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 RIS Download
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