Regulation of skeletal muscle growth and function by the adenosine receptor A2B

腺苷受体 A2B 对骨骼肌生长和功能的调节

• 批准号: 289107305
• 负责人: Dr. Thorsten Gnad
• 金额: --
• 依托单位: Institut für Pharmakologie und Toxikologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/289107305?language=en
• 关键词: Regulation; skeletal; muscle; growth; function

Obesity has reached pandemic dimensions with nearly two billion people being either overweight or obese. Obesity is directly associated with serious medical conditions including type 2 diabetes, cancer and cardiovascular diseases. Hence, there is an increasing medical need for an efficient pharmacological therapy. There are two types of fat: white adipose tissue and brown adipose tissue (BAT). BAT is specialized in burning energy and a process termed non-shivering thermogenesis, which is essential for newborns to maintain body termperature after cold exposure. Importantly, also adults possess metabolically active BAT. The special feature of BAT, burning energy without producing ATP, makes this tissue a self-evident target for an anti-obesity therapy. BAT is highly innervated by sympathetic nerves and activated by norepinephrine (NE) via beta-adrenergic receptors present on brown adipocytes (BA). Besides white and brown adipocytes, recent work has been dealing with brown-like adipoctes within white fat depots. These so called beige or brite (brown in white) adipocytes are recruited to WAT after prolonged cold exposure/beta-adrenergic stimulation - a process called browning. Importantly, browning of WAT has been shown to increase energy expenditure in mice and might have therapeutical potential. However, BAT therapies or induction of browning based on beta-adrenergic agonists are clinically problematic due to cardio-vascular side-effects. Therefore, alternative strategies must be explored. We have recently shown that the purinergic signalling molecule adenosine acts as a physiological activator of human and murine BA. These findings were unexpected as adenosine has previously been reported to inhibit BAT activity. Extracellular adenosine is signalling via four distinct G protein-coupled receptors: A1 and A3 are Gi-coupled whereas A2A and A2B are Gs-coupled. With this proposal, we will study the role of the adenosine A2B receptor in the activation of human and murine BA and in the browning of primary human and murine WA. Our preliminary data show an abundant expression of A2B in BA. Moreover, murine BA can be activated with A2B-specific agonists indicating that A2B might have an important role in the physiological activation of BAT. Within this proposal, we will apply both pharmacological as well as genetic tools to analyse the role of A2B in differentiation and activation of human and murine BA. Moreover, we will study the impact of A2B-signalling on the function of primary human and murine white adipocytes and its effect on browning. Finally, we will analyse adenosine A2B/A2A receptor heterodimerization and if this heterodimerization is a prerequisite for adenosine-mediated activation of BA and BAT.

肥胖已经达到了流行病的程度，近20亿人超重或肥胖。肥胖与严重的医疗状况直接相关，包括2型糖尿病、癌症和心血管疾病。因此，对有效的药理学疗法的医学需求日益增加。有两种类型的脂肪：白色脂肪组织和棕色脂肪组织（BAT）。BAT专门燃烧能量和称为非颤抖产热的过程，这对于新生儿在寒冷暴露后保持体温至关重要。重要的是，成年人也拥有代谢活跃的BAT。BAT的特殊功能，燃烧能量而不产生ATP，使这种组织成为抗肥胖治疗的不言而喻的目标。BAT高度受交感神经支配，并通过棕色脂肪细胞（BA）上的β-肾上腺素能受体被去甲肾上腺素（NE）激活。除了白色和棕色脂肪细胞外，最近的工作一直在研究白色脂肪库中的棕色脂肪样细胞。这些所谓的米色或brite（白色中的棕色）脂肪细胞在长时间的冷暴露/β-肾上腺素能刺激后被招募到WAT-一个称为布朗宁的过程。重要的是，WAT的布朗宁已被证明会增加小鼠的能量消耗，并可能具有治疗潜力。然而，基于β-肾上腺素能激动剂的BAT疗法或布朗宁的诱导由于心血管副作用而在临床上存在问题。因此，必须探索替代战略。我们最近表明，嘌呤能信号分子腺苷作为人类和小鼠BA的生理激活剂。这些发现是出乎意料的，因为之前已经报道腺苷抑制BAT活性。细胞外腺苷通过四种不同的G蛋白偶联受体进行信号传导：A1和A3是Gi偶联的，而A2 A和A2 B是Gs偶联的。根据这个建议，我们将研究腺苷A2 B受体在人和小鼠BA活化和原代人和小鼠WA的布朗宁中的作用。我们的初步数据显示A2 B在BA中有丰富的表达。此外，小鼠BA可以被A2 B特异性激动剂激活，表明A2 B可能在BAT的生理激活中起重要作用。在这个提议中，我们将应用药理学和遗传学工具来分析A2 B在人类和小鼠BA的分化和激活中的作用。此外，我们将研究A2 B信号传导对原代人类和小鼠白色脂肪细胞功能的影响及其对布朗宁的影响。最后，我们将分析腺苷A2 B/A2 A受体异源二聚化，如果这种异源二聚化是腺苷介导的BA和BAT激活的先决条件。