Molecular control of BAT functions by adrenergic/purinergic signaling

通过肾上腺素能/嘌呤能信号传导对 BAT 功能进行分子控制

• 批准号: 9982484
• 负责人: Alessandro Bartolomucci
• 金额: $ 38.5万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-20 至 2021-08-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9982484
• 关键词: Acclimatization; Adipocytes; Adrenergic Agents; Agonist; Attention; Breeding; Brown Fat; Cell model; Chronic; Data; Development; Diabetes Mellitus; Disease; Dose; Epidemiology; Failure; Gene Silencing; Glucose; House mice; Housing; Human; Hypertension; Impairment; In Vitro; Knockout Mice; Knowledge; Lipids; Literature; MAPK14 gene; Malignant Neoplasms; Mediating; Metabolic; Metabolic Diseases; Modeling; Molecular; Molecular Target; Mus; Nerve; Neuraxis; Neuroendocrine Cell; Non-Insulin-Dependent Diabetes Mellitus; Norepinephrine; Nucleotides; Obesity; Organ; Pathway interactions; Pharmacology; Pharmacotherapy; Physiological; Play; Publishing; Purinoceptor; Receptor Activation; Regulation; Risk; Rodent; Role; Secretory Vesicles; Signal Pathway; Signal Transduction; Solid; Specificity; Stress; Sympathetic Nervous System; Testing; Thermogenesis; Tissue Differentiation; Tissues; United States; Work; adipocyte differentiation; adiponectin; base; beta-adrenergic receptor; energy balance; experimental study; in vivo; in vivo evaluation; innovation; noradrenergic; novel; novel therapeutic intervention; optogenetics; pandemic disease; prevent; receptor; receptor expression; recruit; tool; transmission process; uncoupling protein 1

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.

抽象的 流行病学证据表明，肥胖症在美国呈指数级上升，达到流行病水平 国家。当前药理学的失败凸显了对新治疗策略的需求 治疗肥胖的方法。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 为其生热功能提供燃料。 BAT 激活的最佳表征机制是冷诱导， 交感神经系统 - 分泌去甲肾上腺素 (NE) 激活 b-肾上腺素受体 (b-AR) 和 导致组织分化和解偶联蛋白 1 (UCP1) 介导的生热作用。虽然， 我们实验室最近的工作表明，b-AR 对于轻度、冷适应引起的或慢性的来说是可有可无的 服从压力诱导 BAT 招募。其他已发表的数据和初步数据表明 交感神经对于 BAT 褐变是必需的，同时排除 NE 激活 aAR 的主要贡献 在没有 b-AR 表达的情况下。这些数据表明其他交感神经衍生因子对于 BAT功能除了NE之外。该项目将测试肾上腺素能和嘌呤能信号传导作用的假设 作为 BAT 功能的并行和协同调节剂，是最佳组织募集和激活所需的。 该假设将在三个具体目标上进行检验。具体目标 1 是从功能上剖析以下机制： BAT 通过分离嘌呤能的独立和协同贡献来招募和发挥作用 途径，在关键作用的背景下，通过使用创新的 cre-lox 的去甲肾上腺素信号传导发挥作用 体内和体外方法。具体目标 2 是确定 ATP 诱导的受体介导机制 小鼠和人类棕色脂肪细胞的褐变。具体目标 3 是在体内测试以下假设： 肾上腺素能/嘌呤能协同机制可以在低浓度条件下招募和激活 BAT 适应性生热要求，其中 BAT 功能通常很小，例如热中性 住房，从而发挥有益的抗肥胖作用。我们的创新提案基于扎实的初步 数据并且具有翻译相关性，因为初步数据表明嘌呤能信号通路 保存在人类棕色脂肪组织中。我们的项目的成功完成将开发出新颖的创新产品 在啮齿动物和人类细胞模型中操纵嘌呤能途径的工具将确定一种新的机制 BAT 监管，最后将为开发新型药物疗法提供概念证明 肥胖和与肥胖相关的代谢疾病。