The gastrointestinal tract is a major source of the acute metformin-stimulated rise in GDF15
Abstract The hormone GDF15 is secreted in response to cellular stressors. Metformin elevates circulating levels of GDF15, an action important for the drug’s beneficial effects on body weight. Metformin can also inhibit mammalian respiratory complex I, leading to decreases in ATP:AMP ratio, activatio...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2024-01-01
|
| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-024-51866-2 |
| _version_ | 1797276529790550016 |
|---|---|
| author | John W. R. Kincaid Debra Rimmington John A. Tadross Irene Cimino Ilona Zvetkova Arthur Kaser Paul Richards Satish Patel Stephen O’Rahilly Anthony P. Coll |
| author_facet | John W. R. Kincaid Debra Rimmington John A. Tadross Irene Cimino Ilona Zvetkova Arthur Kaser Paul Richards Satish Patel Stephen O’Rahilly Anthony P. Coll |
| author_sort | John W. R. Kincaid |
| collection | DOAJ |
| description | Abstract The hormone GDF15 is secreted in response to cellular stressors. Metformin elevates circulating levels of GDF15, an action important for the drug’s beneficial effects on body weight. Metformin can also inhibit mammalian respiratory complex I, leading to decreases in ATP:AMP ratio, activation of AMP Kinase (AMPK), and increased GDF15 production. We undertook studies using a range of mice with tissue-specific loss of Gdf15 (namely gut, liver and global deletion) to determine the relative contributions of two classical metformin target tissues, the gut and liver, to the elevation of GDF15 seen with metformin. In addition, we performed comparative studies with another pharmacological agent, the AMP kinase pan-activator, MK-8722. Deletion of Gdf15 from the intestinal epithelium significantly reduced the circulating GDF15 response to oral metformin, whereas deletion of Gdf15 from the liver had no effect. In contrast, deletion of Gdf15 from the liver, but not the gut, markedly reduced circulating GDF15 responses to MK-8722. Further, our data show that, while GDF15 restricts high-fat diet-induced weight gain, the intestinal production of GDF15 is not necessary for this effect. These findings add to the body of evidence implicating the intestinal epithelium in key aspects of the pharmacology of metformin action. |
| first_indexed | 2024-03-07T15:29:30Z |
| format | Article |
| id | doaj.art-36d415474a95447299258e0b0a1879b6 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-03-07T15:29:30Z |
| publishDate | 2024-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-36d415474a95447299258e0b0a1879b62024-03-05T16:28:52ZengNature PortfolioScientific Reports2045-23222024-01-0114111310.1038/s41598-024-51866-2The gastrointestinal tract is a major source of the acute metformin-stimulated rise in GDF15John W. R. Kincaid0Debra Rimmington1John A. Tadross2Irene Cimino3Ilona Zvetkova4Arthur Kaser5Paul Richards6Satish Patel7Stephen O’Rahilly8Anthony P. Coll9Institute of Metabolic Science, University of CambridgeInstitute of Metabolic Science, University of CambridgeInstitute of Metabolic Science, University of CambridgeInstitute of Metabolic Science, University of CambridgeInstitute of Metabolic Science, University of CambridgeCambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of CambridgeKallyope, Inc.Institute of Metabolic Science, University of CambridgeInstitute of Metabolic Science, University of CambridgeInstitute of Metabolic Science, University of CambridgeAbstract The hormone GDF15 is secreted in response to cellular stressors. Metformin elevates circulating levels of GDF15, an action important for the drug’s beneficial effects on body weight. Metformin can also inhibit mammalian respiratory complex I, leading to decreases in ATP:AMP ratio, activation of AMP Kinase (AMPK), and increased GDF15 production. We undertook studies using a range of mice with tissue-specific loss of Gdf15 (namely gut, liver and global deletion) to determine the relative contributions of two classical metformin target tissues, the gut and liver, to the elevation of GDF15 seen with metformin. In addition, we performed comparative studies with another pharmacological agent, the AMP kinase pan-activator, MK-8722. Deletion of Gdf15 from the intestinal epithelium significantly reduced the circulating GDF15 response to oral metformin, whereas deletion of Gdf15 from the liver had no effect. In contrast, deletion of Gdf15 from the liver, but not the gut, markedly reduced circulating GDF15 responses to MK-8722. Further, our data show that, while GDF15 restricts high-fat diet-induced weight gain, the intestinal production of GDF15 is not necessary for this effect. These findings add to the body of evidence implicating the intestinal epithelium in key aspects of the pharmacology of metformin action.https://doi.org/10.1038/s41598-024-51866-2 |
| spellingShingle | John W. R. Kincaid Debra Rimmington John A. Tadross Irene Cimino Ilona Zvetkova Arthur Kaser Paul Richards Satish Patel Stephen O’Rahilly Anthony P. Coll The gastrointestinal tract is a major source of the acute metformin-stimulated rise in GDF15 Scientific Reports |
| title | The gastrointestinal tract is a major source of the acute metformin-stimulated rise in GDF15 |
| title_full | The gastrointestinal tract is a major source of the acute metformin-stimulated rise in GDF15 |
| title_fullStr | The gastrointestinal tract is a major source of the acute metformin-stimulated rise in GDF15 |
| title_full_unstemmed | The gastrointestinal tract is a major source of the acute metformin-stimulated rise in GDF15 |
| title_short | The gastrointestinal tract is a major source of the acute metformin-stimulated rise in GDF15 |
| title_sort | gastrointestinal tract is a major source of the acute metformin stimulated rise in gdf15 |
| url | https://doi.org/10.1038/s41598-024-51866-2 |
| work_keys_str_mv | AT johnwrkincaid thegastrointestinaltractisamajorsourceoftheacutemetforminstimulatedriseingdf15 AT debrarimmington thegastrointestinaltractisamajorsourceoftheacutemetforminstimulatedriseingdf15 AT johnatadross thegastrointestinaltractisamajorsourceoftheacutemetforminstimulatedriseingdf15 AT irenecimino thegastrointestinaltractisamajorsourceoftheacutemetforminstimulatedriseingdf15 AT ilonazvetkova thegastrointestinaltractisamajorsourceoftheacutemetforminstimulatedriseingdf15 AT arthurkaser thegastrointestinaltractisamajorsourceoftheacutemetforminstimulatedriseingdf15 AT paulrichards thegastrointestinaltractisamajorsourceoftheacutemetforminstimulatedriseingdf15 AT satishpatel thegastrointestinaltractisamajorsourceoftheacutemetforminstimulatedriseingdf15 AT stephenorahilly thegastrointestinaltractisamajorsourceoftheacutemetforminstimulatedriseingdf15 AT anthonypcoll thegastrointestinaltractisamajorsourceoftheacutemetforminstimulatedriseingdf15 AT johnwrkincaid gastrointestinaltractisamajorsourceoftheacutemetforminstimulatedriseingdf15 AT debrarimmington gastrointestinaltractisamajorsourceoftheacutemetforminstimulatedriseingdf15 AT johnatadross gastrointestinaltractisamajorsourceoftheacutemetforminstimulatedriseingdf15 AT irenecimino gastrointestinaltractisamajorsourceoftheacutemetforminstimulatedriseingdf15 AT ilonazvetkova gastrointestinaltractisamajorsourceoftheacutemetforminstimulatedriseingdf15 AT arthurkaser gastrointestinaltractisamajorsourceoftheacutemetforminstimulatedriseingdf15 AT paulrichards gastrointestinaltractisamajorsourceoftheacutemetforminstimulatedriseingdf15 AT satishpatel gastrointestinaltractisamajorsourceoftheacutemetforminstimulatedriseingdf15 AT stephenorahilly gastrointestinaltractisamajorsourceoftheacutemetforminstimulatedriseingdf15 AT anthonypcoll gastrointestinaltractisamajorsourceoftheacutemetforminstimulatedriseingdf15 |