The nuclear receptor FXR inhibits Glucagon-Like Peptide-1 secretion in response to microbiota-derived Short-Chain Fatty Acids

Autor: Alexis Boulinguiez, Jean-Sébastien Annicotte, Laura Butruille, Anne Tailleux, Olivier Briand, Mohamed-Sami Trabelsi, Laure B. Bindels, Emilie Dorchies, Simon Peschard, Véronique Touche, Sandrine Caron, Emmanuelle Vallez, Sophie Lestavel, Sarah Ducastel, Steve Lancel, Oscar Chávez-Talavera, Nathalie M. Delzenne, Kadiombo Bantubungi, Bart Staels, Margaux Nawrot
Přispěvatelé: UCL - SSS/LDRI - Louvain Drug Research Institute, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Metabolism and Nutrition Research Group [Bruxelles, Belgique], Louvain Drug Research Institute [Bruxelles, Belgique] (LDRI), Université Catholique de Louvain = Catholic University of Louvain (UCL)-Université Catholique de Louvain = Catholic University of Louvain (UCL), This work was supported by grants from 'European Genomic Institute for Diabetes' (E.G.I.D., ANR-10-LABX-46), European Commission and Agence Nationale pour la Recherche (ANR-FXREn). B.S. holds a 'European Research Council advanced Grant' (694717). A.B., M.N., O.C.T. and M.S.T. received a PhD fellowship from the French Ministry of Research., ANR-11-BSV1-0032,FXRen,Rôle du récepteur nucléaire Farnesoid X Receptor (FXR) dans l'homéostasie énergétique(2011), European Project: 694717,H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) ,ImmunoBile(2016), Récepteurs nucléaires, maladies cardiovasculaires et diabète (EGID), Université de Lille, Droit et Santé-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Génomique Intégrative et Modélisation des Maladies Métaboliques (EGID), Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Louvain Drug Research Institute [Bruxelles, Belgique], Université Catholique de Louvain (UCL)-Université Catholique de Louvain (UCL), Bodescot, Myriam, BLANC - Rôle du récepteur nucléaire Farnesoid X Receptor (FXR) dans l'homéostasie énergétique - - FXRen2011 - ANR-11-BSV1-0032 - BLANC - VALID, Bile acid, immune-metabolism, lipid and glucose homeostasis - ImmunoBile - - H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) 2016-09-01 - 2021-08-31 - 694717 - VALID, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M)
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Male
0301 basic medicine
medicine.medical_specialty
Colon
medicine.drug_class
Receptors
Cytoplasmic and Nuclear
lcsh:Medicine
Incretin
030209 endocrinology & metabolism
Enteroendocrine cell
[SDV.BC]Life Sciences [q-bio]/Cellular Biology
Article
Receptors
G-Protein-Coupled
Mice
03 medical and health sciences
0302 clinical medicine
Nuclear receptors
Glucagon-Like Peptide 1
Internal medicine
medicine
Animals
Secretion
Gastrointestinal hormones
lcsh:Science
Receptor
[SDV.BC] Life Sciences [q-bio]/Cellular Biology
Mice
Knockout
Multidisciplinary
Bile acid
Chemistry
Microbiota
lcsh:R
digestive
oral
and skin physiology
Endocrine system and metabolic diseases
Nutrient signalling
Fatty Acids
Volatile
Glucagon-like peptide-1
3. Good health
Mice
Inbred C57BL
030104 developmental biology
Endocrinology
Nuclear receptor
Preclinical research
lcsh:Q
Farnesoid X receptor
Zdroj: Scientific reports, Vol. 10, no.1, p. 174 [1-10] (2020)
Scientific Reports
Scientific Reports, 2020, 10 (1), pp.174. ⟨10.1038/s41598-019-56743-x⟩
Scientific Reports, Nature Publishing Group, 2020, 10 (1), pp.174. ⟨10.1038/s41598-019-56743-x⟩
Scientific Reports, Vol 10, Iss 1, Pp 1-10 (2020)
ISSN: 2045-2322
Popis: The gut microbiota participates in the control of energy homeostasis partly through fermentation of dietary fibers hence producing short-chain fatty acids (SCFAs), which in turn promote the secretion of the incretin Glucagon-Like Peptide-1 (GLP-1) by binding to the SCFA receptors FFAR2 and FFAR3 on enteroendocrine L-cells. We have previously shown that activation of the nuclear Farnesoid X Receptor (FXR) decreases the L-cell response to glucose. Here, we investigated whether FXR also regulates the SCFA-induced GLP-1 secretion. GLP-1 secretion in response to SCFAs was evaluated ex vivo in murine colonic biopsies and in colonoids of wild-type (WT) and FXR knock-out (KO) mice, in vitro in GLUTag and NCI-H716 L-cells activated with the synthetic FXR agonist GW4064 and in vivo in WT and FXR KO mice after prebiotic supplementation. SCFA-induced GLP-1 secretion was blunted in colonic biopsies from GW4064-treated mice and enhanced in FXR KO colonoids. In vitro FXR activation inhibited GLP-1 secretion in response to SCFAs and FFAR2 synthetic ligands, mainly by decreasing FFAR2 expression and downstream Gαq-signaling. FXR KO mice displayed elevated colonic FFAR2 mRNA levels and increased plasma GLP-1 levels upon local supply of SCFAs with prebiotic supplementation. Our results demonstrate that FXR activation decreases L-cell GLP-1 secretion in response to inulin-derived SCFA by reducing FFAR2 expression and signaling. Inactivation of intestinal FXR using bile acid sequestrants or synthetic antagonists in combination with prebiotic supplementation may be a promising therapeutic approach to boost the incretin axis in type 2 diabetes.
Databáze: OpenAIRE
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