GDF15 activates AMPK and inhibits gluconeogenesis and fibrosis in the liver by attenuating the TGF-β1/SMAD3 pathway

Introduction: The levels of the cellular energy sensor AMP-activated protein kinase (AMPK) have been reported to be decreased via unknown mechanisms in the liver of mice deficient in growth differentiation factor 15 (GDF15). This stress response cytokine regulates energy metabolism mainly by reducin...

Descripción completa

Detalles Bibliográficos
Autores: Jurado Aguilar, Javier, Barroso Fernández, Emma, Bernard, Maribel, Zhang, Meijian, Peyman, Mona, Rada, Patricia, Valverde, Ángela M., Wahli, Walter, Palomer Tarridas, Francesc Xavier, Vázquez Carrera, Manuel
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2024
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/219032
Acceso en línea:https://hdl.handle.net/2445/219032
Access Level:acceso abierto
Palabra clave:Antidiabètics
Envelliment
Metabolisme
Hypoglucemic agents
Aging
Metabolism
id ES_e5cd87019cbbee5116ccdf812ea745e5
oai_identifier_str oai:diposit.ub.edu:2445/219032
network_acronym_str ES
network_name_str España
repository_id_str
spelling GDF15 activates AMPK and inhibits gluconeogenesis and fibrosis in the liver by attenuating the TGF-β1/SMAD3 pathwayJurado Aguilar, JavierBarroso Fernández, EmmaBernard, MaribelZhang, MeijianPeyman, MonaRada, PatriciaValverde, Ángela M.Wahli, WalterPalomer Tarridas, Francesc XavierVázquez Carrera, ManuelAntidiabèticsEnvellimentMetabolismeHypoglucemic agentsAgingMetabolismIntroduction: The levels of the cellular energy sensor AMP-activated protein kinase (AMPK) have been reported to be decreased via unknown mechanisms in the liver of mice deficient in growth differentiation factor 15 (GDF15). This stress response cytokine regulates energy metabolism mainly by reducing food intake through its hindbrain receptor GFRAL. Objective: To examine how GDF15 regulates AMPK. Methods: Wild-type and Gdf15-/- mice, mouse primary hepatocytes and the human hepatic cell line Huh-7 were used. Results: Gdf15-/- mice showed glucose intolerance, reduced hepatic phosphorylated AMPK levels, increased levels of phosphorylated mothers against decapentaplegic homolog 3 (SMAD3; a mediator of the fibrotic response), elevated serum levels of transforming growth factor (TGF)-β1, as well as upregulated gluconeogenesis and fibrosis. In line with these observations, recombinant (r)GDF15 promoted AMPK activation and reduced the levels of phosphorylated SMAD3 and the markers of gluconeogenesis and fibrosis in the liver of mice and in mouse primary hepatocytes, suggesting that these effects may be independent of GFRAL. Pharmacological inhibition of SMAD3 phosphorylation in Gdf15-/- mice prevented glucose intolerance, the deactivation of AMPK and the increase in the levels of proteins involved in gluconeogenesis and fibrosis, suggesting that overactivation of the TGF-β1/SMAD3 pathway is responsible for the metabolic alterations in Gdf15-/- mice. Conclusions: Overall, these findings indicate that GDF15 activates AMPK and inhibits gluconeogenesis and fibrosis by lowering the activity of the TGF-β1/SMAD3 pathway. Keywords: AMPK; Fibrosis; GDF15; Gluconeogenesis; SMAD3; TGF-β.Elsevier Inc.2024info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersionapplication/pdfhttps://hdl.handle.net/2445/219032Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésVersió postprint del document publicat a: https://doi.org/10.1016/j.metabol.2023.155772Metabolism, 2024, vol. 152, p. 155772https://doi.org/10.1016/j.metabol.2023.155772cc-by-nc-nd (c) Elsevier Inc., 2024http://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/2190322026-05-27T06:46:51Z
dc.title.none.fl_str_mv GDF15 activates AMPK and inhibits gluconeogenesis and fibrosis in the liver by attenuating the TGF-β1/SMAD3 pathway
title GDF15 activates AMPK and inhibits gluconeogenesis and fibrosis in the liver by attenuating the TGF-β1/SMAD3 pathway
spellingShingle GDF15 activates AMPK and inhibits gluconeogenesis and fibrosis in the liver by attenuating the TGF-β1/SMAD3 pathway
Jurado Aguilar, Javier
Antidiabètics
Envelliment
Metabolisme
Hypoglucemic agents
Aging
Metabolism
title_short GDF15 activates AMPK and inhibits gluconeogenesis and fibrosis in the liver by attenuating the TGF-β1/SMAD3 pathway
title_full GDF15 activates AMPK and inhibits gluconeogenesis and fibrosis in the liver by attenuating the TGF-β1/SMAD3 pathway
title_fullStr GDF15 activates AMPK and inhibits gluconeogenesis and fibrosis in the liver by attenuating the TGF-β1/SMAD3 pathway
title_full_unstemmed GDF15 activates AMPK and inhibits gluconeogenesis and fibrosis in the liver by attenuating the TGF-β1/SMAD3 pathway
title_sort GDF15 activates AMPK and inhibits gluconeogenesis and fibrosis in the liver by attenuating the TGF-β1/SMAD3 pathway
dc.creator.none.fl_str_mv Jurado Aguilar, Javier
Barroso Fernández, Emma
Bernard, Maribel
Zhang, Meijian
Peyman, Mona
Rada, Patricia
Valverde, Ángela M.
Wahli, Walter
Palomer Tarridas, Francesc Xavier
Vázquez Carrera, Manuel
author Jurado Aguilar, Javier
author_facet Jurado Aguilar, Javier
Barroso Fernández, Emma
Bernard, Maribel
Zhang, Meijian
Peyman, Mona
Rada, Patricia
Valverde, Ángela M.
Wahli, Walter
Palomer Tarridas, Francesc Xavier
Vázquez Carrera, Manuel
author_role author
author2 Barroso Fernández, Emma
Bernard, Maribel
Zhang, Meijian
Peyman, Mona
Rada, Patricia
Valverde, Ángela M.
Wahli, Walter
Palomer Tarridas, Francesc Xavier
Vázquez Carrera, Manuel
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Antidiabètics
Envelliment
Metabolisme
Hypoglucemic agents
Aging
Metabolism
topic Antidiabètics
Envelliment
Metabolisme
Hypoglucemic agents
Aging
Metabolism
description Introduction: The levels of the cellular energy sensor AMP-activated protein kinase (AMPK) have been reported to be decreased via unknown mechanisms in the liver of mice deficient in growth differentiation factor 15 (GDF15). This stress response cytokine regulates energy metabolism mainly by reducing food intake through its hindbrain receptor GFRAL. Objective: To examine how GDF15 regulates AMPK. Methods: Wild-type and Gdf15-/- mice, mouse primary hepatocytes and the human hepatic cell line Huh-7 were used. Results: Gdf15-/- mice showed glucose intolerance, reduced hepatic phosphorylated AMPK levels, increased levels of phosphorylated mothers against decapentaplegic homolog 3 (SMAD3; a mediator of the fibrotic response), elevated serum levels of transforming growth factor (TGF)-β1, as well as upregulated gluconeogenesis and fibrosis. In line with these observations, recombinant (r)GDF15 promoted AMPK activation and reduced the levels of phosphorylated SMAD3 and the markers of gluconeogenesis and fibrosis in the liver of mice and in mouse primary hepatocytes, suggesting that these effects may be independent of GFRAL. Pharmacological inhibition of SMAD3 phosphorylation in Gdf15-/- mice prevented glucose intolerance, the deactivation of AMPK and the increase in the levels of proteins involved in gluconeogenesis and fibrosis, suggesting that overactivation of the TGF-β1/SMAD3 pathway is responsible for the metabolic alterations in Gdf15-/- mice. Conclusions: Overall, these findings indicate that GDF15 activates AMPK and inhibits gluconeogenesis and fibrosis by lowering the activity of the TGF-β1/SMAD3 pathway. Keywords: AMPK; Fibrosis; GDF15; Gluconeogenesis; SMAD3; TGF-β.
publishDate 2024
dc.date.none.fl_str_mv 2024
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/219032
url https://hdl.handle.net/2445/219032
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Versió postprint del document publicat a: https://doi.org/10.1016/j.metabol.2023.155772
Metabolism, 2024, vol. 152, p. 155772
https://doi.org/10.1016/j.metabol.2023.155772
dc.rights.none.fl_str_mv cc-by-nc-nd (c) Elsevier Inc., 2024
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by-nc-nd (c) Elsevier Inc., 2024
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier Inc.
publisher.none.fl_str_mv Elsevier Inc.
dc.source.none.fl_str_mv Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869422711488380928
score 15,81155

Similares en LA Referencia