Cell Metabolism
Volume 10, Issue 3, 2 September 2009, Pages 167-177
Journal home page for Cell Metabolism

Article
TGR5-Mediated Bile Acid Sensing Controls Glucose Homeostasis

https://doi.org/10.1016/j.cmet.2009.08.001Get rights and content
Under an Elsevier user license
open archive

Summary

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)-methyl-cholic 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.

HUMDISEASE

Cited by (0)

6

These authors contributed equally to this work

7

Current address: Center of PhenoGenomics, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland