A(2A) adenosine receptors control pancreatic dysfunction in high-fat-diet-induced obesity

作者：Csoka Balazs^*; Toro Gabor; Vindeirinho Joana; Varga Zoltan V; Koscso Balazs; Nemeth Zoltan H; Kokai Endre; Antonioli Luca; Suleiman Mara; Marchetti Piero; Cseri Karolina; Deak Adam; Virag Laszlo; Pacher Pal; Bai Peter; Hasko Gyorgy^*

来源：The FASEB Journal, 2017, 31(11): 4985-4997.

DOI：10.1096/fj.201700398R

• diabetes
• islet
• beta-cell
• beta-cell dedifferentiation

Adenosine, a key extracellular signaling mediator, regulates several aspects of metabolism by activating 4 G-protein-coupled receptors, the A(1), A(2A), A(2B), and A(3) adenosine receptors (ARs). The role of A(2A)ARs in regulating high-fat-diet (HFD)-induced metabolic derangements is unknown. To evaluate the role of A(2A)ARs in regulating glucose and insulin homeostasis in obesity, we fed A(2A)AR-knockout (KO) and control mice an HFD for 16 wk to initiate HFD-induced metabolic disorder. We found that genetic deletion of A(2A)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 A(2A)AR-deficient micewere decreased compared with control mice after consuming an HFD. A(2A)AR-KO mice had decreased expression of the beta-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(2A)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 A(2A)AR-KO mice. Altogether, our data showed that A(2A)ARs control pancreatic dysfunction in HFD-induced obesity.-Csoka, B., Toro, G., Vindeirinho, J., Varga, Z. V., Koscso, B., Nemeth, Z. H., Kokai, E., Antonioli, L., Suleiman, M., Marchetti, P., Cseri, K., Deak, A., Virag, L., Pacher, P., Bai, P., Hasko ', G. A(2A) adenosine receptors control pancreatic dysfunction in high- fat-diet-induced obesity.

• 出版日期2017-11
• 单位rutgers; NIH