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

M Trabelsi ,Fredrik Bäckhed,Olivier Briand,Janne Prawitt,Sophie Lestavel,Kristina Schoonjans,Philippe Marchetti,Yasmine Sebti,Jérôme Kluza,Anne Tailleux,Kadiombo Bantubungi,Emilie Dorchies,Fiona M Gribble,Cheryl A Brighton,Nathalie Hennuyer,Frank Reimann,Mehdi Daoudi,Sarah Ducastel,François Pattou,Emmanuelle Vallez,Alessia Perino,Hélène Dehondt,Grégory Baud,Véronique Touche,Sandrine Caron,Sama I Sayin,Philippe Lefèbvre ,V Spinelli ,Robert Caïazzo

doi:10.1038/ncomms8629

Abstract

Bile acids (BA) are signalling molecules which activate the transmembrane receptor TGR5 and the nuclear receptor FXR. BA sequestrants (BAS) complex BA 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 glycemia 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.

Highlights

Bile acids are signalling molecules, which activate the transmembrane receptor TGR5 and the nuclear receptor FXR
These data demonstrate that glucose metabolism through the glycolysis pathway is necessary for the glucose-dependent Carbohydrate-Responsive Element Binding Protein (ChREBP)-mediated increase of proglucagon gene expression, which is inhibited upon FXR activation
These results show that the glucagon-like peptide-1 (GLP-1)/GLP-1 receptor (GLP-1R) pathway contributes to the improved glucose homeostasis upon FXR deficiency

Summary

Results

FXR decreases proglucagon mRNA levels in mice and humans. Previous studies have reported high expression of FXR in intestinal epithelial cells[22,23]. FXR activation results in the expected induction of mRNA levels of FGF19, the human FGF15 orthologue (Supplementary Fig. 1c), whereas proglucagon gene expression decreases (Fig. 1f). Incubation of GLUTag cells for 24 h with increasing concentrations of GW4064 or with GW4064 (5 mmol l À 1) for different times in standard culture glucose concentrations (5.6 mmol l À 1) decreases proglucagon mRNA levels in a dose- and timedependent manner with a maximum effect at 5 mmol l À 1 (Fig. 3a), a concentration often used to study FXR activation[12,28], after 24 h of treatment (Fig. 3b). Decreases proglucagon mRNA and protein levels in siCtrl cells, whereas such a decrease is not observed in siFxr cells, indicating that FXR is required for the decrease of proglucagon gene expression upon GW4064 treatment (Fig. 3c,d). FXR activation for 24 h with either mRNA relative levels a

Proglucagon

Discussion

Methods