The gastrointestinal tract is a major source of the acute metformin-stimulated rise in GDF15.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
22 Jan 2024
22 Jan 2024
Historique:
received:
23
11
2023
accepted:
10
01
2024
medline:
23
1
2024
pubmed:
23
1
2024
entrez:
22
1
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 38253650
doi: 10.1038/s41598-024-51866-2
pii: 10.1038/s41598-024-51866-2
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1899Subventions
Organisme : Medical Research Council Metabolic Diseases Unit Disease Model Core
ID : MC_UU_00014/5
Organisme : MRC Metabolic Diseases Unit
ID : MC_UU_00014/1
Organisme : NIHR Clinical Lectureship
ID : CL-2019-14-504
Informations de copyright
© 2024. The Author(s).
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