Format

Send to

Choose Destination
Nat Commun. 2015 Jul 2;6:7629. doi: 10.1038/ncomms8629.

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

Author information

1
1] European Genomic Institute for Diabetes (EGID), FR 3508, Lille F-59000, France [2] Université de Lille, Lille F-59000, France [3] INSERM UMR 1011, Lille F-59000, France [4] Institut Pasteur de Lille, Lille F-59000, France.
2
1] Wallenberg Laboratory/Sahlgrenska Center for Cardiovascular and Metabolic Research, Sahlgrenska University Hospital, Gothenburg 413445, Sweden [2] Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg 41345, Sweden.
3
Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne CH-1015, Switzerland.
4
Cambridge Institute for Medical Research and Institute of Metabolic Sciences, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK.
5
1] Université de Lille, Lille F-59000, France [2] INSERM U 837, Lille Cedex F- 59045, France.
6
1] European Genomic Institute for Diabetes (EGID), FR 3508, Lille F-59000, France [2] Université de Lille, Lille F-59000, France [3] Centre de Bio-Pathologie, Plate-forme de Biothérapie, Banque de Tissus, Centre Hospitalier Régional Universitaire, Lille F-59000, France [4] INSERM UMR 859, Lille F-59000, France.
7
1] Wallenberg Laboratory/Sahlgrenska Center for Cardiovascular and Metabolic Research, Sahlgrenska University Hospital, Gothenburg 413445, Sweden [2] Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg 41345, Sweden [3] Section for Metabolic Receptology and Enteroendocrinology, Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen 2200, Denmark.

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.

PMID:
26134028
PMCID:
PMC4579574
DOI:
10.1038/ncomms8629
[Indexed for MEDLINE]
Free PMC Article

Publication type, MeSH terms, Substances, Grant support

Publication type

MeSH terms

Substances

Grant support

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center