Thomas, CharlesGioiello, AntimoNoriega, LiliaStrehle, AxelleOury, JulienRizzo, GiovanniMacchiarulo, AntonioYamamoto, HiroyasuMataki, ChikagePruzanski, MarkPellicciari, RobertoAuwerx, JohanSchoonjans, Kristina2009-09-012009-09-012009-09-01200910.1016/j.cmet.2009.08.001https://infoscience.epfl.ch/handle/20.500.14299/42379WOS:000269600900004TGR5 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 6a-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 invivo, and suggest that pharmacological targeting of TGR5 may constitute a promising incretin-based strategy for the treatment of diabesity and associated metabolic disorders.Protein-Coupled ReceptorFarnesoid-X-ReceptorPeptide-1 SecretionEnergy-ExpenditureCell-LineActivationMiceTgr5FxrDerivativestext::journal::journal article::research article