TGR5-Mediated Bile Acid Sensing Controls Glucose Homeostasis

Institut de Génétique et Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, 67404 Illkirch, France.
Cell metabolism (Impact Factor: 16.75). 10/2009; 10(3):167-77. DOI: 10.1016/j.cmet.2009.08.001
Source: PubMed

ABSTRACT 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.

1 Follower
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Objectives. We determined the serum bile acid (BA) composition in patients with liver diseases and healthy volunteers to investigate the relationship between the etiologies of liver disease and BA metabolism. Material and Methods. Sera from 150 patients with liver diseases and 46 healthy volunteers were obtained. The serum concentrations of the 16 different BAs were determined according to the LC-MS/MS method and were compared between the different liver diseases. Results. A total of 150 subjects, including patients with hepatitis C virus (HCV) (n = 44), hepatitis B virus (HBV) (n = 23), alcoholic liver disease (ALD) (n = 21), biliary tract disease (n = 20), nonalcoholic fatty liver disease (NAFLD) (n = 13), and other liver diseases (n = 29), were recruited. The levels of UDCA and GUDCA were significantly higher in the ALD group, and the levels of DCA and UDCA were significantly lower in the biliary tract diseases group than in viral hepatitis group. In the UDCA therapy (-) subgroup, a significantly lower level of TLCA was observed in the ALD group, with lower levels of CDCA, DCA, and GLCA noted in biliary tract diseases group compared to viral hepatitis group. Conclusions. Analysis of the BA composition may be useful for differential diagnosis in liver disease.
    Gastroenterology Research and Practice 01/2015; 2015:717431. DOI:10.1155/2015/717431 · 1.50 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Bile acids (BAs) regulate energy expenditure by activating G-protein Coupled Bile Acid Receptor Gpbar1/TGR5 by cAMP-dependent mechanisms. Cholecystectomy (XGB) increases BAs recirculation rates resulting in increased tissue exposure to BAs during the light phase of the diurnal cycle in mice. We aimed to determine: 1) the effects of XGB on basal metabolic rate (BMR) and 2) the roles of TGR5 on XGB-dependent changes in BMR. BMR was determined by indirect calorimetry in wild type and Tgr5 deficient (Tgr5-/-) male mice. Bile flow and BAs secretion rates were measured by surgical diversion of biliary duct. Biliary BAs and cholesterol were quantified by enzymatic methods. BAs serum concentration and specific composition was determined by liquid chromatography/tandem mass spectrometry. Gene expression was determined by qPCR analysis. XGB increased biliary BAs and cholesterol secretion rates, and elevated serum BAs concentration in wild type and Tgr5-/- mice during the light phase of the diurnal cycle. BMR was ~25% higher in cholecystectomized wild type mice (p <0.02), whereas no changes were detected in cholecystectomized Tgr5-/- mice compared to wild-type animals. XGB increases BMR by TGR5-dependent mechanisms in mice.
    PLoS ONE 03/2015; 10(3):e0118478. DOI:10.1371/journal.pone.0118478 · 3.53 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Bile salts are steroidal biosurfactants. Micellar systems of bile salts are not only important for solubilisation of cholesterol, but they interact with certain drugs changing thus their bioavailability. The number-average aggregation numbers (n¯) are determined using Moroi-Matsuoka-Sugioka thermodynamic method. Critical micellar concentrations were determined by spectrofluorometric method using pyren and by surface tension measurements. Micelles of ethylidene derivatives posess folowing values for n¯: 7-Eth-D (n¯=11 (50mM) - n¯=14.8 (100mM); 12-Ox-7-Eth-L (n¯≈8.8, without concentration dependence) and 7,12-diOx-3-Eth-Ch (n¯≈2.9,without concentration dependence). In the planes n¯ - ln k and ln CMC - ln k derivative 7-Eth-D is outlier in respect to hydrophobic linear congeneric groups. Gibbs energy of formation for 7-Eth-D anion micelles in adition to the Gibbs energy of hydrophobic interactions consist excess Gibbs energy (G(E)) from hydrogen bond formation between building blocks of micelles. Gibbs energy of formation for 12-diOx-3-Eth-Ch and 12-Ox-7-Eth-L anion micelle is determined by the Gibbs energy of hydrophobic interactions. Relative increase in hydrophobicity and aggregation number for ethylidene derivatives is larger when ethylidene group is introduced from C7 lateral side of steroidal skeleton then it is when ethylidene group is on C3 carbon. Position of outlier towards hydrophobic congeneric groups from n¯ - ln k and ln CMC - ln k planes indicates the existence of excess Gibbs energy (G(E)) which is not of hydrophobic nature (formation of hydrogen bonds). For the bile salts micelles to have G(E) (formation of secondary micelles) it is necessary that steroidal skeleton possess C3-α-(e)-OH and C12-α-(a)-OH groups. Copyright © 2015. Published by Elsevier B.V.
    Biochimica et Biophysica Acta 03/2015; 1850(7). DOI:10.1016/j.bbagen.2015.03.010 · 4.66 Impact Factor

Full-text (2 Sources)

Available from
May 19, 2014