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Farnesoid X receptor inhibits glucagon-like peptide-1 production by enteroendocrine L cells.

  • Trabelsi MS European Genomic Institute for Diabetes (EGID), FR 3508, Lille F-59000, France.
  • Daoudi M European Genomic Institute for Diabetes (EGID), FR 3508, Lille F-59000, France.
  • Prawitt J European Genomic Institute for Diabetes (EGID), FR 3508, Lille F-59000, France.
  • Ducastel S European Genomic Institute for Diabetes (EGID), FR 3508, Lille F-59000, France.
  • Touche V European Genomic Institute for Diabetes (EGID), FR 3508, Lille F-59000, France.
  • Sayin SI Wallenberg Laboratory/Sahlgrenska Center for Cardiovascular and Metabolic Research, Sahlgrenska University Hospital, Gothenburg 413445, Sweden.
  • Perino A Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne CH-1015, Switzerland.
  • Brighton CA Cambridge Institute for Medical Research and Institute of Metabolic Sciences, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK.
  • Sebti Y European Genomic Institute for Diabetes (EGID), FR 3508, Lille F-59000, France.
  • Kluza J Université de Lille, Lille F-59000, France.
  • Briand O European Genomic Institute for Diabetes (EGID), FR 3508, Lille F-59000, France.
  • Dehondt H European Genomic Institute for Diabetes (EGID), FR 3508, Lille F-59000, France.
  • Vallez E European Genomic Institute for Diabetes (EGID), FR 3508, Lille F-59000, France.
  • Dorchies E European Genomic Institute for Diabetes (EGID), FR 3508, Lille F-59000, France.
  • Baud G European Genomic Institute for Diabetes (EGID), FR 3508, Lille F-59000, France.
  • Spinelli V European Genomic Institute for Diabetes (EGID), FR 3508, Lille F-59000, France.
  • Hennuyer N European Genomic Institute for Diabetes (EGID), FR 3508, Lille F-59000, France.
  • Caron S European Genomic Institute for Diabetes (EGID), FR 3508, Lille F-59000, France.
  • Bantubungi K European Genomic Institute for Diabetes (EGID), FR 3508, Lille F-59000, France.
  • Caiazzo R European Genomic Institute for Diabetes (EGID), FR 3508, Lille F-59000, France.
  • Reimann F Cambridge Institute for Medical Research and Institute of Metabolic Sciences, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK.
  • Marchetti P Université de Lille, Lille F-59000, France.
  • Lefebvre P European Genomic Institute for Diabetes (EGID), FR 3508, Lille F-59000, France.
  • Bäckhed F Wallenberg Laboratory/Sahlgrenska Center for Cardiovascular and Metabolic Research, Sahlgrenska University Hospital, Gothenburg 413445, Sweden.
  • Gribble FM Cambridge Institute for Medical Research and Institute of Metabolic Sciences, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK.
  • Schoonjans K Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne CH-1015, Switzerland.
  • Pattou F European Genomic Institute for Diabetes (EGID), FR 3508, Lille F-59000, France.
  • Tailleux A European Genomic Institute for Diabetes (EGID), FR 3508, Lille F-59000, France.
  • Staels B European Genomic Institute for Diabetes (EGID), FR 3508, Lille F-59000, France.
  • Lestavel S European Genomic Institute for Diabetes (EGID), FR 3508, Lille F-59000, France.
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  • 2015-07-03
Published in:
  • Nature communications. - 2015
Animals
Anticholesteremic Agents
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
Bile Acids and Salts
Blood Glucose
Colesevelam Hydrochloride
Colon
Diet, High-Fat
Enteroendocrine Cells
Glucagon-Like Peptide 1
Glycolysis
Humans
Ileum
Insulin
Insulin Secretion
Insulin-Secreting Cells
Intestinal Mucosa
Intestines
Jejunum
Mice
Mice, Knockout
Mice, Obese
Nuclear Proteins
Obesity
Proglucagon
RNA, Messenger
Receptors, Cytoplasmic and Nuclear
Receptors, G-Protein-Coupled
Sequestering Agents
Signal Transduction
Transcription Factors
English 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.
Language
  • English
Open access status
gold
Identifiers
Persistent URL
https://folia.unifr.ch/global/documents/209908
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