Hypothalamic JNK1-hepatic fatty acid synthase axis mediates a metabolic rewiring that prevents hepatic steatosis in male mice treated with olanzapine via intraperitoneal: Additional effects of PTP1B inhibition

Olanzapine (OLA), a widely used second-generation antipsychotic (SGA), causes weight gain and metabolic alterations when administered orally to patients. Recently, we demonstrated that, contrarily to the oral treatment which induces weight gain, OLA administered via intraperitoneal (i.p.) in male mi...

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Autores: Ferreira, Vítor, Folgueira, Cintia, García-Altares, María, Guillén Gómez, María José, Ruíz-Rosario, Mónica, DiNunzio, Giada, García-Martínez, Irma, Alén, Rosa, Bookmeyer, Christoph, Jones, John G., Cigudosa, Juan C., López-Larrubia, Pilar, Correig, Xavier, Davis, Roger J., Sabio, Guadalupe, Rada, Patricia, Valverde, Ángela M.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2023
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/340315
Acceso en línea:http://hdl.handle.net/10261/340315
Access Level:acceso abierto
Palabra clave:Olanzapine
Hypothalamus
Inter-organ crosstalk
Metabolic side-effects
Liver
PTP1B
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dc.title.none.fl_str_mv Hypothalamic JNK1-hepatic fatty acid synthase axis mediates a metabolic rewiring that prevents hepatic steatosis in male mice treated with olanzapine via intraperitoneal: Additional effects of PTP1B inhibition
title Hypothalamic JNK1-hepatic fatty acid synthase axis mediates a metabolic rewiring that prevents hepatic steatosis in male mice treated with olanzapine via intraperitoneal: Additional effects of PTP1B inhibition
spellingShingle Hypothalamic JNK1-hepatic fatty acid synthase axis mediates a metabolic rewiring that prevents hepatic steatosis in male mice treated with olanzapine via intraperitoneal: Additional effects of PTP1B inhibition
Ferreira, Vítor
Olanzapine
Hypothalamus
Inter-organ crosstalk
Metabolic side-effects
Liver
PTP1B
title_short Hypothalamic JNK1-hepatic fatty acid synthase axis mediates a metabolic rewiring that prevents hepatic steatosis in male mice treated with olanzapine via intraperitoneal: Additional effects of PTP1B inhibition
title_full Hypothalamic JNK1-hepatic fatty acid synthase axis mediates a metabolic rewiring that prevents hepatic steatosis in male mice treated with olanzapine via intraperitoneal: Additional effects of PTP1B inhibition
title_fullStr Hypothalamic JNK1-hepatic fatty acid synthase axis mediates a metabolic rewiring that prevents hepatic steatosis in male mice treated with olanzapine via intraperitoneal: Additional effects of PTP1B inhibition
title_full_unstemmed Hypothalamic JNK1-hepatic fatty acid synthase axis mediates a metabolic rewiring that prevents hepatic steatosis in male mice treated with olanzapine via intraperitoneal: Additional effects of PTP1B inhibition
title_sort Hypothalamic JNK1-hepatic fatty acid synthase axis mediates a metabolic rewiring that prevents hepatic steatosis in male mice treated with olanzapine via intraperitoneal: Additional effects of PTP1B inhibition
dc.creator.none.fl_str_mv Ferreira, Vítor
Folgueira, Cintia
García-Altares, María
Guillén Gómez, María José
Ruíz-Rosario, Mónica
DiNunzio, Giada
García-Martínez, Irma
Alén, Rosa
Bookmeyer, Christoph
Jones, John G.
Cigudosa, Juan C.
López-Larrubia, Pilar
Correig, Xavier
Davis, Roger J.
Sabio, Guadalupe
Rada, Patricia
Valverde, Ángela M.
author Ferreira, Vítor
author_facet Ferreira, Vítor
Folgueira, Cintia
García-Altares, María
Guillén Gómez, María José
Ruíz-Rosario, Mónica
DiNunzio, Giada
García-Martínez, Irma
Alén, Rosa
Bookmeyer, Christoph
Jones, John G.
Cigudosa, Juan C.
López-Larrubia, Pilar
Correig, Xavier
Davis, Roger J.
Sabio, Guadalupe
Rada, Patricia
Valverde, Ángela M.
author_role author
author2 Folgueira, Cintia
García-Altares, María
Guillén Gómez, María José
Ruíz-Rosario, Mónica
DiNunzio, Giada
García-Martínez, Irma
Alén, Rosa
Bookmeyer, Christoph
Jones, John G.
Cigudosa, Juan C.
López-Larrubia, Pilar
Correig, Xavier
Davis, Roger J.
Sabio, Guadalupe
Rada, Patricia
Valverde, Ángela M.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Ciencia e Innovación (España)
Agencia Estatal de Investigación (España)
Ministerio de Ciencia, Innovación y Universidades (España)
European Commission
Fundación Ramón Areces
Comunidad de Madrid
Instituto de Salud Carlos III
Fundação para a Ciência e a Tecnologia (Portugal)
Generalitat de Catalunya
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Olanzapine
Hypothalamus
Inter-organ crosstalk
Metabolic side-effects
Liver
PTP1B
topic Olanzapine
Hypothalamus
Inter-organ crosstalk
Metabolic side-effects
Liver
PTP1B
description Olanzapine (OLA), a widely used second-generation antipsychotic (SGA), causes weight gain and metabolic alterations when administered orally to patients. Recently, we demonstrated that, contrarily to the oral treatment which induces weight gain, OLA administered via intraperitoneal (i.p.) in male mice resulted in body weight loss. This protection was due to an increase in energy expenditure (EE) through a mechanism involving the modulation of hypothalamic AMPK activation by higher OLA levels reaching this brain region compared to those of the oral treatment. Since clinical studies have shown hepatic steatosis upon chronic treatment with OLA, herein we further investigated the role of the hypothalamus-liver interactome upon OLA administration in wild-type (WT) and protein tyrosine phosphatase 1B knockout (PTP1B–KO) mice, a preclinical model protected against metabolic syndrome. WT and PTP1B–KO male mice were fed an OLA-supplemented diet or treated via i.p. Mechanistically, we found that OLA i.p. treatment induces mild oxidative stress and inflammation in the hypothalamus in a JNK1-independent and dependent manner, respectively, without features of cell dead. Hypothalamic JNK activation up-regulated lipogenic gene expression in the liver though the vagus nerve. This effect concurred with an unexpected metabolic rewiring in the liver in which ATP depletion resulted in increased AMPK/ACC phosphorylation. This starvation-like signature prevented steatosis. By contrast, intrahepatic lipid accumulation was observed in WT mice treated orally with OLA; this effect being absent in PTP1B–KO mice. We also demonstrated an additional benefit of PTP1B inhibition against hypothalamic JNK activation, oxidative stress and inflammation induced by chronic OLA i.p. treatment, thereby preventing hepatic lipogenesis. The protection conferred by PTP1B deficiency against hepatic steatosis in the oral OLA treatment or against oxidative stress and neuroinflammation in the i.p. treatment strongly suggests that targeting PTP1B might be also a therapeutic strategy to prevent metabolic comorbidities in patients under OLA treatment in a personalized manner.
publishDate 2023
dc.date.none.fl_str_mv 2023
2023
2023
2023
dc.type.none.fl_str_mv info:eu-repo/semantics/article
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Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/340315
url http://hdl.handle.net/10261/340315
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
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info:eu-repo/grantAgreement/AEI//PID-2021-122766OB-100
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dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
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spelling Hypothalamic JNK1-hepatic fatty acid synthase axis mediates a metabolic rewiring that prevents hepatic steatosis in male mice treated with olanzapine via intraperitoneal: Additional effects of PTP1B inhibitionFerreira, VítorFolgueira, CintiaGarcía-Altares, MaríaGuillén Gómez, María JoséRuíz-Rosario, MónicaDiNunzio, GiadaGarcía-Martínez, IrmaAlén, RosaBookmeyer, ChristophJones, John G.Cigudosa, Juan C.López-Larrubia, PilarCorreig, XavierDavis, Roger J.Sabio, GuadalupeRada, PatriciaValverde, Ángela M.OlanzapineHypothalamusInter-organ crosstalkMetabolic side-effectsLiverPTP1BOlanzapine (OLA), a widely used second-generation antipsychotic (SGA), causes weight gain and metabolic alterations when administered orally to patients. Recently, we demonstrated that, contrarily to the oral treatment which induces weight gain, OLA administered via intraperitoneal (i.p.) in male mice resulted in body weight loss. This protection was due to an increase in energy expenditure (EE) through a mechanism involving the modulation of hypothalamic AMPK activation by higher OLA levels reaching this brain region compared to those of the oral treatment. Since clinical studies have shown hepatic steatosis upon chronic treatment with OLA, herein we further investigated the role of the hypothalamus-liver interactome upon OLA administration in wild-type (WT) and protein tyrosine phosphatase 1B knockout (PTP1B–KO) mice, a preclinical model protected against metabolic syndrome. WT and PTP1B–KO male mice were fed an OLA-supplemented diet or treated via i.p. Mechanistically, we found that OLA i.p. treatment induces mild oxidative stress and inflammation in the hypothalamus in a JNK1-independent and dependent manner, respectively, without features of cell dead. Hypothalamic JNK activation up-regulated lipogenic gene expression in the liver though the vagus nerve. This effect concurred with an unexpected metabolic rewiring in the liver in which ATP depletion resulted in increased AMPK/ACC phosphorylation. This starvation-like signature prevented steatosis. By contrast, intrahepatic lipid accumulation was observed in WT mice treated orally with OLA; this effect being absent in PTP1B–KO mice. We also demonstrated an additional benefit of PTP1B inhibition against hypothalamic JNK activation, oxidative stress and inflammation induced by chronic OLA i.p. treatment, thereby preventing hepatic lipogenesis. The protection conferred by PTP1B deficiency against hepatic steatosis in the oral OLA treatment or against oxidative stress and neuroinflammation in the i.p. treatment strongly suggests that targeting PTP1B might be also a therapeutic strategy to prevent metabolic comorbidities in patients under OLA treatment in a personalized manner.This work was funded by grants PID-2021-122766OB-100 (to AMV), PID2019-104399RB-I00 (to GS) and RTI2018-096061-B-I00 (to XCB) funded by MCIN/AEI/10.13039/501100011033 and “ERDF A way of making Europe” by the European Union. We also acknowledge grants H2020 Marie Sklodowska-Curie ITN-TREATMENT (Grant Agreement 721236, European Commission), P2022/BMD-7227 (Comunidad de Madrid, Spain), Fundación Ramón Areces (Spain) and CIBERdem (ISCIII, Spain) to AMV. VF was a recipient of a contract from ITN-TREATMENT and is currently a PhD fellow from the Portuguese Foundation for Science and Technology (2020.08388.BD, FCT, Portugal)/ERDF. CF was awarded with Sara Borrell contract (CD19/00078, ISCIII, Spain). MGA has a postdoctoral contract 2018 BP 00188 funded by AGAUR (Spain), while CB is recipient of a postdoctoral contract from HORIZON-MSCA-2021-PF-01 MASS2 (Proposal number 101067953).Peer reviewedElsevierMinisterio de Ciencia e Innovación (España)Agencia Estatal de Investigación (España)Ministerio de Ciencia, Innovación y Universidades (España)European CommissionFundación Ramón ArecesComunidad de MadridInstituto de Salud Carlos IIIFundação para a Ciência e a Tecnologia (Portugal)Generalitat de CatalunyaConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2023202320232023info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/340315reponame:DIGITAL.CSIC. 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