A _2A adenosine receptors control pancreatic dysfunction in high‐fat‐diet‐induced obesity

Abstract

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.

Bone Marrow and Adipose Tissue Adenosine Receptors Effect on Osteogenesis and Adipogenesis

“…A2aAR KO mice had greater abdominal fat mass, increased adipocyte size than WT mice, greater insulin resistance and glucose intolerance [ 79 , 80 ]. Furthermore, in another study, A2aAR KO mice fed an HFD for 16 weeks had reduced glucose tolerance due to a decrease in insulin secretion by the pancreas rather than a difference in insulin sensitivity [ 81 ]. In an HFD model of obesity in Swiss mice, the administration of CGS21680, an A2aAR agonist, improved glucose homeostasis, as determined by insulin tolerance test, and reduced inflammatory markers such as tumor necrosis factor alpha (TNFα) systemically and in the visceral adipose tissue [ 82 ].…”

Hypoxia enhances indoleamine 2,3-dioxygenase production in dendritic cells

“…During chronic inflammation, a common factor in metabolic syndromes, the local hypoxic microenvironment may upregulate extracellular adenosine production. Adenosine controls insulin signals in adipose tissue, muscle, and liver [ 30 , 31 ], and all four adenosine receptors are reportedly involved in glucose homeostasis, adipogenesis, and insulin resistance [ 32 ]. Increased levels of IDO-generated tryptophan metabolites, the kynurenines, may promote metabolic syndrome development via pro-oxidative, neurotoxic, and apoptotic activities, along with upregulation of inducible nitric oxide synthase, phospholipase A2, arachidonic acid, prostaglandin, 5-lipoxygenase, and leukotriene cascade [ 33 ].…”

KD-64 – a new selective A2Aadenosine receptor antagonist has anti-inflammatory activity but contrary to the non-selective antagonist – caffeine does not reduce diet-induced obesity in mice

“…It has been also demonstrated that A 2A receptor knockout mice exhibit impaired thermogenesis, oxygen consumption, and lipolysis [20]. Moreover, Csóka et al, (2017) observed the reduced food intake in such mice and consequently a lower body mass as compared to control animals [21]. A strong functional interaction between the dopamine D 2 and adenosine A 2A receptors [22] has been further discovered and a blockade of adenosine A 2A receptor can even mimic the action of D 2 agonists [23].…”