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

Mohamed-Sami Trabelsi, Mehdi Daoudi, Janne Prawitt, Sarah Ducastel, Véronique Touche, Sama I. Sayin, Alessia Perino, Cheryl A. Brighton, Yasmine Sebti, Jérôme Kluza, Olivier Briand, Hélène Dehondt, Emmanuelle Vallez, Emilie Dorchies, Grégory Baud, Valeria Spinelli, Nathalie Hennuyer, Sandrine Caron, Kadiombo Bantubungi, Robert Caiazzo, Frank Reimann, Philippe Marchetti, Philippe Lefebvre, Fredrik Bäckhed, Fiona M. Gribble, Kristina Schoonjans, François Pattou, Anne Tailleux, Bart Staels () and Sophie Lestavel
Additional contact information
Mohamed-Sami Trabelsi: European Genomic Institute for Diabetes (EGID)
Mehdi Daoudi: European Genomic Institute for Diabetes (EGID)
Janne Prawitt: European Genomic Institute for Diabetes (EGID)
Sarah Ducastel: European Genomic Institute for Diabetes (EGID)
Véronique Touche: European Genomic Institute for Diabetes (EGID)
Sama I. Sayin: Wallenberg Laboratory/Sahlgrenska Center for Cardiovascular and Metabolic Research, Sahlgrenska University Hospital
Alessia Perino: Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne
Cheryl A. Brighton: Cambridge Institute for Medical Research and Institute of Metabolic Sciences, Addenbrooke’s Hospital
Yasmine Sebti: European Genomic Institute for Diabetes (EGID)
Jérôme Kluza: Université de Lille
Olivier Briand: European Genomic Institute for Diabetes (EGID)
Hélène Dehondt: European Genomic Institute for Diabetes (EGID)
Emmanuelle Vallez: European Genomic Institute for Diabetes (EGID)
Emilie Dorchies: European Genomic Institute for Diabetes (EGID)
Grégory Baud: European Genomic Institute for Diabetes (EGID)
Valeria Spinelli: European Genomic Institute for Diabetes (EGID)
Nathalie Hennuyer: European Genomic Institute for Diabetes (EGID)
Sandrine Caron: European Genomic Institute for Diabetes (EGID)
Kadiombo Bantubungi: European Genomic Institute for Diabetes (EGID)
Robert Caiazzo: European Genomic Institute for Diabetes (EGID)
Frank Reimann: Cambridge Institute for Medical Research and Institute of Metabolic Sciences, Addenbrooke’s Hospital
Philippe Marchetti: Université de Lille
Philippe Lefebvre: European Genomic Institute for Diabetes (EGID)
Fredrik Bäckhed: Wallenberg Laboratory/Sahlgrenska Center for Cardiovascular and Metabolic Research, Sahlgrenska University Hospital
Fiona M. Gribble: Cambridge Institute for Medical Research and Institute of Metabolic Sciences, Addenbrooke’s Hospital
Kristina Schoonjans: Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne
François Pattou: European Genomic Institute for Diabetes (EGID)
Anne Tailleux: European Genomic Institute for Diabetes (EGID)
Bart Staels: European Genomic Institute for Diabetes (EGID)
Sophie Lestavel: European Genomic Institute for Diabetes (EGID)

Nature Communications, 2015, vol. 6, issue 1, 1-13

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8629

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