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

肥胖症已经达到了流行病的程度，有近20亿人超重或肥胖。肥胖与严重的疾病直接相关，包括2型糖尿病、癌症和心血管疾病。因此，医学上对有效的药物治疗的需求越来越大。脂肪有两种类型：白色脂肪组织和棕色脂肪组织(BAT)。蝙蝠专门燃烧能量和一种被称为非颤抖生热的过程，这对新生儿在寒冷暴露后保持体温至关重要。重要的是，成年人也有代谢活跃的蝙蝠。蝙蝠的特殊功能是燃烧能量而不产生三磷酸腺苷，这使得这种组织成为减肥治疗的不言而喻的目标。BAT由交感神经高度支配，并通过棕色脂肪细胞(BA)上存在的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，最近的工作是在白色脂肪库中处理棕色样脂肪细胞。这些所谓的米色或褐褐色(白色中的棕色)脂肪细胞在长期冷暴露/β肾上腺素能刺激后被招募到Wat，这一过程被称为褐化。重要的是，Wat的褐化已被证明可以增加小鼠的能量消耗，并可能具有治疗潜力。然而，由于心血管副作用，基于β-肾上腺素能激动剂的BAT疗法或诱导褐变在临床上是有问题的。因此，必须探索替代战略。我们最近发现，嘌呤能信号分子腺苷是人和小鼠BA的生理激活剂。这些发现是出乎意料的，因为此前有报道称腺苷可以抑制蝙蝠的活性。细胞外腺苷通过四种不同的G蛋白偶联受体传递信号：A1和A3是GI偶联的，而A2A和A2B是Gs偶联的。根据这一建议，我们将研究腺苷A2B受体在人和小鼠BA激活以及原代人和小鼠Wa褐变中的作用。我们的初步数据显示A2B在BA中有丰富的表达。此外，小鼠BA可被A2B特异性激动剂激活，表明A2B可能在BAT的生理激活中起重要作用。在这项建议中，我们将同时应用药理学和遗传学工具来分析A2B在人和小鼠BA分化和激活中的作用。此外，我们还将研究A2B信号对原代人类和小鼠白色脂肪细胞功能的影响及其对褐变的影响。最后，我们将分析腺苷A2B/A2A受体的异二聚化以及这种异二聚化是否是腺苷介导的BA和BAT激活的先决条件。

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.