Genetic and Functional Investigation of Supraclavicular Brown Adipose Tissue

当能量摄入超过能量消耗时发生的肥胖是导致肥胖的主要原因。 II型糖尿病和心血管疾病的发展。能量消耗的一种重要形式是 非颤抖性产热，通过棕色脂肪组织（BAT）将化学能作为热量耗散。的 最近在健康成年人锁骨上区域重新发现BAT表明， 利用BAT功能的策略可以对抗人类的肥胖症及其相关的代谢并发症。到 利用BAT作为治疗工具，我们首先需要了解锁骨上BAT（scBAT）的形成和 功能使用一个忠实的动物模型为人类scBAT。我们最近发现了一个小鼠scBAT库， 在解剖学和分子学上类似于在人类中发现的锁骨上储库。新的初步研究 将产生scBAT的谱系追溯到心脏前区（AHF）的心脏祖细胞， 肌细胞增强因子2c（Mef 2c），揭示了scBAT和心脏之间的谱系关系。 锁骨上棕色前脂肪细胞中Mef 2c转录因子的敲低导致了关键基因的丢失。 棕色脂肪生成调节因子，而选择性切除scBAT扰乱了健康人的代谢稳态。 喂食的老鼠总之，这些发现使我们假设scBAT是一种高度活跃的代谢BAT 来源于心脏前区的心脏祖细胞，并依赖于Mef 2c， 调节其代谢功能。对于具体目标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， 脂肪细胞，在Mef 2c-AHF+细胞的基因消融后分析scBAT的组织缺陷，并鉴定细胞 锁骨上棕色脂肪细胞祖细胞的特异性表面标记。具体目标2： 确定Mef 2c在调节scBAT代谢功能中的作用。我们将调查 Mef 2c对棕色脂肪形成和代谢功能的贡献，使用其中Mef 2c具有 被删除了。对于具体目标3，我们将确定scBAT对能量的生理贡献， 通过研究scBAT在健康小鼠中的损失的影响和潜在的葡萄糖稳态， scBAT调节代谢的作用机制。我们还将确定scBAT是否丢失 进一步破坏高脂饮食诱导的肥胖小鼠的代谢功能。这些研究应该提供 基本了解Mef 2c的起源，Mef 2c对功能和生理功能的贡献， scBAT在小鼠中的重要性，并为如何利用最常见的活性物质提供了新的见解。 BAT在人类中的储存以治疗肥胖及其相关的代谢并发症。

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.