title: Farnesoid X receptor inhibits glucagon-like peptide-1 production by enteroendocrine L cells.
abstract: Bile acids are signalling molecules, which activate the transmembrane receptor TGR5 and the nuclear receptor FXR. BA sequestrants (BAS) complex bile acids in the intestinal lumen and decrease intestinal FXR activity. The BAS-BA complex also induces glucagon-like peptide-1 (GLP-1) production by L cells which potentiates β-cell glucose-induced insulin secretion. Whether FXR is expressed in L cells and controls GLP-1 production is unknown. Here, we show that FXR activation in L cells decreases proglucagon expression by interfering with the glucose-responsive factor Carbohydrate-Responsive Element Binding Protein (ChREBP) and GLP-1 secretion by inhibiting glycolysis. In vivo, FXR deficiency increases GLP-1 gene expression and secretion in response to glucose hence improving glucose metabolism. Moreover, treatment of ob/ob mice with the BAS colesevelam increases intestinal proglucagon gene expression and improves glycaemia in a FXR-dependent manner. These findings identify the FXR/GLP-1 pathway as a new mechanism of BA control of glucose metabolism and a pharmacological target for type 2 diabetes.
authors.affiliation: European Genomic Institute for Diabetes (EGID), FR 3508, Lille F-59000, France.|Université de Lille, Lille F-59000, France.|INSERM UMR 1011, Lille F-59000, France.|Institut Pasteur de Lille, Lille F-59000, France.
authors.forename: Mohamed-Sami
authors.initials: MS
authors.lastname: Trabelsi
authors.affiliation: European Genomic Institute for Diabetes (EGID), FR 3508, Lille F-59000, France.|Université de Lille, Lille F-59000, France.|INSERM UMR 1011, Lille F-59000, France.|Institut Pasteur de Lille, Lille F-59000, France.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Daoudi
authors.affiliation: European Genomic Institute for Diabetes (EGID), FR 3508, Lille F-59000, France.|Université de Lille, Lille F-59000, France.|INSERM UMR 1011, Lille F-59000, France.|Institut Pasteur de Lille, Lille F-59000, France.
authors.forename: Janne
authors.initials: J
authors.lastname: Prawitt
authors.affiliation: European Genomic Institute for Diabetes (EGID), FR 3508, Lille F-59000, France.|Université de Lille, Lille F-59000, France.|INSERM UMR 1011, Lille F-59000, France.|Institut Pasteur de Lille, Lille F-59000, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Ducastel
authors.affiliation: European Genomic Institute for Diabetes (EGID), FR 3508, Lille F-59000, France.|Université de Lille, Lille F-59000, France.|INSERM UMR 1011, Lille F-59000, France.|Institut Pasteur de Lille, Lille F-59000, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Touche
authors.affiliation: Wallenberg Laboratory/Sahlgrenska Center for Cardiovascular and Metabolic Research, Sahlgrenska University Hospital, Gothenburg 413445, Sweden.|Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg 41345, Sweden.
authors.forename: Sama I
authors.initials: SI
authors.lastname: Sayin
authors.affiliation: Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne CH-1015, Switzerland.
authors.forename: Alessia
authors.initials: A
authors.lastname: Perino
authors.affiliation: Cambridge Institute for Medical Research and Institute of Metabolic Sciences, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK.
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Brighton
authors.affiliation: European Genomic Institute for Diabetes (EGID), FR 3508, Lille F-59000, France.|Université de Lille, Lille F-59000, France.|INSERM UMR 1011, Lille F-59000, France.|Institut Pasteur de Lille, Lille F-59000, France.
authors.forename: Yasmine
authors.initials: Y
authors.lastname: Sebti
authors.affiliation: Université de Lille, Lille F-59000, France.|INSERM U 837, Lille Cedex F- 59045, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Kluza
authors.affiliation: European Genomic Institute for Diabetes (EGID), FR 3508, Lille F-59000, France.|Université de Lille, Lille F-59000, France.|INSERM UMR 1011, Lille F-59000, France.|Institut Pasteur de Lille, Lille F-59000, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Briand
authors.affiliation: European Genomic Institute for Diabetes (EGID), FR 3508, Lille F-59000, France.|Université de Lille, Lille F-59000, France.|INSERM UMR 1011, Lille F-59000, France.|Institut Pasteur de Lille, Lille F-59000, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Dehondt
authors.affiliation: European Genomic Institute for Diabetes (EGID), FR 3508, Lille F-59000, France.|Université de Lille, Lille F-59000, France.|INSERM UMR 1011, Lille F-59000, France.|Institut Pasteur de Lille, Lille F-59000, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Vallez
authors.affiliation: European Genomic Institute for Diabetes (EGID), FR 3508, Lille F-59000, France.|Université de Lille, Lille F-59000, France.|INSERM UMR 1011, Lille F-59000, France.|Institut Pasteur de Lille, Lille F-59000, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Dorchies
authors.affiliation: European Genomic Institute for Diabetes (EGID), FR 3508, Lille F-59000, France.|Université de Lille, Lille F-59000, France.|Centre de Bio-Pathologie, Plate-forme de Biothérapie, Banque de Tissus, Centre Hospitalier Régional Universitaire, Lille F-59000, France.|INSERM UMR 859, Lille F-59000, France.
authors.forename: Grégory
authors.initials: G
authors.lastname: Baud
authors.affiliation: European Genomic Institute for Diabetes (EGID), FR 3508, Lille F-59000, France.|Université de Lille, Lille F-59000, France.|INSERM UMR 1011, Lille F-59000, France.|Institut Pasteur de Lille, Lille F-59000, France.
authors.forename: Valeria
authors.initials: V
authors.lastname: Spinelli
authors.affiliation: European Genomic Institute for Diabetes (EGID), FR 3508, Lille F-59000, France.|Université de Lille, Lille F-59000, France.|INSERM UMR 1011, Lille F-59000, France.|Institut Pasteur de Lille, Lille F-59000, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Hennuyer
authors.affiliation: European Genomic Institute for Diabetes (EGID), FR 3508, Lille F-59000, France.|Université de Lille, Lille F-59000, France.|INSERM UMR 1011, Lille F-59000, France.|Institut Pasteur de Lille, Lille F-59000, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Caron
authors.affiliation: European Genomic Institute for Diabetes (EGID), FR 3508, Lille F-59000, France.|Université de Lille, Lille F-59000, France.|INSERM UMR 1011, Lille F-59000, France.|Institut Pasteur de Lille, Lille F-59000, France.
authors.forename: Kadiombo
authors.initials: K
authors.lastname: Bantubungi
authors.affiliation: European Genomic Institute for Diabetes (EGID), FR 3508, Lille F-59000, France.|Université de Lille, Lille F-59000, France.|Centre de Bio-Pathologie, Plate-forme de Biothérapie, Banque de Tissus, Centre Hospitalier Régional Universitaire, Lille F-59000, France.|INSERM UMR 859, Lille F-59000, France.
authors.forename: Robert
authors.initials: R
authors.lastname: Caiazzo
authors.affiliation: Cambridge Institute for Medical Research and Institute of Metabolic Sciences, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK.
authors.forename: Frank
authors.initials: F
authors.lastname: Reimann
authors.affiliation: Université de Lille, Lille F-59000, France.|INSERM U 837, Lille Cedex F- 59045, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Marchetti
authors.affiliation: European Genomic Institute for Diabetes (EGID), FR 3508, Lille F-59000, France.|Université de Lille, Lille F-59000, France.|INSERM UMR 1011, Lille F-59000, France.|Institut Pasteur de Lille, Lille F-59000, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Lefebvre
authors.affiliation: Wallenberg Laboratory/Sahlgrenska Center for Cardiovascular and Metabolic Research, Sahlgrenska University Hospital, Gothenburg 413445, Sweden.|Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg 41345, Sweden.|Section for Metabolic Receptology and Enteroendocrinology, Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen 2200, Denmark.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Bäckhed
authors.affiliation: Cambridge Institute for Medical Research and Institute of Metabolic Sciences, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK.
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Gribble
authors.affiliation: Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne CH-1015, Switzerland.
authors.forename: Kristina
authors.initials: K
authors.lastname: Schoonjans
authors.affiliation: European Genomic Institute for Diabetes (EGID), FR 3508, Lille F-59000, France.|Université de Lille, Lille F-59000, France.|Centre de Bio-Pathologie, Plate-forme de Biothérapie, Banque de Tissus, Centre Hospitalier Régional Universitaire, Lille F-59000, France.|INSERM UMR 859, Lille F-59000, France.
authors.forename: François
authors.initials: F
authors.lastname: Pattou
authors.affiliation: European Genomic Institute for Diabetes (EGID), FR 3508, Lille F-59000, France.|Université de Lille, Lille F-59000, France.|INSERM UMR 1011, Lille F-59000, France.|Institut Pasteur de Lille, Lille F-59000, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Tailleux
authors.affiliation: European Genomic Institute for Diabetes (EGID), FR 3508, Lille F-59000, France.|Université de Lille, Lille F-59000, France.|INSERM UMR 1011, Lille F-59000, France.|Institut Pasteur de Lille, Lille F-59000, France.
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
authors.affiliation: European Genomic Institute for Diabetes (EGID), FR 3508, Lille F-59000, France.|Université de Lille, Lille F-59000, France.|INSERM UMR 1011, Lille F-59000, France.|Institut Pasteur de Lille, Lille F-59000, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Lestavel
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D000069472:Colesevelam Hydrochloride / Q000494:pharmacology; D003106:Colon / Q000166:cytology / Q000378:metabolism; D059305:Diet, High-Fat; D019858:Enteroendocrine Cells / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1 / Q000235:genetics* / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D007082:Ileum / Q000166:cytology / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000166:cytology; D007583:Jejunum / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese; D009687:Nuclear Proteins / Q000378:metabolism; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D052336:Proglucagon / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D064449:Sequestering Agents / Q000494:pharmacology; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D000924:Anticholesteremic Agents; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D001647:Bile Acids and Salts; D001786:Blood Glucose; D000069472:Colesevelam Hydrochloride; D052216:Glucagon-Like Peptide 1; D007328:Insulin; D009687:Nuclear Proteins; D052336:Proglucagon; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D043562:Receptors, G-Protein-Coupled; D064449:Sequestering Agents; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C513561:Gpbar1 protein, mouse; C116385:MLXIPL protein, human; C506001:Mlxipl protein, mouse