The significant roles of the farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5) in regulating metabolic pathways have recently been demonstrated. However, the precise effects of FXR inhibitors on glucose metabolism remain to be elucidated. In this study, we examined the impact of 7β-isopropylchenodeoxycholic acid (7β-ipCDCA), a dual FXR antagonist and TGR5 agonist, on impaired glucose metabolism in mice fed a Western diet. The dual FXR antagonistic/TGR5 agonistic activity of 7β-ipCDCA was confirmed through gene reporter assays. We evaluated its effects on glucose homeostasis using a glucose tolerance test in C57BL/6 mice fed a Western diet supplemented with sugar in drinking water for 24 weeks. The glucose-lowering mechanism was further investigated by measuring GLP-1 release, mRNA expression of glucose transporters, and relevant genes involved in glucose metabolism in intestinal, hepatic, white adipose, and kidney tissues, and in human NCI-H716 and murine GLUTag L cell lines. Additionally, bile acid metabolome and hepatic lipidome analyses were conducted. Results showed that 7β-ipCDCA improves glucose homeostasis altered by a Western diet in mice via enhanced GLP-1 secretion and decreased expression of glucose transporters in the ileum and kidneys. While its impact on liver function was marginal, 7β-ipCDCA increased plasma taurocholic acid levels. Furthermore, 7β-ipCDCA elevated hepatic triacylglycerols in mice on a chow diet, whereas mice on the Western diet were protected from triacylglycerol accumulation. This study highlights the role of FXR in regulating intestinal glucose transporters and GLP-1 secretion, emphasizing the therapeutic potential of combined FXR antagonists/TGR5 agonists in managing hyperglycemia.
