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