Alx3 deficiency disrupts energy homeostasis, alters body composition, and impairs hypothalamic regulation of food intake

The coordination of food intake, energy storage, and expenditure involves complex interactions between hypothalamic neurons and peripheral tissues including pancreatic islets, adipocytes, muscle, and liver. Previous research shows that deficiency of the transcription factor Alx3 alters pancreatic is...

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Detalhes bibliográficos
Autores: Mirasierra, Mercedes, Fernández-Pérez, Antonio, Lizarbe, Blanca, Keiran, Noelia, Ruiz-Cañas, Laura, Casarejos, María José, Cerdán, Sebastián, Vendrell Ortega, Joan Josep, Fernández-Veledo, Sonia, Vallejo, Mario
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2024
País:España
Recursos:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/378589
Acesso em linha:http://hdl.handle.net/10261/378589
https://api.elsevier.com/content/abstract/scopus_id/85201222207
Access Level:acceso abierto
Palavra-chave:Proopiomelanocortin
Alx3
Body mass composition
Energy homeostasis
MC3R
Metabolic partitioning
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dc.title.none.fl_str_mv Alx3 deficiency disrupts energy homeostasis, alters body composition, and impairs hypothalamic regulation of food intake
title Alx3 deficiency disrupts energy homeostasis, alters body composition, and impairs hypothalamic regulation of food intake
spellingShingle Alx3 deficiency disrupts energy homeostasis, alters body composition, and impairs hypothalamic regulation of food intake
Mirasierra, Mercedes
Proopiomelanocortin
Alx3
Body mass composition
Energy homeostasis
MC3R
Metabolic partitioning
title_short Alx3 deficiency disrupts energy homeostasis, alters body composition, and impairs hypothalamic regulation of food intake
title_full Alx3 deficiency disrupts energy homeostasis, alters body composition, and impairs hypothalamic regulation of food intake
title_fullStr Alx3 deficiency disrupts energy homeostasis, alters body composition, and impairs hypothalamic regulation of food intake
title_full_unstemmed Alx3 deficiency disrupts energy homeostasis, alters body composition, and impairs hypothalamic regulation of food intake
title_sort Alx3 deficiency disrupts energy homeostasis, alters body composition, and impairs hypothalamic regulation of food intake
dc.creator.none.fl_str_mv Mirasierra, Mercedes
Fernández-Pérez, Antonio
Lizarbe, Blanca
Keiran, Noelia
Ruiz-Cañas, Laura
Casarejos, María José
Cerdán, Sebastián
Vendrell Ortega, Joan Josep
Fernández-Veledo, Sonia
Vallejo, Mario
author Mirasierra, Mercedes
author_facet Mirasierra, Mercedes
Fernández-Pérez, Antonio
Lizarbe, Blanca
Keiran, Noelia
Ruiz-Cañas, Laura
Casarejos, María José
Cerdán, Sebastián
Vendrell Ortega, Joan Josep
Fernández-Veledo, Sonia
Vallejo, Mario
author_role author
author2 Fernández-Pérez, Antonio
Lizarbe, Blanca
Keiran, Noelia
Ruiz-Cañas, Laura
Casarejos, María José
Cerdán, Sebastián
Vendrell Ortega, Joan Josep
Fernández-Veledo, Sonia
Vallejo, Mario
author2_role author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Economía y Competitividad (España)
Ministerio de Ciencia e Innovación (España)
Agencia Estatal de Investigación (España)
European Commission
Instituto de Salud Carlos III
Centros de Investigación Biomédica en Red (España)
Agència de Gestió d'Ajuts Universitaris i de Recerca
Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (España)
Vallejo, Mario [0000-0002-6422-0323]
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Proopiomelanocortin
Alx3
Body mass composition
Energy homeostasis
MC3R
Metabolic partitioning
topic Proopiomelanocortin
Alx3
Body mass composition
Energy homeostasis
MC3R
Metabolic partitioning
description The coordination of food intake, energy storage, and expenditure involves complex interactions between hypothalamic neurons and peripheral tissues including pancreatic islets, adipocytes, muscle, and liver. Previous research shows that deficiency of the transcription factor Alx3 alters pancreatic islet-dependent glucose homeostasis. In this study we carried out a comprehensive assessment of metabolic alterations in Alx3 deficiency. We report that Alx3-deficient mice exhibit decreased food intake without changes in body weight, along with reduced energy expenditure and altered respiratory exchange ratio. Magnetic resonance imaging reveals increased adiposity and decreased muscle mass, which was associated with markers of motor and sympathetic denervation. By contrast, Alx3-deficient mice on a high-fat diet show attenuated weight gain and improved insulin sensitivity, compared to control mice. Gene expression analysis demonstrates altered lipogenic and lipolytic gene profiles. In wild type mice Alx3 is expressed in hypothalamic arcuate nucleus neurons, but not in major peripheral metabolic organs. Functional diffusion-weighted magnetic resonance imaging reveals selective hypothalamic responses to fasting in the arcuate nucleus of Alx3-deficient mice. Additionally, altered expression of proopiomelanocortin and melanocortin-3 receptor mRNA in the hypothalamus suggests impaired regulation of feeding behavior. This study highlights the crucial role for Alx3 in governing food intake, energy homeostasis, and metabolic nutrient partitioning, thereby influencing body mass composition.
publishDate 2024
dc.date.none.fl_str_mv 2024
2025
2025
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http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
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dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/378589
https://api.elsevier.com/content/abstract/scopus_id/85201222207
url http://hdl.handle.net/10261/378589
https://api.elsevier.com/content/abstract/scopus_id/85201222207
dc.language.none.fl_str_mv Inglés
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spelling Alx3 deficiency disrupts energy homeostasis, alters body composition, and impairs hypothalamic regulation of food intakeMirasierra, MercedesFernández-Pérez, AntonioLizarbe, BlancaKeiran, NoeliaRuiz-Cañas, LauraCasarejos, María JoséCerdán, SebastiánVendrell Ortega, Joan JosepFernández-Veledo, SoniaVallejo, MarioProopiomelanocortinAlx3Body mass compositionEnergy homeostasisMC3RMetabolic partitioningThe coordination of food intake, energy storage, and expenditure involves complex interactions between hypothalamic neurons and peripheral tissues including pancreatic islets, adipocytes, muscle, and liver. Previous research shows that deficiency of the transcription factor Alx3 alters pancreatic islet-dependent glucose homeostasis. In this study we carried out a comprehensive assessment of metabolic alterations in Alx3 deficiency. We report that Alx3-deficient mice exhibit decreased food intake without changes in body weight, along with reduced energy expenditure and altered respiratory exchange ratio. Magnetic resonance imaging reveals increased adiposity and decreased muscle mass, which was associated with markers of motor and sympathetic denervation. By contrast, Alx3-deficient mice on a high-fat diet show attenuated weight gain and improved insulin sensitivity, compared to control mice. Gene expression analysis demonstrates altered lipogenic and lipolytic gene profiles. In wild type mice Alx3 is expressed in hypothalamic arcuate nucleus neurons, but not in major peripheral metabolic organs. Functional diffusion-weighted magnetic resonance imaging reveals selective hypothalamic responses to fasting in the arcuate nucleus of Alx3-deficient mice. Additionally, altered expression of proopiomelanocortin and melanocortin-3 receptor mRNA in the hypothalamus suggests impaired regulation of feeding behavior. This study highlights the crucial role for Alx3 in governing food intake, energy homeostasis, and metabolic nutrient partitioning, thereby influencing body mass composition.This work was funded by the Spanish Ministry of Economy and Competitiveness grant BFU2017-89336-R (M.V.), the Spanish Ministry of Science and Innovation MCIN/AEI/https://doi.org/10.13039/501100011033 grants PID2020-117640RB-I00 (M.V), RTI2018-093919-B-100 and PID2021-122480OB-100 (S.F.-V), and PID2021-126888OA-I00 (BL), the Institute of Health Carlos III (ISCIII) grant PI20/00338 (J.V.), and CIBER–Consorcio Centro de Investigación Biomédica en Red CB07/08/0012 (J.V. and S.F.-V.) and CB07/08/0029 (M.V: ), ISCIII, Ministry of Science and Innovation. S.F.-V. and J.V. acknowledge support from the Agency for Management of University Research Grants of the Generalitat de Catalunya (2021 SGR 01409, 2021 SGR 0089). The Biomedical Research Center in Diabetes and Associated Metabolic Disorders (CIBERDEM) is an initiative or the Instituto de Salud Carlos III. Partially supported by FEDER funds.Peer reviewedSpringerMinisterio de Economía y Competitividad (España)Ministerio de Ciencia e Innovación (España)Agencia Estatal de Investigación (España)European CommissionInstituto de Salud Carlos IIICentros de Investigación Biomédica en Red (España)Agència de Gestió d'Ajuts Universitaris i de RecercaCentro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (España)Vallejo, Mario [0000-0002-6422-0323]Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202520252024info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/378589https://api.elsevier.com/content/abstract/scopus_id/85201222207reponame: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##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/ISCIII/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 (ISCIII)/PI20%2F00338info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BFU2017-89336-Rinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-117640RB-I00info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-093919-B-I00info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2021-122480OB-I00info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2021-126888OA-I00https://doi.org/10.1007/s00018-024-05384-zSíinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3785892026-05-22T06:33:51Z
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