Article Text

Original research
Decoy bypass for appetite suppression in obese adults: role of synergistic nutrient sensing receptors GPR84 and FFAR4 on colonic endocrine cells
  1. Madusha Peiris1,
  2. Rubina Aktar1,
  3. David Reed2,
  4. Vincent Cibert-Goton1,
  5. Ausra Zdanaviciene1,
  6. Writaja Halder1,
  7. Adam Robinow1,
  8. Simon Corke1,
  9. Harween Dogra1,
  10. Charles H Knowles1,
  11. Ashley Blackshaw1
  1. 1 Centre for Neuroscience, Surgery and Trauma, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
  2. 2 Gastrointestinal Diseases Research, Queen's University, Kingston, Queensland, Canada
  1. Correspondence to Dr Madusha Peiris, Neurogastroenterology Group, Queen Mary University of London, London, UK; m.peiris{at}qmul.ac.uk

Abstract

Objective Colonic enteroendocrine cells (EECs) store and release potent anorectic hormones that are key regulators of satiety. EECs express multiple nutrient sensing receptors, particularly for medium-chain fatty acids (MCFAs): GPR84 and FFAR4. Here we show a non-surgical approach with targeted colonic delivery of MCFA, which induces EEC and neuronal activation leading to anorectic effects.

Design A randomised, double-blind, placebo-controlled, cross-over study was performed in obese adults given combined GPR84 and FFAR4 agonists in colonic release capsules before meals. We measured serum hormones, energy intake and appetite perception. Cell type, activation by agonists and hormone/serotonin release were determined in human colonic explants. Mouse colonic afferent nerve responses to nutrients/mediators were recorded electrophysiologically.

Results Subjects receiving GPR84 and FFAR4 agonists had reduced overall calorific intake and increased postprandial levels of PYY versus placebo. Receptors including GPR84 and FFAR4 were coexpressed on human colonic EEC. Activation of GPR84 exclusively induced intracellular pERK, whereas FFAR4 selectively activated pCaMKII. Coactivation of GPR84 and FFAR4 induced both phosphoproteins, and superadditive release of GLP-1 and PYY. Nutrients and hormones convergently activated murine colonic afterent nerves via GLP-1, Y2 and 5-HT3 receptors.

Conclusions Colonic GPR84 and FFAR4 agonists reduce energy intake and increase postprandial PYY in obese adults. Human colonic EECs coexpress these receptors, which activate cells via parallel intracellular pathways and synergistically evoke hormone release. Further synergism occurs in sensory nerve responses to MCFA and EEC mediators. Thus, synergistic activation of colonic endocrine cells via nutrient receptors is an important target for metabolic regulation.

Trail registration number NCT04292236.

  • obesity
  • appetite
  • gut hormones
  • neuroendocrine cells

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

https://creativecommons.org/licenses/by/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.

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Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

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Footnotes

  • Correction notice This article has been published Online First. Reference 25 has been updated and the acknowledgements section added.

  • Contributors MP conceived, designed and conducted experiments and managed the clinical trial. RA, AZ and WH recruited volunteers and conducted the clinical trial. DR developed the electrophysiology technique described. DR and VC-G conducted electrophysiology experiments. AR and SC performed immunohistochemistry. HD obtained biopsies and assisted with hormone/protein assay development. CK provided clinical supervision to the volunteer study. AB conceived and supervised the project and obtained funding. All authors contributed to manuscript preparation.

  • Funding Funding for this study was obtained from the Wellcome Trust, Bowel and Cancer Research, the JP Moulton Charitable Foundation and the Biotechnology and Biological Sciences Research Council (BBSRC) Institute Strategic Programme Gut Microbes and Health BB/R012490/1 and its constituent project (BBS/E/F/000PR10355).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.