Glucagon-like peptide-2 promotes gallbladder refilling via a TGR5-independent, GLP-2R-dependent pathway
Objective: Glucagon-like peptides (GLPs) are secreted from enteroendocrine cells in response to nutrients and bile acids and control metabolism via actions on structurally-related yet distinct G protein coupled receptors. GLP-1 regulates gut motility, appetite, islet function, and glucose homeostasi...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2017-06-01
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| Series: | Molecular Metabolism |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S221287781730131X |
| _version_ | 1818586277359910912 |
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| author | Bernardo Yusta Dianne Matthews Grace B. Flock John R. Ussher Brigitte Lavoie Gary M. Mawe Daniel J. Drucker |
| author_facet | Bernardo Yusta Dianne Matthews Grace B. Flock John R. Ussher Brigitte Lavoie Gary M. Mawe Daniel J. Drucker |
| author_sort | Bernardo Yusta |
| collection | DOAJ |
| description | Objective: Glucagon-like peptides (GLPs) are secreted from enteroendocrine cells in response to nutrients and bile acids and control metabolism via actions on structurally-related yet distinct G protein coupled receptors. GLP-1 regulates gut motility, appetite, islet function, and glucose homeostasis, whereas GLP-2 enhances intestinal nutrient absorption. GLP-1R agonists are used to treat diabetes and obesity, and a GLP-2R agonist is approved to treat short bowel syndrome. Unexpectedly, reports of gallbladder disease have been associated with the use of both GLP-1R and GLP-2R agonists and after bariatric surgery, although the mechanisms remain unknown. Methods: We investigated whether GLP-1 or GLP-2 acutely controls gallbladder (GB) volume and whether GLP-2 regulates GB muscle activity in mice. The expression of Tgr5, Glp2r, and Glp1r was assessed in mouse GB, and the effects of GLP-2 on hepatic bile acid (BA) flow, intestinal and liver BA uptake, and GB gene expression were determined. GLP-2 regulation of GB volume was assessed in wildtype, Glp2r−/− and Tgr5−/− mice. The effect of GLP-2 on GB smooth muscle (GBSM) calcium transients was characterized ex vivo. Results: Acute administration of the GLP-1R agonist exendin-4 lowered glucose but had no effect on GB volume in mice. In contrast, GLP-2 rapidly enhanced GB filling in a dose-dependent manner, actions maintained in the presence of cholecystokinin, and mediated through the canonical GLP-2R. GLP-2 also rapidly induced immediate early gene expression in GB, consistent with detection of the endogenous Glp2r in GB RNA. The ability of GLP-2 to increase GB volume was not abrogated by systemic administration of hexamethonium, propranolol, a vasoactive peptide receptor antagonist or N-Nitroarginine methyl ester, and was maintained in Tgr5−/− mice. In contrast, lithocholic acid, a Tgr5 agonist, increased GB filling in Glp2r−/− but not in Tgr5−/− mice. GLP-2 had no effect on ileal uptake or hepatic clearance of taurocholic acid or on hepatic bile flow, yet reduced the frequency of spontaneous calcium transients in murine GBSM ex vivo, in a tetrodotoxin-sensitive manner. Conclusions: Our data extend endocrine concepts of regulation of GB filling beyond FXR-FGF15/19 and the direct effects of BA via Tgr5, to encompass a novel BA-Tgr5-L cell GLP-2 axis providing nutrient-mediated feedback from BA to terminate meal-related GB contraction. These findings have implications for conditions characterized by elevated circulating levels of GLP-2 such as after bariatric surgery and the development and use of agents that promote Tgr5 activation, L cell secretion, or GLP-2R agonism for the treatment of metabolic disease. Keywords: Bile acids, Gallbladder, Enteroendocrine, Glucagon-like peptide, TGR5, GLP-1, GLP-2 |
| first_indexed | 2024-12-16T08:50:24Z |
| format | Article |
| id | doaj.art-17791cc01a3543ecbd4dd42c3738671f |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-12-16T08:50:24Z |
| publishDate | 2017-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-17791cc01a3543ecbd4dd42c3738671f2022-12-21T22:37:28ZengElsevierMolecular Metabolism2212-87782017-06-0166503511Glucagon-like peptide-2 promotes gallbladder refilling via a TGR5-independent, GLP-2R-dependent pathwayBernardo Yusta0Dianne Matthews1Grace B. Flock2John R. Ussher3Brigitte Lavoie4Gary M. Mawe5Daniel J. Drucker6The Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, Ontario, M5G 1X5, CanadaThe Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, Ontario, M5G 1X5, CanadaThe Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, Ontario, M5G 1X5, CanadaThe Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, Ontario, M5G 1X5, CanadaThe Department of Neurological Sciences, University of Vermont, Burlington, VT, USAThe Department of Neurological Sciences, University of Vermont, Burlington, VT, USAThe Department of Medicine, University of Toronto, Canada; The Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, Ontario, M5G 1X5, Canada; Corresponding author. Mt. Sinai Hospital LTRI, 600 University Ave TCP5-1004, Toronto, Ontario, M5G 1X5, Canada. Fax: +1 416 361 2669.Objective: Glucagon-like peptides (GLPs) are secreted from enteroendocrine cells in response to nutrients and bile acids and control metabolism via actions on structurally-related yet distinct G protein coupled receptors. GLP-1 regulates gut motility, appetite, islet function, and glucose homeostasis, whereas GLP-2 enhances intestinal nutrient absorption. GLP-1R agonists are used to treat diabetes and obesity, and a GLP-2R agonist is approved to treat short bowel syndrome. Unexpectedly, reports of gallbladder disease have been associated with the use of both GLP-1R and GLP-2R agonists and after bariatric surgery, although the mechanisms remain unknown. Methods: We investigated whether GLP-1 or GLP-2 acutely controls gallbladder (GB) volume and whether GLP-2 regulates GB muscle activity in mice. The expression of Tgr5, Glp2r, and Glp1r was assessed in mouse GB, and the effects of GLP-2 on hepatic bile acid (BA) flow, intestinal and liver BA uptake, and GB gene expression were determined. GLP-2 regulation of GB volume was assessed in wildtype, Glp2r−/− and Tgr5−/− mice. The effect of GLP-2 on GB smooth muscle (GBSM) calcium transients was characterized ex vivo. Results: Acute administration of the GLP-1R agonist exendin-4 lowered glucose but had no effect on GB volume in mice. In contrast, GLP-2 rapidly enhanced GB filling in a dose-dependent manner, actions maintained in the presence of cholecystokinin, and mediated through the canonical GLP-2R. GLP-2 also rapidly induced immediate early gene expression in GB, consistent with detection of the endogenous Glp2r in GB RNA. The ability of GLP-2 to increase GB volume was not abrogated by systemic administration of hexamethonium, propranolol, a vasoactive peptide receptor antagonist or N-Nitroarginine methyl ester, and was maintained in Tgr5−/− mice. In contrast, lithocholic acid, a Tgr5 agonist, increased GB filling in Glp2r−/− but not in Tgr5−/− mice. GLP-2 had no effect on ileal uptake or hepatic clearance of taurocholic acid or on hepatic bile flow, yet reduced the frequency of spontaneous calcium transients in murine GBSM ex vivo, in a tetrodotoxin-sensitive manner. Conclusions: Our data extend endocrine concepts of regulation of GB filling beyond FXR-FGF15/19 and the direct effects of BA via Tgr5, to encompass a novel BA-Tgr5-L cell GLP-2 axis providing nutrient-mediated feedback from BA to terminate meal-related GB contraction. These findings have implications for conditions characterized by elevated circulating levels of GLP-2 such as after bariatric surgery and the development and use of agents that promote Tgr5 activation, L cell secretion, or GLP-2R agonism for the treatment of metabolic disease. Keywords: Bile acids, Gallbladder, Enteroendocrine, Glucagon-like peptide, TGR5, GLP-1, GLP-2http://www.sciencedirect.com/science/article/pii/S221287781730131X |
| spellingShingle | Bernardo Yusta Dianne Matthews Grace B. Flock John R. Ussher Brigitte Lavoie Gary M. Mawe Daniel J. Drucker Glucagon-like peptide-2 promotes gallbladder refilling via a TGR5-independent, GLP-2R-dependent pathway Molecular Metabolism |
| title | Glucagon-like peptide-2 promotes gallbladder refilling via a TGR5-independent, GLP-2R-dependent pathway |
| title_full | Glucagon-like peptide-2 promotes gallbladder refilling via a TGR5-independent, GLP-2R-dependent pathway |
| title_fullStr | Glucagon-like peptide-2 promotes gallbladder refilling via a TGR5-independent, GLP-2R-dependent pathway |
| title_full_unstemmed | Glucagon-like peptide-2 promotes gallbladder refilling via a TGR5-independent, GLP-2R-dependent pathway |
| title_short | Glucagon-like peptide-2 promotes gallbladder refilling via a TGR5-independent, GLP-2R-dependent pathway |
| title_sort | glucagon like peptide 2 promotes gallbladder refilling via a tgr5 independent glp 2r dependent pathway |
| url | http://www.sciencedirect.com/science/article/pii/S221287781730131X |
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