Intestine-selective reduction of Gcg expression reveals the importance of the distal gut for GLP-1 secretion
Objective: Glucagon-like peptide-1 is a nutrient-sensitive hormone secreted from enteroendocrine L cells within the small and large bowel. Although GLP-1 levels rise rapidly in response to food ingestion, the greatest density of L cells is localized to the distal small bowel and colon. Here, we asse...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-07-01
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| Series: | Molecular Metabolism |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877820300648 |
| _version_ | 1818501248851116032 |
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| author | Brandon L. Panaro Bernardo Yusta Dianne Matthews Jacqueline A. Koehler Youngmi Song Darleen A. Sandoval Daniel J. Drucker |
| author_facet | Brandon L. Panaro Bernardo Yusta Dianne Matthews Jacqueline A. Koehler Youngmi Song Darleen A. Sandoval Daniel J. Drucker |
| author_sort | Brandon L. Panaro |
| collection | DOAJ |
| description | Objective: Glucagon-like peptide-1 is a nutrient-sensitive hormone secreted from enteroendocrine L cells within the small and large bowel. Although GLP-1 levels rise rapidly in response to food ingestion, the greatest density of L cells is localized to the distal small bowel and colon. Here, we assessed the importance of the distal gut in the acute L cell response to diverse secretagogues. Methods: Circulating levels of glucose and plasma GLP-1 were measured in response to the administration of L cell secretagogues in wild-type mice and in mice with (1) genetic reduction of Gcg expression throughout the small bowel and large bowel (GcgGut−/-) and (2) selective reduction of Gcg expression in the distal gut (GcgDistalGut−/-). Results: The acute GLP-1 response to olive oil or arginine administration was markedly diminished in GcgGut−/- but preserved in GcgDistalGut−/- mice. In contrast, the increase in plasma GLP-1 levels following the administration of the GPR119 agonist AR231453, or the melanocortin-4 receptor (MC4R) agonist LY2112688, was markedly diminished in the GcgDistalGut−/- mice. The GLP-1 response to LPS was also markedly attenuated in the GcgGut−/- mice and remained submaximal in the GcgDistalGut−/- mice. Doses of metformin sufficient to lower glucose and increase GLP-1 levels in the GcgGut+/+ mice retained their glucoregulatory activity, yet they failed to increase GLP-1 levels in the GcgGut−/- mice. Surprisingly, the actions of metformin to increase plasma GLP-1 levels were substantially attenuated in the GcgDistalGut−/- mice. Conclusion: These findings further establish the importance of the proximal gut for the acute response to nutrient-related GLP-1 secretagogues. In contrast, we identify essential contributions of the distal gut to (i) the rapid induction of circulating GLP-1 levels in response to pharmacological selective agonism of G-protein-coupled receptors, (ii) the increased GLP-1 levels following the activation of Toll-Like Receptors with LPS, and iii) the acute GLP-1 response to metformin. Collectively, these results reveal that distal gut Gcg + endocrine cells are rapid responders to structurally and functionally diverse GLP-1 secretagogues. |
| first_indexed | 2024-12-10T20:53:35Z |
| format | Article |
| id | doaj.art-1094acce8f4b47ebb87235202b9bfaef |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-12-10T20:53:35Z |
| publishDate | 2020-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-1094acce8f4b47ebb87235202b9bfaef2022-12-22T01:34:01ZengElsevierMolecular Metabolism2212-87782020-07-0137100990Intestine-selective reduction of Gcg expression reveals the importance of the distal gut for GLP-1 secretionBrandon L. Panaro0Bernardo Yusta1Dianne Matthews2Jacqueline A. Koehler3Youngmi Song4Darleen A. Sandoval5Daniel J. Drucker6Department of Medicine and the Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, Ontario, Canada; Corresponding author. Mt. Sinai Hospital, 600 University Avenue Mailbox 39, TCP5-1004, Toronto, M5G1X5, ON Canada.V416-361-2661.Department of Medicine and the Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, Ontario, CanadaDepartment of Medicine and the Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, Ontario, CanadaDepartment of Medicine and the Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, Ontario, CanadaDepartment of Medicine and the Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, Ontario, CanadaDepartment of Surgery, University of Michigan, Ann Arbor, MI, USADepartment of Medicine and the Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, Ontario, CanadaObjective: Glucagon-like peptide-1 is a nutrient-sensitive hormone secreted from enteroendocrine L cells within the small and large bowel. Although GLP-1 levels rise rapidly in response to food ingestion, the greatest density of L cells is localized to the distal small bowel and colon. Here, we assessed the importance of the distal gut in the acute L cell response to diverse secretagogues. Methods: Circulating levels of glucose and plasma GLP-1 were measured in response to the administration of L cell secretagogues in wild-type mice and in mice with (1) genetic reduction of Gcg expression throughout the small bowel and large bowel (GcgGut−/-) and (2) selective reduction of Gcg expression in the distal gut (GcgDistalGut−/-). Results: The acute GLP-1 response to olive oil or arginine administration was markedly diminished in GcgGut−/- but preserved in GcgDistalGut−/- mice. In contrast, the increase in plasma GLP-1 levels following the administration of the GPR119 agonist AR231453, or the melanocortin-4 receptor (MC4R) agonist LY2112688, was markedly diminished in the GcgDistalGut−/- mice. The GLP-1 response to LPS was also markedly attenuated in the GcgGut−/- mice and remained submaximal in the GcgDistalGut−/- mice. Doses of metformin sufficient to lower glucose and increase GLP-1 levels in the GcgGut+/+ mice retained their glucoregulatory activity, yet they failed to increase GLP-1 levels in the GcgGut−/- mice. Surprisingly, the actions of metformin to increase plasma GLP-1 levels were substantially attenuated in the GcgDistalGut−/- mice. Conclusion: These findings further establish the importance of the proximal gut for the acute response to nutrient-related GLP-1 secretagogues. In contrast, we identify essential contributions of the distal gut to (i) the rapid induction of circulating GLP-1 levels in response to pharmacological selective agonism of G-protein-coupled receptors, (ii) the increased GLP-1 levels following the activation of Toll-Like Receptors with LPS, and iii) the acute GLP-1 response to metformin. Collectively, these results reveal that distal gut Gcg + endocrine cells are rapid responders to structurally and functionally diverse GLP-1 secretagogues.http://www.sciencedirect.com/science/article/pii/S2212877820300648PeptidesIntestinePancreasDiabetesObesityMetformin |
| spellingShingle | Brandon L. Panaro Bernardo Yusta Dianne Matthews Jacqueline A. Koehler Youngmi Song Darleen A. Sandoval Daniel J. Drucker Intestine-selective reduction of Gcg expression reveals the importance of the distal gut for GLP-1 secretion Molecular Metabolism Peptides Intestine Pancreas Diabetes Obesity Metformin |
| title | Intestine-selective reduction of Gcg expression reveals the importance of the distal gut for GLP-1 secretion |
| title_full | Intestine-selective reduction of Gcg expression reveals the importance of the distal gut for GLP-1 secretion |
| title_fullStr | Intestine-selective reduction of Gcg expression reveals the importance of the distal gut for GLP-1 secretion |
| title_full_unstemmed | Intestine-selective reduction of Gcg expression reveals the importance of the distal gut for GLP-1 secretion |
| title_short | Intestine-selective reduction of Gcg expression reveals the importance of the distal gut for GLP-1 secretion |
| title_sort | intestine selective reduction of gcg expression reveals the importance of the distal gut for glp 1 secretion |
| topic | Peptides Intestine Pancreas Diabetes Obesity Metformin |
| url | http://www.sciencedirect.com/science/article/pii/S2212877820300648 |
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