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Purinergic Signalling

, Volume 13, Issue 4, pp 497–510 | Cite as

Colonic motor dysfunctions in a mouse model of high-fat diet-induced obesity: an involvement of A2B adenosine receptors

  • Luca Antonioli
  • Carolina Pellegrini
  • Matteo FornaiEmail author
  • Erika Tirotta
  • Daniela Gentile
  • Laura Benvenuti
  • Maria Cecilia Giron
  • Valentina Caputi
  • Ilaria Marsilio
  • Genny Orso
  • Nunzia Bernardini
  • Cristina Segnani
  • Chiara Ippolito
  • Balázs Csóka
  • Zoltán H. Németh
  • György Haskó
  • Carmelo Scarpignato
  • Corrado Blandizzi
  • Rocchina Colucci
Original Article

Abstract

Adenosine A2B receptors (A2BR) regulate several enteric functions. However, their implication in the pathophysiology of intestinal dysmotility associated with high-fat diet (HFD)-induced obesity has not been elucidated. We investigated the expression of A2BR in mouse colon and their role in the mechanisms underlying the development of enteric dysmotility associated with obesity. Wild-type C57BL/6J mice were fed with HFD (60% kcal from fat) or normocaloric diet (NCD; 18% kcal from fat) for 8 weeks. Colonic A2BR localization was examined by immunofluorescence. The role of A2BR in the control of colonic motility was examined in functional experiments on longitudinal muscle preparations (LMPs). In NCD mice, A2BR were predominantly located in myenteric neurons; in HFD animals, their expression increased throughout the neuromuscular layer. Functionally, the A2BR antagonist MRS1754 enhanced electrically induced NK1-mediated tachykininergic contractions in LMPs from HFD mice, while it was less effective in tissues from NCD mice. The A2B receptor agonist BAY 60-6583 decreased colonic tachykininergic contractions in LMPs, with higher efficacy in preparations from obese mice. Both A2BR ligands did not affect contractions elicited by exogenous substance P. Obesity is related with a condition of colonic inflammation, leading to an increase of A2BR expression. A2BR, modulating the activity of excitatory tachykininergic nerves, participate to the enteric dysmotility associated with obesity.

Keywords

A2B receptors Colonic motor dysfunctions Substance P Obesity 

Notes

Acknowledgements

This work was supported by grants from San Camillo Hospital, Treviso (Italy), to MCG. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author contributions

LA, RC, MF, CP, GH, and CB designed the study; ET, DG, MCG, VC, IM, GO, NB, CS, CI, BC, and ZHN collected and analyzed the data; and LA, RC, MF, CS, CP, GH, and CB wrote the manuscript. All of the authors discussed the results and commented on the manuscript.

Compliance with ethical standards

Conflicts of interest

Luca Antonioli declares that he has no conflict of interest.

Carolina Pellegrini declares that she has no conflict of interest.

Matteo Fornai declares that he has no conflict of interest.

Erika Tirotta declares that she has no conflict of interest.

Daniela Gentile declares that she has no conflict of interest.

Laura Benvenuti declares that she has no conflict of interest.

Maria Cecilia Giron declares that she has no conflict of interest.

Valentina Caputi declares that she has no conflict of interest.

Ilaria Marsilio declares that she has no conflict of interest.

Genny Orso declares that she has no conflict of interest.

Nunzia Bernardini declares that she has no conflict of interest.

Cristina Segnani declares that she has no conflict of interest.

Chiara Ippolito declares that she has no conflict of interest.

Balázs Csóka declares that he has no conflict of interest.

Zoltán H. Németh declares that he has no conflict of interest.

György Haskó declares that he has no conflict of interest.

Carmelo Scarpignato declares that he has no conflict of interest.

Corrado Blandizzi declares that he has no conflict of interest.

Rocchina Colucci declares that she has no conflict of interest.

Ethical approval

The experiments were approved by the Ethical Committee for Animal Experimentation of the University of Pisa and by the Italian Ministry of Health (authorization no. 744/2015-PR).

Supplementary material

11302_2017_9577_Fig9_ESM.gif (111 kb)
Supplemental Fig. 1

Preparations of colonic longitudinal smooth muscle obtained from mice fed with normocaloric diet (NCD) or high-fat diet (HFD) maintained in standard Krebs solution. (A) Effects of increasing concentrations of MRS 1754 (0.001–1 μM) on contractions induced by electrical stimulation (ES, 10 Hz). (B) Effects of MRS 1754 (0.01 μM) on contractile responses to ES in the presence of 1,3-dipropyl-8-cyclopentylxanthine (DPCPX; 0.01 μM), 4-(2-[7-Amino-2-(2-furyl) [1,2,4] triazolo[2,3-a] [1, 3, 5]triazin-5-ylamino]ethyl)phenol (ZM 241385; 0.01 μM) and N-[9-Chloro-2-(2-furanyl)[1,2,4]-triazolo[1,5-c]quinazolin-5-yl]benzene acetamide (MRS 1220; 0.1 μM). Each column represents the mean ± standard error of mean value obtained from six experiments. *P < 0.05 vs control. (GIF 111 kb).

11302_2017_9577_MOESM1_ESM.tif (84 kb)
High resolution image (TIFF 84 kb).

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Copyright information

© Springer Science+Business Media B.V. 2017

Authors and Affiliations

  • Luca Antonioli
    • 1
    • 2
  • Carolina Pellegrini
    • 1
  • Matteo Fornai
    • 1
    Email author
  • Erika Tirotta
    • 1
  • Daniela Gentile
    • 1
  • Laura Benvenuti
    • 1
  • Maria Cecilia Giron
    • 3
  • Valentina Caputi
    • 3
    • 4
  • Ilaria Marsilio
    • 3
  • Genny Orso
    • 5
  • Nunzia Bernardini
    • 1
  • Cristina Segnani
    • 1
  • Chiara Ippolito
    • 1
  • Balázs Csóka
    • 2
  • Zoltán H. Németh
    • 6
  • György Haskó
    • 2
  • Carmelo Scarpignato
    • 7
  • Corrado Blandizzi
    • 1
  • Rocchina Colucci
    • 3
  1. 1.Department of Clinical and Experimental MedicineUniversity of PisaPisaItaly
  2. 2.Department of Surgery and Center for Immunity and Inflammation, Rutgers New Jersey Medical SchoolNewarkUSA
  3. 3.Department of Pharmaceutical and Pharmacological SciencesUniversity of PadovaPadovaItaly
  4. 4.San Camillo HospitalTrevisoItaly
  5. 5.Scientific Institute IRCCS Eugenio MedeaLeccoItaly
  6. 6.Department of Surgery, Morristown Medical CenterMorristownUSA
  7. 7.Laboratory of Clinical PharmacologyUniversity of ParmaParmaItaly

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