Regulation of Adipose Tissue Remodeling Through Axon Guidance Molecule Slit3

项目摘要 棕色脂肪组织(BAT)是一种特殊类型的脂肪，主要负责调节身体 温度。一旦被冷激活，蝙蝠就会在一个称为适应性的过程中将化学能以热量的形式消散。 生热作用。激活和扩张生热脂肪组织是增加能量的诱人方式 它还提供了一系列开支，并为防治肥胖症和心脏代谢性疾病提供了有希望的战略。一个严重的障碍 利用BAT的潜力来增强人类的心脏代谢健康是缺乏对 参与激活BAT产热的多种途径。慢性冷暴露刺激蝙蝠 棕色脂肪生成、血管生成和交感神经协同刺激的生热作用 神经支配。然而，这些不同的过程如何在时空上协调尚不清楚。使用单一的- BAT的细胞转录分析，我们最近发现了BAT中的细胞相互作用组网络 生热脂肪利基。这一建议是建立在我们最近发现的狭缝引导配体3(SLIT3)作为一种 通过控制血管生成和交感神经支配来调节蝙蝠的产热 蝙蝠。这项建议研究了SLIT3片段刺激血管内皮细胞和 交感神经突起促进血管生成和交感神经支配。我们假设N-末端 和SLIT3的C末端片段(SLIT3-N和SLIT3-C)与内皮细胞上不同的受体结合，并 交感神经刺激血管生成和交感神经支配。在目标1中，我们将使用AAV中介 在BAT中过表达SLIT3片段的基因传递及其对血管生成的影响 以及交感神经。在目标2中，我们将使用一组体外和体内模型来识别特定的 介导SLIT3片段作用于血管内皮细胞和交感神经的受体 太紧张了。拟议的研究将提供一个广泛和深入的了解，SLIT3如何监管这两个 参与蝙蝠产热、血管生成和交感神经支配的基本过程。这些研究 将通过刺激健康的人来确定肥胖和代谢性疾病的潜在干预节点 生热脂肪的膨胀。

Project Summary Brown adipose tissue (BAT) is a specialized type of adipose that is primarily responsible for regulating body temperature. Once activated by cold, BAT dissipates the chemical energy as heat in a process called adaptive thermogenesis. Activating and expanding the thermogenic adipose tissue are attractive ways to increase energy expenditure and offer promising strategies to combat obesity and cardiometabolic diseases. A critical barrier to harnessing the potential of BAT to enhance cardiometabolic health in humans is the lack of understanding of the full range of pathways involved in the activation of BAT thermogenesis. Chronic cold exposure stimulates BAT thermogenesis through the coordinated stimulation of brown adipogenesis, angiogenesis, and sympathetic innervation. However, how these distinct processes are spatiotemporally coordinated is not known. Using single- cell transcriptomic analysis of BAT, we have recently identified the network of cellular interactome in the thermogenic adipose niche. This proposal is built on our recent discovery of Slit guidance ligand 3 (Slit3) as an essential regulator of BAT thermogenesis through controlling both angiogenesis and sympathetic innervation in BAT. This proposal examines the mechanisms by which Slit3 fragments stimulate vascular endothelial cells and sympathetic neurites to promote angiogenesis and sympathetic innervation. We hypothesize that the N-terminal and C-terminal fragments of Slit3 (Slit3-N and Slit3-C) bind to distinct receptors on endothelial cells and sympathetic nerves to stimulate angiogenesis and sympathetic innervation. In aim 1, we will use AAV-mediated gene delivery to overexpress Slit3 fragments in BAT and determine the effects of each fragment on angiogenesis and sympathetic innervation. In aim 2, we will use a panel of in vitro and in vivo models to identify the specific receptors responsible for mediating the effects of Slit3 fragments in vascular endothelial cells and sympathetic nerves. The proposed studies will provide a broad and deep understanding of how Slit3 regulates the two essential processes involved in BAT thermogenesis, angiogenesis, and sympathetic innervation. These studies will identify new potential nodes of intervention for obesity and metabolic diseases by stimulating the healthy expansion of thermogenic fat.