TGR5 agonist(Intercept Pharmaceuticals/Servier)

Numerous G protein–coupled receptors (GPCRs) expressed in the gastrointestinal tract serve as crucial transducers to regulate a variety of physiological functions upon activation. Takeda G protein–coupled receptor 5 (TGR5), a prominent gastrointestinal GPCR expressed on enteroendocrine L cells, is activated by intestinal bile acids and plays a role in glucose utilization. However, the development of TGR5 agonists has been hindered by the hepatobiliary toxicity associated with long-term supplementation with exogenous agonists. Here, we designed and characterized a biomimetic receptor agonist, which we termed TGR5-targeted carrier-drug conjugate (TGR5-CaDC), that combined the TGR5-activating capabilities of deoxycholic acid, a TGR5 agonist, with the nonabsorbable properties of a carrier. Unlike traditional agonists or carrier-based drug delivery systems, nonabsorbable TGR5-CaDC remained localized in the intestines of mice and pigs, providing high surface concentrations of TGR5 agonists in addition to ensuring strong L cell specificity and TGR5 affinity. TGR5-CaDC treatment also promoted TGR5 cluster aggregation, signal amplification, and increased glucagon-like peptide 1 secretion. Notably, TGR5-CaDC demonstrated sustained glycemic effects with reduced toxicity compared with deoxycholic acid alone or liraglutide in diabetic mice and Bama minipigs. By targeting extracellular binding domains and mimicking native ligand-receptor binding patterns, the design concept underlying this carrier-drug conjugate has the potential for applications in a variety of GPCR-mediated gastrointestinal diseases.

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.