Molecular control of BAT functions by adrenergic/purinergic signaling

摘要 流行病学证据表明，在美国，肥胖症正呈指数级上升， States.新的治疗策略的需要突出了当前药理学的失败， 治疗肥胖症的方法。新战略需要新知识。棕色脂肪组织（BAT）是一种器官， 由于有效的葡萄糖和脂质清除作用，可能在能量平衡、肥胖和糖尿病中发挥重要作用 以促进其产热功能。BAT激活的最佳表征机制是冷诱导， 交感神经系统-去甲肾上腺素（NE）的分泌激活b-肾上腺素能受体（b-AR）， 导致组织分化和解偶联蛋白1（UCP 1）介导的产热作用。尽管如此， 我们实验室最近的工作表明，b-AR是温和的，冷适应诱导或慢性 服从压力导致的BAT招聘。其他公布的和初步的数据表明， 交感神经是BAT布朗宁所必需的，而排除NE激活的阿尔斯的主要贡献 在不存在b-AR表达的情况下。这些数据表明，其他交感神经源性因素是至关重要的， 除了NE之外，BAT还发挥作用。本项目将检验肾上腺素能和嘌呤能信号作用的假说， 作为BAT功能的平行和协同调节剂，是最佳组织募集和激活所需的。 这一假设将在三个具体目标中得到检验。具体目标1是从功能上剖析 BAT募集和功能通过分离嘌呤能的独立和协同作用 途径，在关键作用的背景下，由去甲肾上腺素能信号传导使用创新的cre-lox 方法在体内和体外。具体目标2是确定ATP诱导的受体介导的机制。 小鼠和人棕色脂肪细胞中的布朗宁。具体目标3是在体内测试以下假设： 协同的肾上腺素能/嘌呤能机制可以参与招募和激活BAT在低的条件下， 适应性产热要求，其中BAT功能通常是最小的，例如，热中性 从而发挥有益的抗肥胖效果。我们的创新建议是基于坚实的初步 因为初步数据表明，嘌呤能信号通路 在人类棕色脂肪组织中是保守的。我们的项目的成功完成将开发新的创新 在啮齿动物和人类细胞模型中操纵嘌呤能通路的工具，将确定一种新的机制， 最后，将为开发新的药物疗法提供概念证明， 肥胖和肥胖相关的代谢疾病。

ABSTRACT Epidemiological evidence demonstrates that obesity is rising exponentially to pandemic levels in the United States. The need of new therapeutic strategies is highlighted by the failure of current pharmacological approaches to treat obesity. New strategies require new knowledge. The brown adipose tissue (BAT) is an organ likely to play a major role in energy balance, obesity, and diabetes due to a potent glucose and lipid clearance to fuel its thermogenic function. The best characterized mechanism for BAT activation is cold-induced, sympathetic nervous system-secretion of norepinephrine (NE) activating b-adrenergic receptors (b-ARs) and resulting in tissue differentiation and uncoupling protein 1 (UCP1)-mediated thermogenesis. Notwithstanding, recent work from our lab demonstrated that b-ARs are dispensable for mild, cold acclimation-induced or chronic subordination stress-induced BAT recruitment. Other published and preliminary data demonstrate that sympathetic nerves are necessary for BAT browning while excluding a major contribution of NE-activating aARs in absence of b-ARs expression. These data suggest that other sympathetic nerve-derived factors are critical for BAT functions in addition to NE. This project will test the hypothesis that adrenergic and purinergic signaling act as parallel and synergistic modulators of BAT functions, required for optimal tissue recruitment and activation. This hypothesis will be tested in three specific aims. Specific Aim 1 is to functionally dissect the mechanisms of BAT recruitment and functions by isolating the independent and synergistic contribution of the purinergic pathway, in the context of the pivotal role, exerted by noradrenergic signaling using innovative cre-lox approaches in vivo and in vitro. Specific Aim 2 is to identify the receptor-mediated mechanism of ATP-induced browning in mouse and human brown adipocytes. Specific Aim 3 is to test, in vivo, the hypothesis that the synergistic adrenergic/purinergic mechanism can be engaged to recruit and activate the BAT in conditions of low adaptive thermogenesis requirements in which BAT functions are normally minimal, e.g., thermoneutrality housing, thereby, exerting beneficial anti-obesity effects. Our innovative proposal is based on solid preliminary data and is translationally relevant because preliminary data demonstrate that the purinergic signaling pathway is conserved in human brown adipose tissue. Successful completion of our project will develop novel innovative tools to manipulate the purinergic pathway in rodent and human cellular models, will identify a novel mechanism of BAT regulation and finally, will offer proof of concept for the development of novel pharmacotherapies for obesity and obesity-associated metabolic diseases.