The farnesoid X receptor (FXR) antagonist 7β-isopropylchenodeoxycholic acid improves glucose metabolism in mice on Western diet

ABSTRACT: The roles of the farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5) in regulating metabolic pathways were highlighted recently. Nevertheless, the impact of FXR inhibitors on glucose metabolism remains unclear. In this study, we explored the effects of 7β-isopropylchenodeoxycholic acid (7β-ipCDCA), a combined FXR antagonist and TGR5 agonist, on impaired glucose metabolism in mice fed Western diet. A dual FXR antagonistic/TGR5 agonistic activity of 7β-ipCDCA was confirmed on gene reporter assays. Its effects on glucose homeostasis were evaluated using a glucose tolerance test in C57BL/6J mice mimicking metabolic syndrome condition induced by Western diet with additional sugar in drinking water for 24 weeks. The glucose-lowering mechanism was investigated by measuring glucagon-like peptide 1 (GLP-1) release, mRNA expression of glucose transporters and genes involved in glucose metabolism in intestinal, hepatic, white adipose, and kidney tissues, and in human intestinal NCI-H716 and murine GLUTag cells. Additionally, bile acid metabolome and liver lipidome were determined. 7β-ipCDCA restored blood glucose homeostasis altered by Western diet in mice via enhanced GLP-1 release and inhibition of glucose transporters in the ileum. While changes in the liver function were marginal, 7β-ipCDCA augmented taurocholic acid plasma concentration. 7β-ipCDCA increased liver triglycerides exclusively in mice fed a chow diet, whereas mice on the Western diet were protected from hepatic triglyceride accumulation. This study revealed a novel role of FXR in regulating intestinal glucose transporters and GLP-1 secretion, emphasizing the potential of FXR antagonists/TGR5 agonists in modulating hyperglycemia.

ORGANISM(S): Mus musculus

PROVIDER: GSE291059 | GEO | 2025/09/20

REPOSITORIES: GEO