Novel Small Molecule Agonist of TGR5 Possesses Anti-Diabetic Effects but Causes Gallbladder Filling in Mice (original) (raw)
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Bariatric surgery reveals a gut-restricted TGR5 agonist that exhibits anti-diabetic effects
2020
Bariatric surgery, the most effective treatment for obesity and type 2 diabetes, is consistently associated with increased levels of the incretin hormone GLP-1 and changes in overall levels of circulating bile acids. The levels of individual bile acids in the GI tract following surgery, however, have remained largely unstudied. Using UPLC-MS-based quantification, we observed an increase in an endogenous bile acid, cholic acid-7-sulfate (CA7S), in the GI tract of both mice and humans after sleeve gastrectomy. We show that CA7S is a TGR5 agonist that induces GLP-1 secretion in vitro and in vivo and that CA7S administration increases glucose tolerance in insulin-resistant mice in a GLP-1 receptor-dependent manner. CA7S remains gut-restricted, minimizing off-target effects previously observed for TGR5 agonists absorbed into circulation. By studying changes in individual metabolites following surgery, this study has revealed a naturally occurring TGR5 agonist that exerts systemic glucore...
TGR5-Mediated Bile Acid Sensing Controls Glucose Homeostasis
Cell Metabolism, 2009
TGR5 is a G-protein coupled receptor expressed in brown adipose tissue and muscle where its activation by bile acids triggers an increase in energy expenditure and attenuates diet-induced obesity. Using a combination of pharmacological and genetic gain-and loss-of function studies in vivo, we show here that TGR5 signaling induces intestinal glucagon-like peptide-1 (GLP-1) release, leading to improved liver and pancreatic function and enhanced glucose tolerance in obese mice. In addition, we show that the induction of GLP-1 release in enteroendocrine cells by 6α-ethyl-23(S)-methylcholic acid (EMCA, INT-777), a specific TGR5 agonist, is linked to an increase of the intracellular ATP/ADP ratio and a subsequent rise in intracellular calcium mobilization. Altogether, these data show that the TGR5 signaling pathway is critical in regulating intestinal GLP-1 secretion in vivo and suggest that pharmacological targeting of TGR5 may constitute a promising incretin-based strategy for the treatment of diabesity and associated metabolic disorders.
Intestinal TGR5 agonism improves hepatic steatosis and insulin sensitivity in Western diet-fed mice
American Journal of Physiology-Gastrointestinal and Liver Physiology, 2019
Takeda G protein-coupled receptor 5 (TGR5) agonists induce systemic release of glucagon-like peptides (GLPs) from intestinal L cells, a potentially therapeutic action against metabolic diseases such as nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), and Type 2 diabetes. Historically, TGR5 agonist use has been hindered by side effects, including inhibition of gallbladder emptying. Here, we characterize RDX8940, a novel, orally administered TGR5 agonist designed to have minimal systemic effects and investigate its activity in mice fed a Western diet, a model of NAFLD and mild insulin resistance. Agonist activity, binding selectivity, toxicity, solubility, and permeability of RDX8940 were characterized in standard in vitro models. RDX8940 pharmacokinetics and effects on GLP secretion, insulin sensitivity, and liver steatosis were assessed in C57BL/6 mice fed normal or Western diet chow and given single or repeated doses of RDX8940 or vehicle, with or without dipeptidyl peptidase-4 (DPP4) inhibitors. Gallbladder effects were assessed in CD-1 mice fed normal chow and given RDX8940 or a systemic TGR5 agonist or vehicle. Our results showed that RDX8940 is minimally systemic, potent, and selective, and induces incretin (GLP-1, GLP-2, and peptide YY) secretion. RDX8940-induced increases in plasma active GLP-1 (aGLP-1) levels were enhanced by repeated dosing and by coadministration of DPP4 inhibitors. RDX8940 increased hepatic exposure to aGLP-1 without requiring coadministration of a DPP4 inhibitor. In mice fed a Western diet, RDX8940 improved liver steatosis and insulin sensitivity. Unlike systemic TGR5 agonists, RDX8940 did not inhibit gallbladder emptying. These results indicate that RDX8940 may have therapeutic potential in patients with NAFLD/NASH. NEW & NOTEWORTHY Takeda G protein-coupled receptor 5 (TGR5) agonists have potential as a treatment for nonalcoholic steatohepatitis and nonalcoholic fatty liver disease (NAFLD) but have until now been associated with undesirable side effects associated with systemic TGR5 agonism, including blockade of gallbladder emptying. We demonstrate that RDX8940, a potent, selective, minimally systemic oral TGR5 agonist, improves liver steatosis and insulin sensitivity in a mouse model of NAFLD and does not inhibit gallbladder emptying in mice.
Molecular metabolism, 2017
Glucagon-like peptides (GLPs) are secreted from enteroendocrine cells in response to nutrients and bile acids and control metabolism via actions on structurally-related yet distinct G protein coupled receptors. GLP-1 regulates gut motility, appetite, islet function, and glucose homeostasis, whereas GLP-2 enhances intestinal nutrient absorption. GLP-1R agonists are used to treat diabetes and obesity, and a GLP-2R agonist is approved to treat short bowel syndrome. Unexpectedly, reports of gallbladder disease have been associated with the use of both GLP-1R and GLP-2R agonists and after bariatric surgery, although the mechanisms remain unknown. We investigated whether GLP-1 or GLP-2 acutely controls gallbladder (GB) volume and whether GLP-2 regulates GB muscle activity in mice. The expression of Tgr5, Glp2r, and Glp1r was assessed in mouse GB, and the effects of GLP-2 on hepatic bile acid (BA) flow, intestinal and liver BA uptake, and GB gene expression were determined. GLP-2 regulatio...
Journal of Medicinal Chemistry
Coupled Bile Acid Receptor 1 (GP-BAR1), also known as Takeda Gprotein-coupled receptor 5 (TGR5) is a G Protein Coupled Receptor sensitive to bile acids. Its role in various organs, tissues and cell types, specifically in intestinal endocrine L cells and brown adipose tissue, has made it a promising therapeutical target in several diseases, especially type 2 diabetes and metabolic syndrome. However, recent studies have also shown deleterious on-target effects of systemic TGR5 agonists. To avoid these systemic effects while stimulating the incretin Glucagon Like Peptide-1 (GLP-1) secreting enteroendocrine L-cells, we have designed and obtained a series of potent TGR5 agonists with low intestinal permeability. Some of our weakly permeable compounds display potent GLP-1 secretagogue effect and low effect on gallbladder volume, which translates into improved glucose homeostasis in a preclinical murine model of diet-induced obesity and insulin-resistance. Herein we describe the design, synthesis, characterization, and biological evaluation of such compounds, making the proof of concept of the potential of topical intestinal TGR5 agonists as therapeutic agents in type 2 diabetes using compound 24. INTRODUCTION. Bile acids have been known for over a decade to act not only as lipid solubilizing agents during digestion, but also as signaling molecules, through two main receptors 1 : the nuclear receptor FXR 2 (identified in 1999), and the G-Protein-Coupled Bile Acid Receptor TGR5 3,4 (aka GP-BAR1, GPR131, M-BAR identified in 2002). TGR5 acts as a sensor of the prandial state of the organism, by detecting bile acids in various tissues, organs, and cells, such as enteroendocrine Lcells, brown adipose tissue, skeletal striated muscles, but also gallbladder, immune cells and neurons. Based on the existing functional and pharmacological data in preclinical models, TGR5 1 2 3 N-Methylation Scaffold switching *
Pharmacological activation of TGR5 promotes intestinal growth via a GLP-2 dependent pathway in mice
American Journal of Physiology-Gastrointestinal and Liver Physiology
Glucagon-like peptide-1 and 2 (GLP-1 and GLP-2) secreting L cells have been shown to express the bile acid receptor takeda-G-protein-receptor-5 (TGR5) and increase secretion upon receptor activation. Previous studies have explored GLP-1 secretion following acute TGR5 activation but chronic activation and GLP-2 responses have not been characterized. In this study, we aimed to investigate the consequences of pharmacological TGR5 receptor activation on L cell hormone production in vivo using the specific TGR5 agonist RO5527239 and the GLP-2 receptor knockout mouse. Here, we show 1) TGR5 receptor activation led to increased GLP-1 and GLP-2 content in the colon, which 2) was associated with an increased small intestinal weight that 3) was GLP-2 dependent. Additionally, we report that TGR5 mediated gallbladder filling occurred independently of GLP-2 signaling. In conclusion, we demonstrate that pharmacological TGR5 receptor activation stimulates L cells triggering GLP-2 dependent intestin...
Biochemical and Biophysical Research Communications, 2012
Bile acids act as signaling molecules and stimulate the G protein coupled receptor, TGR5, in addition to nuclear farnesoid X receptor to regulate lipid, glucose and energy metabolism. Bile acid induced activation of TGR5 in the enteroendocrine cells promotes glucagon like peptide-1 (GLP-1) release, which has insulinotropic effect in the pancreatic β cells. In the present study, we have identified the expression of TGR5 in pancreatic β cell line MIN6 and also in mouse and human pancreatic islets. TGR5 selective ligands, oleanolic acid (OA) and INT-777 selectively activated Gα s and caused an increase in intracellular cAMP and Ca 2+. OA and INT-777 also increased phosphoinositide (PI) hydrolysis and the increase was blocked by NF449 (a selective Gα s inhibitor) or U73122 (PI hydrolysis inhibitor). OA, INT-777 and lithocholic acid increased insulin release in MIN6 and human islets and the increase was inhibited by treatment with NF449, U73122 or BAPTA-AM (chelator of calcium), but not with myristoylated PKI (PKA inhibitor), suggesting that the release is dependent on G s /cAMP/Ca 2+ pathway. 8-pCPT-2′-O-Me-cAMP, a cAMP analogue, which activates Epac, but not PKA also stimulated PI hydrolysis. In conclusion, our study demonstrates that the TGR5 expressed in the pancreatic β cells regulates insulin secretion and highlights the importance of ongoing therapeutic strategies targeting TGR5 in the control of glucose homeostasis.
Discovery of a Potent and Orally Efficacious TGR5 Receptor Agonist
TGR5 is a G protein-coupled receptor (GPCR), activation of which promotes secretion of glucagon-like peptide-1 (GLP-1) and modulates insulin secretion. The 2-thio-imidazole derivative 6g was identified as a novel, potent, and selective TGR5 agonist (hTGR5 EC 50 = 57 pM, mTGR5 = 62 pM) with a favorable pharmacokinetic profile. The compound 6g was found to have potent glucose lowering effects in vivo during an oral glucose tolerance test in DIO C57 mice with ED 50 of 7.9 mg/kg and ED 90 of 29.2 mg/ kg.
Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy, 2013
Background: Patients with diabesity have a significantly increased risk of developing cardiovascular disease. Therefore, therapy addressing the multiple metabolic abnormalities linked with diabesity and leading to further reduction of cardiovascular risk is highly desirable. Activation of the TGR5 receptor holds therapeutic potential for diabesity. In the present study, we evaluated the efficacy of TRC210258, a novel TGR5 agonist, in clinically relevant animal models of diabesity. Methods: A novel small molecule, TRC210258 (N-(4-chlorophenyl)-2-(4-fluorophenoxy)-Nmethylimidazo (1, 2-a) pyrimidine-3-carboxamide), was synthesized. The in vitro TGR5 receptor activation potential of TRC210258 was assessed by cyclic adenosine monophosphate (cAMP) assay and cAMP-responsive element reporter assay using cells overexpressing the human TGR5 receptor. The effect of TRC210258 on glucagon-like peptide-1 release was evaluated in vitro using a human enteroendocrine cell line. The effect of TRC210258 on energy expenditure and glycemic control was evaluated in high-fat diet-induced obese mice. Additionally, the effect of TRC210258 on dyslipidemic parameters was determined in high fat-fed hamsters. Results: TRC210258 demonstrated potent TGR5 agonist activity, with enhanced glucagon-like peptide-1 release and energy expenditure. Treatment with TRC210258 resulted in better glycemic control and improved parameters of dyslipidemia such as plasma triglyceride, low-density lipoprotein cholesterol, and non-high-density lipoprotein cholesterol levels. Treatment with TRC210258 also improved emerging dyslipidemic cardiovascular risk parameters, including remnant cholesterol and triglyceride clearance. Conclusion: This study highlights the potential of TRC210258, a novel TGR5 agonist, to improve dyslipidemic cardiovascular risk beyond glycemic control in patients with type 2 diabetes.