Abstract
The role played by adenosine A2B receptors (A2BRs) in the regulation of enteric glial cell (EGC) functions remains unclear. This study was aimed at investigating the involvement of A2BRs in the control of EGC functions in a model of obesity. C57BL/6 mice were fed with standard diet (SD) or high fat diet (HFD) for eight weeks. Colonic tachykininergic contractions were recorded in the presence of BAY60-6583 (A2BRs agonist), MRS1754 (A2BRs antagonist), and the gliotoxin fluorocitrate. Immunofluorescence distribution of HuC/D, S100β, and A2BRs was assessed in whole mount preparations of colonic myenteric plexus. To mimic HFD, EGCs were incubated in vitro with palmitate (PA) and lipopolysaccharide (LPS), in the absence or in the presence of A2BR ligands. Toll-like receptor 4 (TLR4) expression was assessed by Western blot analysis. Interleukin-1β (IL-1β), substance P (SP), and glial cell derived neurotrophic factor (GDNF) release were determined by enzyme-linked immunosorbent assay (ELISA) assays. MRS1754 enhanced electrically evoked tachykininergic contractions of colonic preparations from HFD mice. BAY60-6583 decreased the evoked tachykininergic contractions, with higher efficacy in HFD mice. Such effects were blunted upon incubation with fluorocitrate. In in vitro experiments on EGCs, PA and LPS increased TLR4 expression as well as IL-1β, GDNF, and SP release. Incubation with BAY60-6583 reduced TLR4 expression as well as IL-1β, GDNF, and SP release. Such effects were blunted by MRS1754. The present results suggest that A2BRs, expressed on EGCs, participate in the modulation of enteric inflammation and altered tachykininergic responses associated with obesity, thus representing a potential therapeutic target.
Highlights
Enteric glial cells (EGCs), the major component of the enteric nervous system (ENS), play a pivotal role in the regulation of intestinal homeostasis [1,2]
A recent paper from our group showed that EGCs are involved in the development of enteric motor disorders associated with a high fat diet (HFD), through an increase in the release of pro-inflammatory mediators and tachykininergic neurotransmission [9]
Fourth day, cells were lysed for analysis of toll-like receptor 4 (TLR4) expression and the culture media were collected for analysis of substance P (SP), glial cell derived neurotrophic factor (GDNF), and interleukin (IL)-1β release
Summary
Enteric glial cells (EGCs), the major component of the enteric nervous system (ENS), play a pivotal role in the regulation of intestinal homeostasis [1,2]. On the basis of this knowledge, the enteric glia is emerging as a new frontier in neuro-gastroenterology, representing a potential therapeutic target in several gastrointestinal (GI) disorders [3] In this regard, several studies have shown that morphofunctional alterations of EGCs participate in the onset of intestinal neuronal alterations and maintenance of inflammatory conditions [2,4], suggesting their putative involvement in gut abnormalities under adverse conditions, including obesity. On the basis of this background, the present study aimed at investigating the role played by A2B Rs in the modulation of EGC functions in a murine model of diet-induced obesity, in order to identify novel pharmacological therapeutic targets potentially suitable for the management of GI motor dysfunctions associated with obesity
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
