Intestine farnesoid X receptor agonist and the gut microbiota activate G-protein bile acid receptor-1 signaling to improve metabolism.
Male; Animals; Mice; Random Allocation; Sensitivity and Specificity; *Signal Transduction; Lipid Metabolism; Bile Acids and Salts/*metabolism; GTP-Binding Proteins/*metabolism; Receptors; Inbred C57BL; Animal; Disease Models; G-Protein-Coupled/*metabolism; Gastrointestinal Microbiome/*drug effects; Glucagon-Like Peptide 1/metabolism; Cytoplasmic and Nuclear/*antagonists & inhibitors/pharmacology
Bile acids activate farnesoid X receptor (FXR) and G protein-coupled bile acid receptor-1 (aka Takeda G protein-coupled receptor-5 [TGR5]) to regulate bile acid metabolism and glucose and insulin sensitivity. FXR and TGR5 are coexpressed in the enteroendocrine L cells, but their roles in integrated regulation of metabolism are not completely understood. We reported recently that activation of FXR induces TGR5 to stimulate glucagon-like peptide-1 (GLP-1) secretion to improve insulin sensitivity and hepatic metabolism. In this study, we used the intestine-restricted FXR agonist fexaramine (FEX) to study the effect of activation of intestinal FXR on the gut microbiome, bile acid metabolism, and FXR and TGR5 signaling. The current study revealed that FEX markedly increased taurolithocholic acid, increased secretion of fibroblast growth factors 15 and 21 and GLP-1, improved insulin and glucose tolerance, and promoted white adipose tissue browning in mice. Analysis of 16S ribosomal RNA sequences of the gut microbiome identified the FEX-induced and lithocholic acid-producing bacteria Acetatifactor and Bacteroides. Antibiotic treatment completely reversed the
Pathak Preeti; Xie Cen; Nichols Robert G; Ferrell Jessica M; Boehme Shannon; Krausz Kristopher W; Patterson Andrew D; Gonzalez Frank J; Chiang John Y L
Hepatology (Baltimore, Md.)
2018
2018-10
<a href="http://doi.org/10.1002/hep.29857" target="_blank" rel="noreferrer noopener">10.1002/hep.29857</a>
Specificity of metabotropic glutamate receptor 2 coupling to G proteins.
Amino Acid; Amino Acid Sequence; Animals; Calcium/metabolism; Electrophysiology; Gi-Go/metabolism; GTP-Binding Protein alpha Subunits; GTP-Binding Proteins/*metabolism; Metabotropic Glutamate/*metabolism; Molecular Sequence Data; Neurons/*drug effects/metabolism; Pertussis Toxin/*pharmacology; Rats; Receptors; Sequence Homology; Superior Cervical Ganglion/cytology; Wistar
Metabotropic glutamate receptor 2 (mGluR2) is a class 3 G protein-coupled receptor and an important mediator of synaptic activity in the central nervous system. Previous work demonstrated that mGluR2 couples to pertussis toxin (PTX)-sensitive G proteins. However, the specificity of mGluR2 coupling to individual members of the G(i/o) family is not known. Using heterologously expressed mGluR2 in rat sympathetic neurons from the superior cervical ganglion (SCG), the mGluR2/G protein coupling profile was characterized by reconstituting coupling in PTX-treated cells expressing PTX-insensitive mutant Galpha proteins and Gbetagamma. By employing this method, it was demonstrated that mGluR2 coupled strongly with Galphaob, Galphai1, Galphai2, and Galphai3, although coupling to Galphaoa was less efficient. In addition, mGluR2 did not seem to couple to the most divergent member of the G(i/o) family, Galphaz, although Galphaz coupled strongly to the endogenous alpha2 adrenergic receptor. To determine which Galpha proteins may be natively expressed in SCG neurons, the presence of mRNA for various Galpha proteins was tested using reverse transcription-polymerase chain reaction. Strong bands were detected for all members of the G(i/o) family (Galphao, Galphai1, Galphai2, Galphai3, Galphaz) as well as for Galpha11 and Galphas. A weak signal was detected for Galphaq and no Galpha15 mRNA was detected.
Kammermeier Paul J; Davis Margaret I; Ikeda Stephen R
Molecular pharmacology
2003
2003-01
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<a href="http://doi.org/10.1124/mol.63.1.183" target="_blank" rel="noreferrer noopener">10.1124/mol.63.1.183</a>