室以前的工作已经证明棕色脂肪形成发生在空间限定的组织中 区，并涉及脂肪细胞祖细胞，组织单核细胞/巨噬细胞，毛细血管 内皮细胞以及未表征的基质细胞群。本提案的总体目标是 是解构成年蝙蝠的新生带，并测试特定的机制， 肾上腺素能信号传导诱导BAT新生。 我们建议使用单细胞RNA测序（scRNA-seq）来解构存在于细胞中的细胞类型。 全面、公正地研究了棕色新生带。单细胞分析过程中， 冷诱导的新生将定义所涉及的细胞类型，并确定 激活的棕色脂肪祖细胞。此外，我们将讨论具体机制， 神经激活使用新的遗传功能丧失分析触发组织扩张。 该项目不仅将大大推进我们对棕色脂肪成分的理解， 组织和β肾上腺素能受体激活如何导致体内新生，但将引入新的， 创新工具，如smFISH和scRNA-seq。导师团队，具有高度的 互补的专业知识，将提供综合的、多学科的培训体验。

Project Summary/Abstract Global incidence of Type 2 Diabetes (T2D) has reached epidemic proportions, and increasing evidence indicates that dysfunctional adipose tissue is an important contributor to the pathogenesis of T2D. Expanding catabolic adipocyte phenotypes within adipose tissues through adrenergic activation improves energy balance and insulin sensitivity. In order to exploit this remodeling of adipose tissue for therapeutic benefit, we need to understand the mechanisms by which adrenergic signaling expand the population of catabolic adipocytes in vivo. Brown adipose tissue (BAT) is a thermogenic organ and experimental activation of BAT in rodents improves metabolic profiles in models of T2D. BAT is also present in adult humans, where cold-induced activity is correlated with metabolic health. However, the amount of human BAT is highly variable and has low thermogenic activity. Therefore, in order to expand the thermogenic activity of BAT in humans, it is necessary to understand the source of new brown adipocytes and how they are recruited and maintained in adult mammals. BAT neogenesis is the principal means by which cold exposure expands thermogenic capacity, and thus cold-induced neogenesis provides a physiologically relevant model of brown adipogenesis in vivo. Previous work from our lab has demonstrated that brown adipogenesis occurs within a spatially defined tissue zone and involves the proliferation of adipocytes progenitors, tissue monocytes/macrophages, capillary endothelial cells, as well as an uncharacterized population of stromal cells. The overall goal of this proposal is to deconstruct the neogenic zone in adult BAT, and to test specific mechanisms by which adrenergic signaling induces BAT neogenesis. We proposed to use single cell RNA-sequencing (scRNA-seq) to deconstruct the cell types present in the brown neogenic zone in a comprehensive and unbiased fashion. Single cell profiling over the course of cold-induced neogenesis will define the cell types involved, and identify the differentiation trajectories of activated brown adipocyte progenitors in vivo. In addition, we will address specific mechanisms by which neural activation triggers tissue expansion using novel genetic loss-of-function analyses. The project will not only significantly advanced our understanding of the composition of brown adipose tissue and how beta adrenergic receptor activation leads to neogenesis in vivo, but will introduce new and innovative tools to the field, such as smFISH and scRNA-seq. The team of mentors, having highly complementary expertise, will provide an integrative, multidisciplinary training experience.