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，肥胖症正在指数上升到联合的大流行水平 国家。当前药理的失败强调了新的治疗策略的需求 治疗肥胖症的方法。新策略需要新的知识。棕色脂肪组织（BAT）是器官 由于有效的葡萄糖和脂质间隙，可能在能量平衡，肥胖和糖尿病中起主要作用 为了增强其热功能。蝙蝠激活的最佳特征机制是冷诱导的， 去甲肾上腺素（NE）激活B-肾上腺素能受体（B-ARS）的交感神经系统分泌和 导致组织分化和解耦蛋白1（UCP1）介导的热发生。虽然， 我们实验室的最新工作表明，B-ARS对于轻度，冷适应引起的或慢性 从属应力引起的蝙蝠募集。其他发布和初步数据表明 同情神经对于蝙蝠褐变是必需的，同时排除了Ne-Activing AAR的主要贡献 在没有B-ARS表达的情况下。这些数据表明，其他交感神经衍生的因素对于 BAT功能除了NE。该项目将测试肾上腺素和嘌呤能信号传导的假设 作为BAT功能的平行和协同调节剂，最佳组织募集和激活必需。 该假设将以三个特定目的进行检验。具体目的1是在功能上剖析机制 通过隔离嘌呤能的独立和协同贡献来招募蝙蝠和功能 途径，在关键作用的背景下，使用创新的cre-lox通过去甲肾上腺素能信号传导施加 在体内和体外接近。具体目标2是识别ATP诱导的受体介导的机制 小鼠和人棕色脂肪细胞中的褐变。特定目的3是在体内检验的假设，即 协同肾上腺素能/嘌呤能机制可以在低的条件下招募和激活BAT 蝙蝠功能通常最小的自适应热生成要求，例如热责任 外壳，从而发挥有益的抗肥胖作用。我们的创新提议基于牢固的初步 数据，并且在翻译上是相关的，因为初步数据表明嘌呤能信号通路 在人棕色脂肪组织中保守。成功完成我们的项目将发展新颖的创新性 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型机制 蝙蝠管制的法规，最后将为开发新型药物治疗提供概念证明 肥胖和肥胖相关的代谢疾病。