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Bariatric surgery reveals a gut-restricted TGR5 agonist with anti-diabetic effects
- Source :
- Nature Chemical Biology. 17:20-29
- Publication Year :
- 2020
- Publisher :
- Springer Science and Business Media LLC, 2020.
-
Abstract
- Bariatric surgery, the most effective treatment for obesity and type 2 diabetes, is associated with increased levels of the incretin hormone glucagon-like peptide-1 (GLP-1) and changes in levels of circulating bile acids. The levels of individual bile acids in the gastrointestinal (GI) tract after surgery have, however, remained largely unstudied. Using ultra-high performance liquid chromatography-mass spectrometry-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 Takeda G-protein receptor 5 (TGR5) agonist that increases Tgr5 expression and induces GLP-1 secretion. Furthermore, CA7S administration increases glucose tolerance in insulin-resistant mice in a TGR5-dependent manner. CA7S remains gut restricted, minimizing off-target effects previously observed for TGR5 agonists absorbed into the circulation. By studying changes in individual metabolites after surgery, the present study has revealed a naturally occurring TGR5 agonist that exerts systemic glucoregulatory effects while remaining confined to the gut.
- Subjects :
- Agonist
0303 health sciences
medicine.medical_specialty
Sleeve gastrectomy
Glucose tolerance test
Bile acid
medicine.diagnostic_test
medicine.drug_class
business.industry
medicine.medical_treatment
030302 biochemistry & molecular biology
Cell Biology
Type 2 diabetes
medicine.disease
G protein-coupled bile acid receptor
Surgery
03 medical and health sciences
Insulin resistance
medicine
business
Receptor
Molecular Biology
030304 developmental biology
Subjects
Details
- ISSN :
- 15524469 and 15524450
- Volume :
- 17
- Database :
- OpenAIRE
- Journal :
- Nature Chemical Biology
- Accession number :
- edsair.doi...........8f795e82e70f11e255f4cc5531af33f7