Anales RANF

S9-02 ROLE OF ADENOSINE IN METABOLISM Alexander Pfeifer 1*, Thorsten Gnad 1 , Gemma Brugal 2,3 , Rafael Franco 2,3 1 Institute of Pharmacology and Toxicology, University of Bonn, Germany; 2 Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, Barcelona, Spain. 3 Centro de Investigación en Red, Enfermedades Neurodegenerativas (CiberNed). Instituto de Salud Carlos III. Madrid. Spain Background: Obesity has reached pandemic dimensions and is considered as one of today’s most pressing public health problems. Obesity and overweight are associated with non-communicable diseases like type 2 diabetes, cardiovascular disease (stroke and myocardial infarction) and certain types of cancer. Our laboratory is focusing on the role of adenosine signaling in adipose tissue and in obesity. Two types of fat can be distinguished: white adipose tissue (WAT) is the largest sore of energy in our body. In contrast, brown adipose tissue (BAT) is specialized in dissipating energy by uncoupling ATP synthesis through its unique uncoupling protein 1 (UCP1). BAT abundance is correlated with leanness in humans. We recently showed that adenosine activates human and murine brown adipocytes. This was not expected since previous studies in hamster showed an inhibitory effect of adenosine on BAT energy expenditure. Interestingly, adenosine receptor expression is different in hamster versus murine and human BAT, with high A 1 expression levels in hamster and low A 1 expression in murine and human BAT. Interestingly, mice are protected from diet-induced obesity when treated with an adenosine receptor A 2A agonist. [1] Besides A 2A , the adenosine A 2B receptor is abundantly expressed in murine BAT. Here, we analyzed the function of the A 2B receptor in murine and human BAT. Material and methods: We analysed the role of adenosine receptor A 2B in BAT in mice using either pharmacological stimulation (Bay 60-6583) or mice deficient of A 2B . Moreover, we investigated expression of A 2B and its correlation with functional activity in human BAT. Results: Adipose tissue-specific deletion of A 2B decreased BAT-dependent energy expenditure. Pharmacological stimulation of A 2B increased energy expenditure as well as glucose uptake and counteracted diet-induced obesity along with improved glucose tolerance. Moreover, A 2B stimulation induced browning of white fat. In humans, A 2B expression correlated with BAT activity. Moreover, we found that A 2B and A 2A receptor can interact and that this interaction regulates adenosine signalling in brown adipocytes. Conclusion: Activation of A 2B has profound effects on whole-body metabolism by increasing BAT-dependent energy expenditure and browning of white fat. Moreover, A 2B expression might be crucial for human BAT activity. Thus, chronically increasing energy expenditure via A 2B stimulation might counteract obesity. 1. Gnad T, Scheibler S, von Kugelgen I, Scheele C, Kilic A, et al. (2014) Adenosine activates brown adipose tissue and recruits beige adipocytes via A2A receptors. Nature 516: 395-399.