Article Text

Original article
Apelin targets gut contraction to control glucose metabolism via the brain
  1. Audren Fournel1,2,3,
  2. Anne Drougard1,2,3,
  3. Thibaut Duparc2,4,
  4. Alysson Marlin1,2,3,
  5. Stuart M Brierley5,6,7,
  6. Joel Castro5,
  7. Sophie Le-Gonidec1,2,3,
  8. Bernard Masri8,
  9. André Colom1,2,3,
  10. Alexandre Lucas1,2,3,
  11. Perrine Rousset3,9,
  12. Nicolas Cenac3,9,
  13. Nathalie Vergnolle3,9,
  14. Philippe Valet1,2,3,
  15. Patrice D Cani2,4,
  16. Claude Knauf1,2,3
  1. 1Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Toulouse Cedex 4, France
  2. 2NeuroMicrobiota, European Associated Laboratory (EAL) INSERM/UCL
  3. 3Université Paul Sabatier, Toulouse, France
  4. 4Université Catholique de Louvain (UCL), Louvain Drug Research Institute, LDRI, Metabolism and Nutrition research group, WELBIO (Walloon Excellence in Life sciences and BIOtechnology), Brussels, Belgium
  5. 5Visceral Pain Group, Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, University of Adelaide, South Australia Health and Medical Research Institute (SAHMRI), Adelaide, South Australia, Australia
  6. 6Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, South Australia, Australia
  7. 7Discipline of Physiology, Faculty of Health Sciences, The University of Adelaide, Adelaide, South Australia, Australia
  8. 8Institut National de la Santé et de la Recherche Médicale (INSERM), U1037, Centre de Recherches en Cancérologie de Toulouse (CRCT), CHU Rangueil, Toulouse, Cedex 4, France
  9. 9Institut National de la Santé et de la Recherche Médicale (INSERM), U1043, Centre de Physiopathologie de Toulouse Purpan (CPTP), CHU Purpan, Toulouse, Cedex 03, France
  1. Correspondence to Professor Patrice D Cani, Université Catholique de Louvain (UCL), Louvain Drug Research Institute, LDRI, Metabolism and Nutrition research group, WELBIO, WELBIO (Walloon Excellence in Life sciences and BIOtechnology), Av. E. Mounier, 73 B1.73.11, Brussels B-1200, Belgium; Patrice.cani{at}uclouvain.be
  2. Professor Claude Knauf, Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Paul Sabatier, CHU Rangueil, 1 Avenue Jean Poulhès, BP84225, 31432 Toulouse Cedex 4, France; Claude.knauf{at}inserm.fr

Abstract

Objective The gut–brain axis is considered as a major regulatory checkpoint in the control of glucose homeostasis. The detection of nutrients and/or hormones in the duodenum informs the hypothalamus of the host's nutritional state. This process may occur via hypothalamic neurons modulating central release of nitric oxide (NO), which in turn controls glucose entry into tissues. The enteric nervous system (ENS) modulates intestinal contractions in response to various stimuli, but the importance of this interaction in the control of glucose homeostasis via the brain is unknown. We studied whether apelin, a bioactive peptide present in the gut, regulates ENS-evoked contractions, thereby identifying a new physiological partner in the control of glucose utilisation via the hypothalamus.

Design We measured the effect of apelin on electrical and mechanical duodenal responses via telemetry probes and isotonic sensors in normal and obese/diabetic mice. Changes in hypothalamic NO release, in response to duodenal contraction modulated by apelin, were evaluated in real time with specific amperometric probes. Glucose utilisation in tissues was measured with orally administrated radiolabeled glucose.

Results In normal and obese/diabetic mice, glucose utilisation is improved by the decrease of ENS/contraction activities in response to apelin, which generates an increase in hypothalamic NO release. As a consequence, glucose entry is significantly increased in the muscle.

Conclusions Here, we identify a novel mode of communication between the intestine and the hypothalamus that controls glucose utilisation. Moreover, our data identified oral apelin administration as a novel potential target to treat metabolic disorders.

  • OBESITY
  • ENTERIC NERVOUS SYSTEM
  • GUT HORMONES
  • GASTROINTESTINAL PHYSIOLOGY
  • GLUCOSE METABOLISM

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Footnotes

  • Contributors AF and AD contributed equally. AF, AD, TD, AM, SMB, JC, SL-G, BM, AC, AL, PR, NC, PDC and CK acquired data. AF, AD, PDC and CK have performed the study concept and design. AF, AD, PDC and CK analysed and interpreted the data. AF, AD, TD, SMB, JC, NC, NV, PV, PDC and CK wrote the manuscript.

  • Funding This work was supported by the Fonds de la Recherche Scientifique—FNRS for the FRFS-WELBIO under grant: WELBIO-CR-2012S-02R. This work was supported in part by the Funds InBev-Baillet Latour (Grant for Medical Research 2015). The authors thank the Societe Francaise de Nutrition (SFN) and the Fondation Recherche Médicale (FRM) (Grant ING20150532586) for financial support. PDC is the recipient of grants from FNRS (convention J.0084.15, convention 3.4579.11), PDR (Projet de Recherche, convention: T.0138.14), FRM (Fondation Recherche Medicale) and ARC (Action de Recherche Concertée—Communauté française de Belgique convention: 12/17-047). PDC is also a recipient of an ERC Starting Grant 2013 (European Research Council, Starting grant 336452-ENIGMO). NV is recipient of an ERC (Consolidator Grant, PIPE). SMB is an NHMRC Australia R.D Wright Biomedical Fellow.

  • Competing interests None declared.

  • Ethics approval Experiments were conducted according to the European Community regulations concerning the protection of experimental animals and were approved by the local Animal Care and Use Committee.

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

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