Liver-specific insulin receptor isoform A expression enhances hepatic glucose uptake and ameliorates liver steatosis in a mouse model of diet-induced obesity

Among the main complications associated to obesity is insulin resistance and an altered glucose and lipid metabolism within the liver. It has been previously described that insulin receptor isoform A (IRA) favors glucose uptake and glycogen storage in hepatocytes as compared to isoform B (IRB) impro...

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Autores: Raposo López-Pastor, Andrea, Gómez Hernández, María De La Almudena, Díaz Castroverde, Sabela, González-Aseguinolaza Gloria, González Rodríguez, Águeda, García, Gema, Fernández, Silvia, Escribano Illanes, Óscar, Benito, Manuel
Tipo de recurso: artículo
Fecha de publicación:2019
País:España
Institución:Universidad Complutense de Madrid (UCM)
Repositorio:Docta Complutense
Idioma:inglés
OAI Identifier:oai:docta.ucm.es:20.500.14352/93392
Acceso en línea:https://hdl.handle.net/20.500.14352/93392
Access Level:acceso abierto
Palabra clave:577.2
Adeno-associated viruses
Gene therapy
Glucose metabolism
Insulin receptor isoforms
Insulin resistance
Non-alcoholic fatty liver disease
Biología molecular (Farmacia)
2415 Biología Molecular
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oai_identifier_str oai:docta.ucm.es:20.500.14352/93392
network_acronym_str ES
network_name_str España
repository_id_str
spelling Liver-specific insulin receptor isoform A expression enhances hepatic glucose uptake and ameliorates liver steatosis in a mouse model of diet-induced obesityRaposo López-Pastor, AndreaGómez Hernández, María De La AlmudenaDíaz Castroverde, SabelaGonzález-Aseguinolaza GloriaGonzález Rodríguez, ÁguedaGarcía, GemaFernández, SilviaEscribano Illanes, ÓscarBenito, Manuel577.2Adeno-associated virusesGene therapyGlucose metabolismInsulin receptor isoformsInsulin resistanceNon-alcoholic fatty liver diseaseBiología molecular (Farmacia)2415 Biología MolecularAmong the main complications associated to obesity is insulin resistance and an altered glucose and lipid metabolism within the liver. It has been previously described that insulin receptor isoform A (IRA) favors glucose uptake and glycogen storage in hepatocytes as compared to isoform B (IRB) improving glucose homeostasis in mice lacking liver insulin receptor. Thus, we hypothesized that IRA could also improve glucose and lipid metabolism in a mouse model of high fat diet-induced obesity. We addressed the role of insulin receptor isoforms on glucose and lipid metabolism in vivo. We expressed IRA or IRB specifically in the liver by using adeno-associated viruses (AAV) in a mouse model of diet-induced insulin resistance and obesity. IRA expression, but not IRB, induced an increased glucose uptake in the liver and muscle improving insulin tolerance. Regarding lipid metabolism, we found that AAV-mediated IRA expression also ameliorated hepatic steatosis by decreasing the expression of Fasn, Pgc1a, Acaca and Dgat2 and increasing Scd-1. Taking together, our results further unravel the role of insulin receptor isoforms in hepatic glucose and lipid metabolism in an insulin-resistant scenario. Our data strongly suggest that IRA is more efficient than IRB favoring hepatic glucose uptake, improving insulin tolerance and ameliorating hepatic steatosis. Therefore, we conclude that a gene therapy approach for hepatic IRA expression could be a safe and promising tool for the regulation of hepatic glucose consumption and lipid metabolism, two key processes in the development of non-alcoholic fatty liver disease (NAFLD) associated to obesity.Universidad Complutense de Madrid20192019-01-0120192019-01-01journal articlehttp://purl.org/coar/resource_type/c_6501info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/20.500.14352/93392reponame:Docta Complutenseinstname:Universidad Complutense de Madrid (UCM)InglésengCT1 18-CT2 18 BMD-4111Agencia Estatal de Investigación http://dx.doi.org/10.13039/501100011033 Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016 SAF2017-82133-R PAPEL DE LOS MECANISMOS DE DINAMICA Y CONTROL DE CALIDAD MITOCONDRIALES EN LA AMPLIFICACION DE LA TERMOGENESIS FUNCIONAL O DISFUNCIONALSAF2014 51795-R Not availableMinisterio de Economía y Competitividad http://dx.doi.org/10.13039/501100003329 Not available PIE14%2F00061 Molecular links between diabetes and neurodegenerative disordersCB07 08 0001SAF2011 22555 Not availableCT1 18-CT2 18 BMD-4111open accesshttp://purl.org/coar/access_right/c_abf2Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:docta.ucm.es:20.500.14352/933922026-06-02T12:44:21Z
dc.title.none.fl_str_mv Liver-specific insulin receptor isoform A expression enhances hepatic glucose uptake and ameliorates liver steatosis in a mouse model of diet-induced obesity
title Liver-specific insulin receptor isoform A expression enhances hepatic glucose uptake and ameliorates liver steatosis in a mouse model of diet-induced obesity
spellingShingle Liver-specific insulin receptor isoform A expression enhances hepatic glucose uptake and ameliorates liver steatosis in a mouse model of diet-induced obesity
Raposo López-Pastor, Andrea
577.2
Adeno-associated viruses
Gene therapy
Glucose metabolism
Insulin receptor isoforms
Insulin resistance
Non-alcoholic fatty liver disease
Biología molecular (Farmacia)
2415 Biología Molecular
title_short Liver-specific insulin receptor isoform A expression enhances hepatic glucose uptake and ameliorates liver steatosis in a mouse model of diet-induced obesity
title_full Liver-specific insulin receptor isoform A expression enhances hepatic glucose uptake and ameliorates liver steatosis in a mouse model of diet-induced obesity
title_fullStr Liver-specific insulin receptor isoform A expression enhances hepatic glucose uptake and ameliorates liver steatosis in a mouse model of diet-induced obesity
title_full_unstemmed Liver-specific insulin receptor isoform A expression enhances hepatic glucose uptake and ameliorates liver steatosis in a mouse model of diet-induced obesity
title_sort Liver-specific insulin receptor isoform A expression enhances hepatic glucose uptake and ameliorates liver steatosis in a mouse model of diet-induced obesity
dc.creator.none.fl_str_mv Raposo López-Pastor, Andrea
Gómez Hernández, María De La Almudena
Díaz Castroverde, Sabela
González-Aseguinolaza Gloria
González Rodríguez, Águeda
García, Gema
Fernández, Silvia
Escribano Illanes, Óscar
Benito, Manuel
author Raposo López-Pastor, Andrea
author_facet Raposo López-Pastor, Andrea
Gómez Hernández, María De La Almudena
Díaz Castroverde, Sabela
González-Aseguinolaza Gloria
González Rodríguez, Águeda
García, Gema
Fernández, Silvia
Escribano Illanes, Óscar
Benito, Manuel
author_role author
author2 Gómez Hernández, María De La Almudena
Díaz Castroverde, Sabela
González-Aseguinolaza Gloria
González Rodríguez, Águeda
García, Gema
Fernández, Silvia
Escribano Illanes, Óscar
Benito, Manuel
author2_role author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universidad Complutense de Madrid
dc.subject.none.fl_str_mv 577.2
Adeno-associated viruses
Gene therapy
Glucose metabolism
Insulin receptor isoforms
Insulin resistance
Non-alcoholic fatty liver disease
Biología molecular (Farmacia)
2415 Biología Molecular
topic 577.2
Adeno-associated viruses
Gene therapy
Glucose metabolism
Insulin receptor isoforms
Insulin resistance
Non-alcoholic fatty liver disease
Biología molecular (Farmacia)
2415 Biología Molecular
description Among the main complications associated to obesity is insulin resistance and an altered glucose and lipid metabolism within the liver. It has been previously described that insulin receptor isoform A (IRA) favors glucose uptake and glycogen storage in hepatocytes as compared to isoform B (IRB) improving glucose homeostasis in mice lacking liver insulin receptor. Thus, we hypothesized that IRA could also improve glucose and lipid metabolism in a mouse model of high fat diet-induced obesity. We addressed the role of insulin receptor isoforms on glucose and lipid metabolism in vivo. We expressed IRA or IRB specifically in the liver by using adeno-associated viruses (AAV) in a mouse model of diet-induced insulin resistance and obesity. IRA expression, but not IRB, induced an increased glucose uptake in the liver and muscle improving insulin tolerance. Regarding lipid metabolism, we found that AAV-mediated IRA expression also ameliorated hepatic steatosis by decreasing the expression of Fasn, Pgc1a, Acaca and Dgat2 and increasing Scd-1. Taking together, our results further unravel the role of insulin receptor isoforms in hepatic glucose and lipid metabolism in an insulin-resistant scenario. Our data strongly suggest that IRA is more efficient than IRB favoring hepatic glucose uptake, improving insulin tolerance and ameliorating hepatic steatosis. Therefore, we conclude that a gene therapy approach for hepatic IRA expression could be a safe and promising tool for the regulation of hepatic glucose consumption and lipid metabolism, two key processes in the development of non-alcoholic fatty liver disease (NAFLD) associated to obesity.
publishDate 2019
dc.date.none.fl_str_mv 2019
2019-01-01
2019
2019-01-01
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/20.500.14352/93392
url https://hdl.handle.net/20.500.14352/93392
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv CT1 18-CT2 18 BMD-4111
Agencia Estatal de Investigación http://dx.doi.org/10.13039/501100011033 Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016 SAF2017-82133-R PAPEL DE LOS MECANISMOS DE DINAMICA Y CONTROL DE CALIDAD MITOCONDRIALES EN LA AMPLIFICACION DE LA TERMOGENESIS FUNCIONAL O DISFUNCIONAL
SAF2014 51795-R Not available
Ministerio de Economía y Competitividad http://dx.doi.org/10.13039/501100003329 Not available PIE14%2F00061 Molecular links between diabetes and neurodegenerative disorders
CB07 08 0001
SAF2011 22555 Not available
CT1 18-CT2 18 BMD-4111
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Docta Complutense
instname:Universidad Complutense de Madrid (UCM)
instname_str Universidad Complutense de Madrid (UCM)
reponame_str Docta Complutense
collection Docta Complutense
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.300719

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