A_2A 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, A_2A, A_2B, and A₃ adenosine receptors (ARs). The role of A_2AARs in regulating high-fat-diet (HFD)-induced metabolic derangements is unknown. To evaluate the role of A_2AARs in regulating glucose and insulin homeostasis in obesity, we fed A_2AAR-knockout (KO) and control mice an HFD for 16 wk to initiate HFD-induced metabolic disorder. We found that genetic deletion of A_2AARs 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 A_2AAR-deficient mice were decreased compared with control mice after consuming an HFD. A_2AAR-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 A_2AARs 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 A_2AAR-KO mice. Altogether, our data showed that A_2AARs 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. A_2A adenosine receptors control pancreatic dysfunction in high-fat-diet-induced obesity.