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

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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.