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

被引：30

作者：

Csoka, Balazs ^{[1
,2
]}

Toro, Gabor ^{[1
,2
]}

Vindeirinho, Joana ^{[1
]}

Varga, Zoltan V. ^{[3
]}

Koscso, Balazs ^{[4
]}

Nemeth, Zoltan H. ^{[1
,5
]}

Kokai, Endre ^{[6
]}

Antonioli, Luca ^{[8
]}

Suleiman, Mara ^{[8
]}

Marchetti, Piero ^{[8
]}

Cseri, Karolina ^{[6
]}

Deak, Adam ^{[7
]}

Virag, Laszlo ^{[6
,9
]}

Pacher, Pal ^{[3
]}

Bai, Peter ^{[6
,9
]}

Hasko, Gyorgy ^{[1
,2
,6
]}

机构：

[1] Rutgers New Jersey Med Sch, Dept Surg, Newark, NJ USA

[2] Rutgers New Jersey Med Sch, Ctr Immun & Inflammat, Newark, NJ USA

[3] NIAAA, NIH, Bethesda, MD USA

[4] Penn State Univ Coll Med, Dept Microbiol & Immunol, Hershey, PA USA

[5] Morristown Mem Med Ctr, Dept Surg, Morristown, NJ USA

[6] Univ Debrecen, Dept Med Chem, Fac Med, Debrecen, Hungary

[7] Univ Debrecen, Dept Operat Tech & Surg Res, Inst Surg, Debrecen, Hungary

[8] Univ Pisa, Dept Clin & Expt Med, Pisa, Italy

[9] Hungarian Acad Sci, Cell Biol & Signalling Res Grp, Debrecen, Hungary

来源：

FASEB JOURNAL | 2017年 / 31卷 / 11期

基金：

美国国家卫生研究院; 匈牙利科学研究基金会;

关键词：

diabetes; islet; beta-cell; beta-cell dedifferentiation; BETA-CELL DEDIFFERENTIATION; ENDOPLASMIC-RETICULUM STRESS; CHRONIC OXIDATIVE STRESS; INSULIN-SECRETION; ADIPOSE-TISSUE; GLUCOSE TOXICITY; MACROPHAGES; INFLAMMATION; SURVIVAL; MICE;

D O I：

10.1096/fj.201700398R

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：4985 / 4997

页数：13