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TGR5-mediated bile acid sensing controls glucose homeostasis.

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 6alpha-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.

Pubmed ID: 19723493


  • Thomas C
  • Gioiello A
  • Noriega L
  • Strehle A
  • Oury J
  • Rizzo G
  • Macchiarulo A
  • Yamamoto H
  • Mataki C
  • Pruzanski M
  • Pellicciari R
  • Auwerx J
  • Schoonjans K


Cell metabolism

Publication Data

September 2, 2009

Associated Grants

  • Agency: NIDDK NIH HHS, Id: P01 DK059820-080006
  • Agency: NIDDK NIH HHS, Id: R01 DK067320-04

Mesh Terms

  • Adenosine Triphosphate
  • Animals
  • Bile Acids and Salts
  • CHO Cells
  • Calcium
  • Cell Line
  • Cholic Acids
  • Cricetinae
  • Cricetulus
  • Enteroendocrine Cells
  • Glucagon-Like Peptide 1
  • Glucose
  • Homeostasis
  • Humans
  • Insulin
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Obese
  • Oxidative Phosphorylation
  • Receptors, G-Protein-Coupled
  • Signal Transduction