Insulin regulates neurovascular coupling through astrocytes

Fernández, Ana M.; Martinez-Rachadell, Laura; Navarrete, Marta; Pose-Utrilla, Julia; Dávila, José C.; Pignatelli Garrigos, Jaime; Diaz-Pacheco, Sonia; Guerra-Cantera, Santiago; Viedma-Moreno, Emilia; Ruiz de Martin Esteban, Samuel; Mostany, Ricardo; García-Cáceres, Cristina; Tschöp, Matthias; Iglesias, Teresa; Ceballos, María L. de; Gutiérrez, A.; Torres Alemán, Ignacio

Insulin regulates neurovascular coupling through astrocytes

Mice with insulin receptor (IR)-deficient astrocytes (GFAP-IR knockout [KO] mice) show blunted responses to insulin and reduced brain glucose uptake, whereas IRdeficient astrocytes show disturbed mitochondrial responses to glucose. While exploring the functional impact of disturbed mitochondrial fun...

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Autores:	Fernández, Ana M., Martinez-Rachadell, Laura, Navarrete, Marta, Pose-Utrilla, Julia, Dávila, José C., Pignatelli Garrigos, Jaime, Diaz-Pacheco, Sonia, Guerra-Cantera, Santiago, Viedma-Moreno, Emilia, Ruiz de Martin Esteban, Samuel, Mostany, Ricardo, García-Cáceres, Cristina, Tschöp, Matthias, Iglesias, Teresa, Ceballos, María L. de, Gutiérrez, A., Torres Alemán, Ignacio
Tipo de recurso:	artículo
Estado:	Versión publicada
Fecha de publicación:	2022
País:	España
Institución:	Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:	DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:	oai:digital.csic.es:10261/279102
Acceso en línea:	http://hdl.handle.net/10261/279102
Access Level:	acceso abierto
Palabra clave:	Astrocytes Insulin neurovascular coupling

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network_name_str	España
repository_id_str
dc.title.none.fl_str_mv	Insulin regulates neurovascular coupling through astrocytes
title	Insulin regulates neurovascular coupling through astrocytes
spellingShingle	Insulin regulates neurovascular coupling through astrocytes Fernández, Ana M. Astrocytes Insulin neurovascular coupling
title_short	Insulin regulates neurovascular coupling through astrocytes
title_full	Insulin regulates neurovascular coupling through astrocytes
title_fullStr	Insulin regulates neurovascular coupling through astrocytes
title_full_unstemmed	Insulin regulates neurovascular coupling through astrocytes
title_sort	Insulin regulates neurovascular coupling through astrocytes
dc.creator.none.fl_str_mv	Fernández, Ana M. Martinez-Rachadell, Laura Navarrete, Marta Pose-Utrilla, Julia Dávila, José C. Pignatelli Garrigos, Jaime Diaz-Pacheco, Sonia Guerra-Cantera, Santiago Viedma-Moreno, Emilia Ruiz de Martin Esteban, Samuel Mostany, Ricardo García-Cáceres, Cristina Tschöp, Matthias Iglesias, Teresa Ceballos, María L. de Gutiérrez, A. Torres Alemán, Ignacio
author	Fernández, Ana M.
author_facet	Fernández, Ana M. Martinez-Rachadell, Laura Navarrete, Marta Pose-Utrilla, Julia Dávila, José C. Pignatelli Garrigos, Jaime Diaz-Pacheco, Sonia Guerra-Cantera, Santiago Viedma-Moreno, Emilia Ruiz de Martin Esteban, Samuel Mostany, Ricardo García-Cáceres, Cristina Tschöp, Matthias Iglesias, Teresa Ceballos, María L. de Gutiérrez, A. Torres Alemán, Ignacio
author_role	author
author2	Martinez-Rachadell, Laura Navarrete, Marta Pose-Utrilla, Julia Dávila, José C. Pignatelli Garrigos, Jaime Diaz-Pacheco, Sonia Guerra-Cantera, Santiago Viedma-Moreno, Emilia Ruiz de Martin Esteban, Samuel Mostany, Ricardo García-Cáceres, Cristina Tschöp, Matthias Iglesias, Teresa Ceballos, María L. de Gutiérrez, A. Torres Alemán, Ignacio
author2_role	author author author author author author author author author author author author author author author author
dc.contributor.none.fl_str_mv	Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (España) Instituto de Salud Carlos III Ministerio de Ciencia e Innovación (España) Junta de Andalucía European Commission Comunidad de Madrid Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv	Astrocytes Insulin neurovascular coupling
topic	Astrocytes Insulin neurovascular coupling
description	Mice with insulin receptor (IR)-deficient astrocytes (GFAP-IR knockout [KO] mice) show blunted responses to insulin and reduced brain glucose uptake, whereas IRdeficient astrocytes show disturbed mitochondrial responses to glucose. While exploring the functional impact of disturbed mitochondrial function in astrocytes, we observed that GFAP-IR KO mice show uncoupling of brain blood flow with glucose uptake. Since IR-deficient astrocytes show higher levels of reactive oxidant species (ROS), this leads to stimulation of hypoxia-inducible factor-1¿ and, consequently, of the vascular endothelial growth factor angiogenic pathway. Indeed, GFAP-IR KO mice show disturbed brain vascularity and blood flow that is normalized by treatment with the antioxidant N-acetylcysteine (NAC). NAC ameliorated high ROS levels, normalized angiogenic signaling and mitochondrial function in IR-deficient astrocytes, and normalized neurovascular coupling in GFAP-IR KO mice. Our results indicate that by modulating glucose uptake and angiogenesis, insulin receptors in astrocytes participate in neurovascular coupling.
publishDate	2022
dc.date.none.fl_str_mv	2022 2022 2022 2022
dc.type.none.fl_str_mv	info:eu-repo/semantics/article http://purl.org/coar/resource_type/c_6501 Publisher's version info:eu-repo/semantics/publishedVersion
format	article
status_str	publishedVersion
dc.identifier.none.fl_str_mv	http://hdl.handle.net/10261/279102
url	http://hdl.handle.net/10261/279102
dc.language.none.fl_str_mv	Inglés
language_invalid_str_mv	Inglés
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dc.rights.none.fl_str_mv	info:eu-repo/semantics/openAccess
eu_rights_str_mv	openAccess
dc.publisher.none.fl_str_mv	National Academy of Sciences (U.S.)
publisher.none.fl_str_mv	National Academy of Sciences (U.S.)
dc.source.none.fl_str_mv	reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str	Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str	DIGITAL.CSIC. Repositorio Institucional del CSIC
collection	DIGITAL.CSIC. Repositorio Institucional del CSIC
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spelling	Insulin regulates neurovascular coupling through astrocytesFernández, Ana M.Martinez-Rachadell, LauraNavarrete, MartaPose-Utrilla, JuliaDávila, José C.Pignatelli Garrigos, JaimeDiaz-Pacheco, SoniaGuerra-Cantera, SantiagoViedma-Moreno, EmiliaRuiz de Martin Esteban, SamuelMostany, RicardoGarcía-Cáceres, CristinaTschöp, MatthiasIglesias, TeresaCeballos, María L. deGutiérrez, A.Torres Alemán, IgnacioAstrocytesInsulinneurovascular couplingMice with insulin receptor (IR)-deficient astrocytes (GFAP-IR knockout [KO] mice) show blunted responses to insulin and reduced brain glucose uptake, whereas IRdeficient astrocytes show disturbed mitochondrial responses to glucose. While exploring the functional impact of disturbed mitochondrial function in astrocytes, we observed that GFAP-IR KO mice show uncoupling of brain blood flow with glucose uptake. Since IR-deficient astrocytes show higher levels of reactive oxidant species (ROS), this leads to stimulation of hypoxia-inducible factor-1¿ and, consequently, of the vascular endothelial growth factor angiogenic pathway. Indeed, GFAP-IR KO mice show disturbed brain vascularity and blood flow that is normalized by treatment with the antioxidant N-acetylcysteine (NAC). NAC ameliorated high ROS levels, normalized angiogenic signaling and mitochondrial function in IR-deficient astrocytes, and normalized neurovascular coupling in GFAP-IR KO mice. Our results indicate that by modulating glucose uptake and angiogenesis, insulin receptors in astrocytes participate in neurovascular coupling.We are thankful to M.Garcia and R. Cañadas for technical support. This work was funded by Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED) (Instituto de Salud CarlosIII, Spain) to I.T.A., A.G., and T.I.; an Inter-CIBER project (PIE14/00061) to I.T.A.that forms part of the projects PID2019-104376RB-I00 (I.T.A.) and RTI2018-094887-B-I00 (M.N.) funded by MCIN/AEI/10.13039/501100011033; a grant from Junta de Andalucia Consejería de Economía y Conocimiento (P18-RT-2233 to A.G.) cofinanced by Programa Operativo FEDER 2014–2020; a grant from Instituto de Salud Carlos III Spain (cofinanced by FEDER funds from the European Union; PI21/00915 to A.G.); Grant PID2020-115218RB-I00 to T.I. funded by Ministerio de Ciencia e Innovación/Agencia Española de Investigación (MCIN/AEI/10.13039/501100011033); and a grant from Comunidad de Madrid through the European Social Fund (ESF)–financed programme Neurometabolismo-Comunidad de Madrid (NEUROMETAB-CM) (B2017/BMD-3700 to I.T.A.and T.I.). M.N. was also supported by the Spanish Ministry of Science and Innovation (Ramón y Cajal RYC-2016-20414). J.P.-U. was contracted by CIBERNED.National Academy of Sciences (U.S.)Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (España)Instituto de Salud Carlos IIIMinisterio de Ciencia e Innovación (España)Junta de AndalucíaEuropean CommissionComunidad de MadridConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2022202220222022info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/279102reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-104376RB-I00info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-094887-B-I00info:eu-repo/grantAgreement/ISCIII/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 (ISCIII)/PI21info:eu-repo/grantAgreement/MINECO//PIE14info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-115218RB-I00http://dx.doi.org/10.1073/pnas.2204527119Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2791022026-05-22T06:33:51Z
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Insulin regulates neurovascular coupling through astrocytes

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