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

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.

Targeting the gastrointestinal tract to treat type 2 diabetes

“…Furthermore, treatment with a gut-specific FXR agonist, fexaramine, reduces diet-induced increases in hepatic glucose production in mice, likely due to a robust increase in FGF 15 (Fang et al 2015). In contrast, some studies suggest that intestinal inhibition of FXR may in fact be beneficial via a reduction in intestinally derived ceramides , Jiang et al 2015, or via increased GLP-1 signalling (Trabelsi et al 2015), warranting further research into FXR agonism/antagonism for the treatment of diabetes. Interestingly, it has also been proposed that FXR-mediated metabolic improvements are due to alterations of the gut microbiota (Ryan et al 2014).…”

The intestinal microbiota, energy balance, and malnutrition: emphasis on the role of short-chain fatty acids

“…Another bile acid receptor is GPR TGR5, which increases thermogenesis and energy expenditure in BAT [60]. Both FXR and TGR5 are expressed on enteroendocrine L-cells and regulate GLP-1 synthesis: TGR5 induces GLP-1 synthesis [60], whereas FXR activation reduced it [61]. Thus, the intestinal microbiota may ultimately influence lipid uptake and host glucose metabolism through its effects on bile acids.…”

Mice lacking have reduced signs of metabolic syndrome and non-alcoholic fatty liver disease

“…Intestinal FXR knockout animals have been shown to be resistant to diet-induced obesity, insulin resistance, and NAFLD (58)(59)(60). It has also been shown that loss of intestinal FXR activity leads to induced GLP-1 (glucagon-like peptide 1) production, which leads to improved glucose metabolism (61). We saw a larger bile acid pool with a high hydrophobicity index in the SI of Arv1 -/ -animals.…”