A positive feedback loop between AMPK and GDF15 promotes metformin antidiabetic effects.

BACKGROUND AND AIMS: Metformin, the most prescribed drug for the treatment of type 2 diabetes mellitus, has been recently reported to promote weight loss by upregulating the anorectic cytokine growth differentiation factor 15 (GDF15). Since the antidiabetic effects of metformin are mostly mediated b...

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Autores: Aguilar-Recarte D, Barroso E, Zhang M, Rada P, Pizarro-Delgado J, Peña L, Palomer X, Valverde ÁM, Wahli W, Vázquez-Carrera M
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2023
País:España
Institución:Fundació Sant Joan de Déu
Repositorio:r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
OAI Identifier:oai:fsjd.fundanetsuite.com:p22574
Acceso en línea:https://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=22574
Access Level:acceso abierto
Palabra clave:AMPK
GDF15
Glucose tolerance
Metformin
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spelling A positive feedback loop between AMPK and GDF15 promotes metformin antidiabetic effects.Aguilar-Recarte DBarroso EZhang MRada PPizarro-Delgado JPeña LPalomer XValverde ÁMWahli WVázquez-Carrera MAMPKGDF15Glucose toleranceMetforminBACKGROUND AND AIMS: Metformin, the most prescribed drug for the treatment of type 2 diabetes mellitus, has been recently reported to promote weight loss by upregulating the anorectic cytokine growth differentiation factor 15 (GDF15). Since the antidiabetic effects of metformin are mostly mediated by the activation of AMPK, a key metabolic sensor in energy homeostasis, we examined whether the activation of this kinase by metformin was dependent on GDF15. METHODS: Cultured hepatocytes and myotubes, and wild-type and Gdf15(-/-) mice were utilized in a series of studies to investigate the involvement of GDF15 in the activation of AMPK by metformin. RESULTS: A low dose of metformin increased GDF15 levels without significantly reducing body weight or food intake, but it ameliorated glucose intolerance and activated AMPK in the liver and skeletal muscle of wild-type mice but not Gdf15(-/-) mice fed a high-fat diet. Cultured hepatocytes and myotubes treated with metformin showed AMPK-mediated increases in GDF15 levels independently of its central receptor GFRAL, while Gdf15 knockdown blunted the effect of metformin on AMPK activation, suggesting that AMPK is required for the metformin-mediated increase in GDF15, which in turn is needed to sustain the full activation of this kinase independently of the CNS. CONCLUSION: Overall, these findings uncover a novel mechanism through which GDF15 upregulation by metformin is involved in achieving and sustaining full AMPK activation by this drug independently of the CNS.ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD2023info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=22574PHARMACOLOGICAL RESEARCHISSN: 10436618ISSNe: 10961186reponame:r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déuinstname:Fundació Sant Joan de DéuInglésinfo:eu-repo/semantics/openAccessoai:fsjd.fundanetsuite.com:p225742026-05-27T12:37:41Z
dc.title.none.fl_str_mv A positive feedback loop between AMPK and GDF15 promotes metformin antidiabetic effects.
title A positive feedback loop between AMPK and GDF15 promotes metformin antidiabetic effects.
spellingShingle A positive feedback loop between AMPK and GDF15 promotes metformin antidiabetic effects.
Aguilar-Recarte D
AMPK
GDF15
Glucose tolerance
Metformin
title_short A positive feedback loop between AMPK and GDF15 promotes metformin antidiabetic effects.
title_full A positive feedback loop between AMPK and GDF15 promotes metformin antidiabetic effects.
title_fullStr A positive feedback loop between AMPK and GDF15 promotes metformin antidiabetic effects.
title_full_unstemmed A positive feedback loop between AMPK and GDF15 promotes metformin antidiabetic effects.
title_sort A positive feedback loop between AMPK and GDF15 promotes metformin antidiabetic effects.
dc.creator.none.fl_str_mv Aguilar-Recarte D
Barroso E
Zhang M
Rada P
Pizarro-Delgado J
Peña L
Palomer X
Valverde ÁM
Wahli W
Vázquez-Carrera M
author Aguilar-Recarte D
author_facet Aguilar-Recarte D
Barroso E
Zhang M
Rada P
Pizarro-Delgado J
Peña L
Palomer X
Valverde ÁM
Wahli W
Vázquez-Carrera M
author_role author
author2 Barroso E
Zhang M
Rada P
Pizarro-Delgado J
Peña L
Palomer X
Valverde ÁM
Wahli W
Vázquez-Carrera M
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv AMPK
GDF15
Glucose tolerance
Metformin
topic AMPK
GDF15
Glucose tolerance
Metformin
description BACKGROUND AND AIMS: Metformin, the most prescribed drug for the treatment of type 2 diabetes mellitus, has been recently reported to promote weight loss by upregulating the anorectic cytokine growth differentiation factor 15 (GDF15). Since the antidiabetic effects of metformin are mostly mediated by the activation of AMPK, a key metabolic sensor in energy homeostasis, we examined whether the activation of this kinase by metformin was dependent on GDF15. METHODS: Cultured hepatocytes and myotubes, and wild-type and Gdf15(-/-) mice were utilized in a series of studies to investigate the involvement of GDF15 in the activation of AMPK by metformin. RESULTS: A low dose of metformin increased GDF15 levels without significantly reducing body weight or food intake, but it ameliorated glucose intolerance and activated AMPK in the liver and skeletal muscle of wild-type mice but not Gdf15(-/-) mice fed a high-fat diet. Cultured hepatocytes and myotubes treated with metformin showed AMPK-mediated increases in GDF15 levels independently of its central receptor GFRAL, while Gdf15 knockdown blunted the effect of metformin on AMPK activation, suggesting that AMPK is required for the metformin-mediated increase in GDF15, which in turn is needed to sustain the full activation of this kinase independently of the CNS. CONCLUSION: Overall, these findings uncover a novel mechanism through which GDF15 upregulation by metformin is involved in achieving and sustaining full AMPK activation by this drug independently of the CNS.
publishDate 2023
dc.date.none.fl_str_mv 2023
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=22574
url https://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=22574
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
publisher.none.fl_str_mv ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
dc.source.none.fl_str_mv PHARMACOLOGICAL RESEARCH
ISSN: 10436618
ISSNe: 10961186
reponame:r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
instname:Fundació Sant Joan de Déu
instname_str Fundació Sant Joan de Déu
reponame_str r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
collection r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
repository.name.fl_str_mv
repository.mail.fl_str_mv
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