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A2A adenosine receptors control pancreatic dysfunction in high‐fat‐diet‐induced obesity

Adenosine, a key extracellular signaling mediator, regulates several aspects of metabolism by activating 4 G‐protein‐coupled receptors, the A1, A2A, A2B, and A3 adenosine receptors (ARs). The role of A2A ARs in regulating high‐fat‐diet (HFD)‐induced metabolic derangements is unknown. To evaluate the role of A2A ARs in regulating glucose and insulin homeostasis in obesity, we fed A2A AR‐knockout (KO) and control mice an HFD for 16 wk to initiate HFD‐induced metabolic disorder. We found that genetic deletion of A2A ARs caused impaired glucose tolerance in mice fed an HFD. This impaired glucose tolerance was caused by a decrease in insulin secretion but not in insulin sensitivity. Islet size and insulin content in pancreata of A2A AR‐deficient mice were decreased compared with control mice after consuming an HFD. A2A AR‐KO mice had decreased expression of the β‐cell‐specific markers pdx1, glut2, mafA, and nkx6.1 and increased expression of the dedifferentiation markers sox2 and hes1. Ex vivo islet experiments confirmed the role of A2A ARs in protecting against decreased insulin content and release caused by HFD. Other experiments with bone marrow chimeras revealed that inflammation was not the primary cause of decreased insulin secretion in A2A AR‐KO mice. Altogether, our data showed that A2A ARs control pancreatic dysfunction in HFD‐induced obesity.—Csóka, B., Törő, G., Vindeirinho, J., Varga, Z. V., Koscsó, B., Németh, Z. H., Kókai, E., Antonioli, L., Suleiman, M., Marchetti, P., Cseri, K., Deák, Á., Virág L., Pacher, P., Bai, P., Haskó, G. A2A adenosine receptors control pancreatic dysfunction in high‐fat‐diet‐induced obesity. FASEB J. 31,4985–4997 (2017). www.fasebj.org