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.
Thomas
Charles
C
Institut de Génétique et Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, 67404 Illkirch, France.
Gioiello
Antimo
A
Noriega
Lilia
L
Strehle
Axelle
A
Oury
Julien
J
Rizzo
Giovanni
G
Macchiarulo
Antonio
A
Yamamoto
Hiroyasu
H
Mataki
Chikage
C
Pruzanski
Mark
M
Pellicciari
Roberto
R
Auwerx
Johan
J
Schoonjans
Kristina
K
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002793:Cholic Acids / Q000737:chemistry / Q000494:pharmacology*; D006224:Cricetinae; D003412:Cricetulus; D019858:Enteroendocrine Cells / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D007328:Insulin / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D010085:Oxidative Phosphorylation; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction
C545501:6alpha-ethyl-23(S)-methylcholic acid; D001647:Bile Acids and Salts; D002793:Cholic Acids; C473772:GPBAR1 protein, human; C513561:Gpbar1 protein, mouse; D007328:Insulin; D043562:Receptors, G-Protein-Coupled; D052216:Glucagon-Like Peptide 1; D000255:Adenosine Triphosphate; D005947:Glucose; D002118:Calcium