GDF15 mediates the metabolic effects of PPARβ/δ by activating AMPK

Peroxisome proliferator-activated receptor β/ (PPARβ/) activates AMP-activated protein kinase (AMPK) and plays a crucial role in glucose and lipid metabolism. Here, we examined whether the beneficial effects of PPARβ/δ activation depended on growth differentiation factor 15 (GDF15), a stress respo...

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Autores: Aguilar-Recarte, David, Barroso Fernández, Emma, Gumà i Garcia, Anna Maria, Pizarro Delgado, Javier, Peña, Lucía, Ruart, Maria, Palomer Tarridas, Francesc Xavier, Wahli, Walter, Vázquez Carrera, Manuel
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/180474
Acceso en línea:https://hdl.handle.net/2445/180474
Access Level:acceso abierto
Palabra clave:Trastorns del metabolisme dels lípids
Àcids grassos
Receptors nuclears (Bioquímica)
Glucosa
Lipid metabolism disorders
Fatty acids
Nuclear receptors (Biochemistry)
Glucose
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spelling GDF15 mediates the metabolic effects of PPARβ/δ by activating AMPKAguilar-Recarte, DavidBarroso Fernández, EmmaGumà i Garcia, Anna MariaPizarro Delgado, JavierPeña, LucíaRuart, MariaPalomer Tarridas, Francesc XavierWahli, WalterVázquez Carrera, ManuelTrastorns del metabolisme dels lípidsÀcids grassosReceptors nuclears (Bioquímica)GlucosaLipid metabolism disordersFatty acidsNuclear receptors (Biochemistry)GlucosePeroxisome proliferator-activated receptor β/ (PPARβ/) activates AMP-activated protein kinase (AMPK) and plays a crucial role in glucose and lipid metabolism. Here, we examined whether the beneficial effects of PPARβ/δ activation depended on growth differentiation factor 15 (GDF15), a stress response cytokine that regulates energy metabolism. Pharmacological PPARβ/δ activation increased GDF15 levels and ameliorated glucose intolerance, fatty acid oxidation, endoplasmic reticulum stress, inflammation and activated AMPK in HFD-fed mice, whereas these effects were abrogated by the injection of a GDF15 neutralizing antibody and in Gdf15-/- mice. The AMPK-p53 pathway was involved in the PPARβ/δ-mediated increase in GDF15, which in turn activated again AMPK. Finally, Gdf15-/- mice showed reduced AMPK activation in skeletal muscle, whereas GDF15 administration resulted in AMPK activation in this organ. Collectively, these data reveal a novel mechanism by which PPARβ/δ activation increases the levels of GDF15 via AMPK and p53, which in turn mediates the metabolic effects of PPARβ/δ by sustaining AMPK activation. Abbreviations: Acadm, acyl-CoA dehydrogenase medium chain; Acox, acyl-CoA oxidase; AMPK, AMP-activated protein kinase; ATF4, activating transcription factor 4; BiP/GRP78, Binding immunoglobulin protein/78-kDa glucose-regulated protein; CC, compound C; Chop, C/EBP homologous protein; Cpt-1, carnitine palmitoyl-transferase 1; eIF2eukaryotic translation initiation factor 2 ER, endoplasmic reticulum; ERK, extracellular signal-regulated kinase; FGF21, fibroblast growth factor 21; GDF15, growth differentiation factor 15; GFRAL, glial-derived neurotrophic factor receptor α-like; HFD, high-fat diet; Pdk4, pyruvate dehydrogenase kinase 4; IRS, insulin receptor substrate; PGC-1PPAR co-activator 1 PPAR peroxisome proliferator-activated receptor; SOCS3, suppressor of cytokine signaling 3; STAT3, signal transducer and activator of transcription 3; Vldlr, very-low density lipoprotein receptor.Elsevier2021202120212021info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttps://hdl.handle.net/2445/180474Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.1016/j.celrep.2021.109501Cell Reports, 2021, vol. 36, num. 6, p. 109501https://doi.org/10.1016/j.celrep.2021.109501cc-by (c) Aguilar-Recarte, David et al., 2021https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:recercat.cat:2445/1804742026-05-29T05:05:01Z
dc.title.none.fl_str_mv GDF15 mediates the metabolic effects of PPARβ/δ by activating AMPK
title GDF15 mediates the metabolic effects of PPARβ/δ by activating AMPK
spellingShingle GDF15 mediates the metabolic effects of PPARβ/δ by activating AMPK
Aguilar-Recarte, David
Trastorns del metabolisme dels lípids
Àcids grassos
Receptors nuclears (Bioquímica)
Glucosa
Lipid metabolism disorders
Fatty acids
Nuclear receptors (Biochemistry)
Glucose
title_short GDF15 mediates the metabolic effects of PPARβ/δ by activating AMPK
title_full GDF15 mediates the metabolic effects of PPARβ/δ by activating AMPK
title_fullStr GDF15 mediates the metabolic effects of PPARβ/δ by activating AMPK
title_full_unstemmed GDF15 mediates the metabolic effects of PPARβ/δ by activating AMPK
title_sort GDF15 mediates the metabolic effects of PPARβ/δ by activating AMPK
dc.creator.none.fl_str_mv Aguilar-Recarte, David
Barroso Fernández, Emma
Gumà i Garcia, Anna Maria
Pizarro Delgado, Javier
Peña, Lucía
Ruart, Maria
Palomer Tarridas, Francesc Xavier
Wahli, Walter
Vázquez Carrera, Manuel
author Aguilar-Recarte, David
author_facet Aguilar-Recarte, David
Barroso Fernández, Emma
Gumà i Garcia, Anna Maria
Pizarro Delgado, Javier
Peña, Lucía
Ruart, Maria
Palomer Tarridas, Francesc Xavier
Wahli, Walter
Vázquez Carrera, Manuel
author_role author
author2 Barroso Fernández, Emma
Gumà i Garcia, Anna Maria
Pizarro Delgado, Javier
Peña, Lucía
Ruart, Maria
Palomer Tarridas, Francesc Xavier
Wahli, Walter
Vázquez Carrera, Manuel
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Trastorns del metabolisme dels lípids
Àcids grassos
Receptors nuclears (Bioquímica)
Glucosa
Lipid metabolism disorders
Fatty acids
Nuclear receptors (Biochemistry)
Glucose
topic Trastorns del metabolisme dels lípids
Àcids grassos
Receptors nuclears (Bioquímica)
Glucosa
Lipid metabolism disorders
Fatty acids
Nuclear receptors (Biochemistry)
Glucose
description Peroxisome proliferator-activated receptor β/ (PPARβ/) activates AMP-activated protein kinase (AMPK) and plays a crucial role in glucose and lipid metabolism. Here, we examined whether the beneficial effects of PPARβ/δ activation depended on growth differentiation factor 15 (GDF15), a stress response cytokine that regulates energy metabolism. Pharmacological PPARβ/δ activation increased GDF15 levels and ameliorated glucose intolerance, fatty acid oxidation, endoplasmic reticulum stress, inflammation and activated AMPK in HFD-fed mice, whereas these effects were abrogated by the injection of a GDF15 neutralizing antibody and in Gdf15-/- mice. The AMPK-p53 pathway was involved in the PPARβ/δ-mediated increase in GDF15, which in turn activated again AMPK. Finally, Gdf15-/- mice showed reduced AMPK activation in skeletal muscle, whereas GDF15 administration resulted in AMPK activation in this organ. Collectively, these data reveal a novel mechanism by which PPARβ/δ activation increases the levels of GDF15 via AMPK and p53, which in turn mediates the metabolic effects of PPARβ/δ by sustaining AMPK activation. Abbreviations: Acadm, acyl-CoA dehydrogenase medium chain; Acox, acyl-CoA oxidase; AMPK, AMP-activated protein kinase; ATF4, activating transcription factor 4; BiP/GRP78, Binding immunoglobulin protein/78-kDa glucose-regulated protein; CC, compound C; Chop, C/EBP homologous protein; Cpt-1, carnitine palmitoyl-transferase 1; eIF2eukaryotic translation initiation factor 2 ER, endoplasmic reticulum; ERK, extracellular signal-regulated kinase; FGF21, fibroblast growth factor 21; GDF15, growth differentiation factor 15; GFRAL, glial-derived neurotrophic factor receptor α-like; HFD, high-fat diet; Pdk4, pyruvate dehydrogenase kinase 4; IRS, insulin receptor substrate; PGC-1PPAR co-activator 1 PPAR peroxisome proliferator-activated receptor; SOCS3, suppressor of cytokine signaling 3; STAT3, signal transducer and activator of transcription 3; Vldlr, very-low density lipoprotein receptor.
publishDate 2021
dc.date.none.fl_str_mv 2021
2021
2021
2021
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://hdl.handle.net/2445/180474
url https://hdl.handle.net/2445/180474
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1016/j.celrep.2021.109501
Cell Reports, 2021, vol. 36, num. 6, p. 109501
https://doi.org/10.1016/j.celrep.2021.109501
dc.rights.none.fl_str_mv cc-by (c) Aguilar-Recarte, David et al., 2021
https://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Aguilar-Recarte, David et al., 2021
https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica)
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.81155

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