期刊
NATURE CHEMICAL BIOLOGY
卷 17, 期 1, 页码 20-29出版社
NATURE PORTFOLIO
DOI: 10.1038/s41589-020-0604-z
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资金
- Harvard Catalyst [4Kl2TR001100-04]
- Boston Area Diabetes and Endocrinology Research Center (BADERC) [NIH/NIDDK P30 DK057521]
- NIH MIRA grant [R35 GM128618]
- Blavatnik Biomedical Accelerator at Harvard University
- Quadrangle Fund for the Advancement and Seeding of Translational Research at Harvard Medical School (Q-FASTR)
- American Heart Association Postdoctoral Fellowship
- HMS Department of Biological Chemistry and Molecular Pharmacology Fellowship
- American College of Surgeons fellowship
- NIH
- DRC PAMP
- F program grant from the Joslin Diabetes Center [P30DK036836]
After bariatric surgery, levels of the endogenous bile acid cholic acid-7-sulfate (CA7S) increase in the gastrointestinal tract of both mice and humans. CA7S acts as a G-protein-coupled receptor TGR5 agonist to increase glucose tolerance during insulin resistance. This agonist remains gut-restricted, minimizing off-target effects previously observed for TGR5 agonists absorbed into the circulation.
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. Levels of the endogenous bile acid cholic acid-7-sulfate (CA7S) increase in the gastrointestinal tract of both mice and humans after sleeve gastrectomy. CA7S acts through the G-protein-coupled receptor TGR5 to increase glucose tolerance during insulin resistance.
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