Genetic and Functional Investigation of Supraclavicular Brown Adipose Tissue

当能量摄入超过能量消耗时，肥胖就会发生，它是导致 二型糖尿病和心血管疾病的发展。能源消耗的一种重要形式是 非颤抖生热作用，即棕色脂肪组织(BAT)将化学能作为热量散失。这个 最近在健康成年人的锁骨上区域重新发现BAT表明，治疗 利用BAT功能的策略可以对抗肥胖及其相关的人类代谢并发症。至 利用BAT作为治疗工具，我们首先需要了解锁骨上BAT(ScBAT)是如何形成的 使用人类scBAT的忠实动物模型进行功能。我们最近发现了一个老鼠SCBAT仓库 在解剖学和分子上与在人类中发现的锁骨上窝相似。新的初步研究 将导致scBAT的谱系追溯到心脏前区(AHF)表达的心脏前体细胞 心肌细胞增强因子2c(MEF2C)，揭示了scBAT与心脏之间的谱系关系。 锁骨上棕色前脂肪细胞中MEF2C转录因子的敲除导致Key的丢失 棕色脂肪生成调节剂选择性消融scBAT扰乱健康人代谢稳态 喂食食物的小鼠。综上所述，这些发现使我们假设scBAT是一种高度活跃的代谢蝙蝠 起源于心脏前区的心脏前体细胞的仓库，依赖于MEF2C 对其代谢功能的调节。对于特定的目标1，我们将确定 通过确定多能心脏祖细胞是否可以被直接诱导成棕色来进行scBAT 脂肪细胞，分析MEF2C-AHF+细胞遗传消融后组织缺陷的scBAT，并鉴定细胞 锁骨上棕色脂肪细胞前体细胞的表面标志物。对于具体目标2，我们将 确定MEF2C在scBAT代谢功能调节中的作用。我们将调查 MEF2C在棕色脂肪形成和代谢功能中的作用 已被删除。对于特定的目标3，我们将确定scBAT对能量和 通过研究单链BAT缺失对健康小鼠体内葡萄糖稳态的影响及其机制 ScBAT调节代谢的作用机制。我们还将确定scBAT的损失是否 进一步扰乱高脂饮食诱导的肥胖小鼠的代谢功能。总之，这些研究应该提供 对MEF2C的起源、对其功能的贡献以及对生理的基本理解 ScBAT在小鼠中的意义，并为如何潜在地利用最常见的活性物质提供了新的见解 用于治疗肥胖及其相关代谢并发症的人体BAT仓库。

Obesity, which occurs when energy intake exceeds energy expenditure, is a major contributor to the development of type II diabetes and cardiovascular disease. One significant form of energy expenditure is nonshivering thermogenesis, the dissipation of chemical energy as heat by brown adipose tissue (BAT). The recent rediscovery of BAT in the supraclavicular region in healthy human adults suggests that therapeutic strategies utilizing BAT function could combat obesity and its related metabolic complications in humans. To utilize BAT as a therapeutic tool, we first need to understand how supraclavicular BAT (scBAT) forms and functions using a faithful animal model for human scBAT. We recently identified a mouse scBAT depot that anatomically and molecularly resembles the supraclavicular depot found in humans. New preliminary studies traced the lineage giving rise to scBAT to cardiac progenitor cells in the anterior heart field (AHF) that express Myocyte enhancer factor 2c (Mef2c), revealing a lineage relationship between scBAT and the heart. Knockdown of the Mef2c transcription factor in supraclavicular brown preadipocytes led to the loss of key brown adipogenesis regulators, while selective ablation of scBAT perturbed metabolic homeostasis in healthy chow-fed mice. Together, these findings led us to hypothesize that scBAT is a highly active metabolic BAT depot that originates from cardiac progenitor cells in the anterior heart field and is dependent on Mef2c for the regulation of its metabolic function. For specific aim 1, we will determine the developmental origin of scBAT by determining if polypotent cardiac progenitor cells can be directly induced to become brown adipocytes, analyzing scBAT for tissue defects after genetic ablation of Mef2c-AHF+ cells, and identifying cell surface markers specific for supraclavicular brown adipocyte progenitors. For specific aim 2, we will determine the role of Mef2c in the regulation of metabolic function of scBAT. We will investigate the contribution of Mef2c to brown adipogenesis and metabolic function using cells and mice in which Mef2c has been deleted. For specific aim 3, we will determine the physiological contribution of scBAT to energy and glucose homeostasis in vivo by investigating the effects of loss of scBAT in healthy mice and the underlying mechanism of action by which scBAT regulates metabolism. We will also determine whether loss of scBAT further disrupts metabolic function in high-fat diet induced obese mice. Together these studies should provide fundamental understanding of the origin of, the contribution of Mef2c to the function of, and physiological significance of scBAT in mice and provide new insight into how to potentially utilize the most common active BAT depot in humans to treat obesity and its related metabolic complications.