CPT1A in AgRP neurons is required for sex-dependent regulation of feeding and thirst
Background: Fatty acid metabolism in the hypothalamus has an important role in food intake, but its specific role in AgRP neurons is poorly understood. Here, we examined whether carnitinea palmitoyltransferase 1A (CPT1A), a key enzyme in mitochondrial fatty acid oxidation, affects energy balance. Me...
| Autores: | , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| 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:10261/337383 |
| Acceso en línea: | http://hdl.handle.net/10261/337383 |
| Access Level: | acceso abierto |
| Palabra clave: | CPT1A Fatty acid metabolism AgRP neurons Energy balance Food intake Thirst |
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oai:digital.csic.es:10261/337383 |
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CPT1A in AgRP neurons is required for sex-dependent regulation of feeding and thirst |
| title |
CPT1A in AgRP neurons is required for sex-dependent regulation of feeding and thirst |
| spellingShingle |
CPT1A in AgRP neurons is required for sex-dependent regulation of feeding and thirst Zagmutt, Sebastián CPT1A Fatty acid metabolism AgRP neurons Energy balance Food intake Thirst |
| title_short |
CPT1A in AgRP neurons is required for sex-dependent regulation of feeding and thirst |
| title_full |
CPT1A in AgRP neurons is required for sex-dependent regulation of feeding and thirst |
| title_fullStr |
CPT1A in AgRP neurons is required for sex-dependent regulation of feeding and thirst |
| title_full_unstemmed |
CPT1A in AgRP neurons is required for sex-dependent regulation of feeding and thirst |
| title_sort |
CPT1A in AgRP neurons is required for sex-dependent regulation of feeding and thirst |
| dc.creator.none.fl_str_mv |
Zagmutt, Sebastián Mera, Paula González-García, Ismael Ibeas, Kevin Romero, María del Mar Obri, Arnaud Martin, Beatriz Esteve-Codina, Anna Soler-Vázquez, M. Carmen Bastias-Pérez, Marianela Cañes, Laia Augé, Elisabeth Pelegri, Carme Vilaplana, Jordi Ariza, Xavier García, Jordi Martínez-González, José Casals, Núria López, Miguel Palmiter, Richard Sanz, Elisenda Quintana, Albert Herrero, Laura Serra, Dolors |
| author |
Zagmutt, Sebastián |
| author_facet |
Zagmutt, Sebastián Mera, Paula González-García, Ismael Ibeas, Kevin Romero, María del Mar Obri, Arnaud Martin, Beatriz Esteve-Codina, Anna Soler-Vázquez, M. Carmen Bastias-Pérez, Marianela Cañes, Laia Augé, Elisabeth Pelegri, Carme Vilaplana, Jordi Ariza, Xavier García, Jordi Martínez-González, José Casals, Núria López, Miguel Palmiter, Richard Sanz, Elisenda Quintana, Albert Herrero, Laura Serra, Dolors |
| author_role |
author |
| author2 |
Mera, Paula González-García, Ismael Ibeas, Kevin Romero, María del Mar Obri, Arnaud Martin, Beatriz Esteve-Codina, Anna Soler-Vázquez, M. Carmen Bastias-Pérez, Marianela Cañes, Laia Augé, Elisabeth Pelegri, Carme Vilaplana, Jordi Ariza, Xavier García, Jordi Martínez-González, José Casals, Núria López, Miguel Palmiter, Richard Sanz, Elisenda Quintana, Albert Herrero, Laura Serra, Dolors |
| author2_role |
author author author author author author author 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, Innovación y Universidades (España) Agencia Estatal de Investigación (España) European Commission Ministerio de Ciencia e Innovación (España) Ministerio de Economía y Competitividad (España) Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición (España) Generalitat de Catalunya Fundació La Marató de TV3 Instituto de Salud Carlos III Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72] |
| dc.subject.none.fl_str_mv |
CPT1A Fatty acid metabolism AgRP neurons Energy balance Food intake Thirst |
| topic |
CPT1A Fatty acid metabolism AgRP neurons Energy balance Food intake Thirst |
| description |
Background: Fatty acid metabolism in the hypothalamus has an important role in food intake, but its specific role in AgRP neurons is poorly understood. Here, we examined whether carnitinea palmitoyltransferase 1A (CPT1A), a key enzyme in mitochondrial fatty acid oxidation, affects energy balance. Methods: To obtain Cpt1aKO mice and their control littermates, Cpt1a mice were crossed with tamoxifen-inducible AgRP mice. Food intake and body weight were analyzed weekly in both males and females. At 12 weeks of age, metabolic flexibility was determined by ghrelin-induced food intake and fasting–refeeding satiety tests. Energy expenditure was analyzed by calorimetric system and thermogenic activity of brown adipose tissue. To study fluid balance the analysis of urine and water intake volumes; osmolality of urine and plasma; as well as serum levels of angiotensin and components of RAAS (renin–angiotensin–aldosterone system) were measured. At the central level, changes in AgRP neurons were determined by: (1) analyzing specific AgRP gene expression in RiboTag–Cpt1aKO mice obtained by crossing Cpt1aKO mice with RiboTag mice; (2) measuring presynaptic terminal formation in the AgRP neurons with the injection of the AAV1-EF1a-DIO-synaptophysin-GFP in the arcuate nucleus of the hypothalamus; (3) analyzing AgRP neuronal viability and spine formations by the injection AAV9-EF1a-DIO-mCherry in the arcuate nucleus of the hypothalamus; (4) analyzing in situ the specific AgRP mitochondria in the ZsGreen-Cpt1aKO obtained by breeding ZsGreen mice with Cpt1aKO mice. Two-way ANOVA analyses were performed to determine the contributions of the effect of lack of CPT1A in AgRP neurons in the sex. Results: Changes in food intake were just seen in male Cpt1aKO mice while only female Cpt1aKO mice increased energy expenditure. The lack of Cpt1a in the AgRP neurons enhanced brown adipose tissue activity, mainly in females, and induced a substantial reduction in fat deposits and body weight. Strikingly, both male and female Cpt1aKO mice showed polydipsia and polyuria, with more reduced serum vasopressin levels in females and without osmolality alterations, indicating a direct involvement of Cpt1a in AgRP neurons in fluid balance. AgRP neurons from Cpt1aKO mice showed a sex-dependent gene expression pattern, reduced mitochondria and decreased presynaptic innervation to the paraventricular nucleus, without neuronal viability alterations. Conclusions: Our results highlight that fatty acid metabolism and CPT1A in AgRP neurons show marked sex differences and play a relevant role in the neuronal processes necessary for the maintenance of whole-body fluid and energy balance. |
| publishDate |
2023 |
| dc.date.none.fl_str_mv |
2023 2023 2023 2023 |
| 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 |
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article |
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publishedVersion |
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http://hdl.handle.net/10261/337383 |
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http://hdl.handle.net/10261/337383 |
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Inglés |
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Inglés |
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info:eu-repo/semantics/openAccess |
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CPT1A in AgRP neurons is required for sex-dependent regulation of feeding and thirstZagmutt, SebastiánMera, PaulaGonzález-García, IsmaelIbeas, KevinRomero, María del MarObri, ArnaudMartin, BeatrizEsteve-Codina, AnnaSoler-Vázquez, M. CarmenBastias-Pérez, MarianelaCañes, LaiaAugé, ElisabethPelegri, CarmeVilaplana, JordiAriza, XavierGarcía, JordiMartínez-González, JoséCasals, NúriaLópez, MiguelPalmiter, RichardSanz, ElisendaQuintana, AlbertHerrero, LauraSerra, DolorsCPT1AFatty acid metabolismAgRP neuronsEnergy balanceFood intakeThirstBackground: Fatty acid metabolism in the hypothalamus has an important role in food intake, but its specific role in AgRP neurons is poorly understood. Here, we examined whether carnitinea palmitoyltransferase 1A (CPT1A), a key enzyme in mitochondrial fatty acid oxidation, affects energy balance. Methods: To obtain Cpt1aKO mice and their control littermates, Cpt1a mice were crossed with tamoxifen-inducible AgRP mice. Food intake and body weight were analyzed weekly in both males and females. At 12 weeks of age, metabolic flexibility was determined by ghrelin-induced food intake and fasting–refeeding satiety tests. Energy expenditure was analyzed by calorimetric system and thermogenic activity of brown adipose tissue. To study fluid balance the analysis of urine and water intake volumes; osmolality of urine and plasma; as well as serum levels of angiotensin and components of RAAS (renin–angiotensin–aldosterone system) were measured. At the central level, changes in AgRP neurons were determined by: (1) analyzing specific AgRP gene expression in RiboTag–Cpt1aKO mice obtained by crossing Cpt1aKO mice with RiboTag mice; (2) measuring presynaptic terminal formation in the AgRP neurons with the injection of the AAV1-EF1a-DIO-synaptophysin-GFP in the arcuate nucleus of the hypothalamus; (3) analyzing AgRP neuronal viability and spine formations by the injection AAV9-EF1a-DIO-mCherry in the arcuate nucleus of the hypothalamus; (4) analyzing in situ the specific AgRP mitochondria in the ZsGreen-Cpt1aKO obtained by breeding ZsGreen mice with Cpt1aKO mice. Two-way ANOVA analyses were performed to determine the contributions of the effect of lack of CPT1A in AgRP neurons in the sex. Results: Changes in food intake were just seen in male Cpt1aKO mice while only female Cpt1aKO mice increased energy expenditure. The lack of Cpt1a in the AgRP neurons enhanced brown adipose tissue activity, mainly in females, and induced a substantial reduction in fat deposits and body weight. Strikingly, both male and female Cpt1aKO mice showed polydipsia and polyuria, with more reduced serum vasopressin levels in females and without osmolality alterations, indicating a direct involvement of Cpt1a in AgRP neurons in fluid balance. AgRP neurons from Cpt1aKO mice showed a sex-dependent gene expression pattern, reduced mitochondria and decreased presynaptic innervation to the paraventricular nucleus, without neuronal viability alterations. Conclusions: Our results highlight that fatty acid metabolism and CPT1A in AgRP neurons show marked sex differences and play a relevant role in the neuronal processes necessary for the maintenance of whole-body fluid and energy balance.This study was supported by the Spanish Ministry of Economy and Competitiveness (MINECO) (SAF2017-83813-C3-1-R to DS and LH, cofunded by the European Regional Development Fund [ERDF] and PID2020-114953RB-C21 to LH and DS, RTI2018-094727-B-100 to JMG; SAF2017-88108-R to AQ; AEI (PID2020-114977RB-I00) to AQ, ERC-2014-StG-638106 to AQ, MICINN RYC2019-028501-I to ES; MICIU RTI2018-101838-J-I00 to ES; a doctoral fellowship to SZ, and a Juan de la Cierva-Incorporación Research Fellowship [IJCI-2016-28313] to PM and DS), the Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN) (CB06/03/0001 to DS and LH), the Government of Catalonia (2014SGR465 to DS), and La Marató de TV3 (201627-30 to DS). AO is supported by a Miguel Servet contract (CP19/00083) from Instituto de Salud Carlos III co-financed by European Regional Development Fund [ERDF]. AE is funded by ISCIII /MINECO (PT17/0009/0019) and co-funded by FEDER.BioMed CentralMinisterio de Ciencia, Innovación y Universidades (España)Agencia Estatal de Investigación (España)European CommissionMinisterio de Ciencia e Innovación (España)Ministerio de Economía y Competitividad (España)Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición (España)Generalitat de CatalunyaFundació La Marató de TV3Instituto de Salud Carlos IIIConsejo 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/10261/337383reponame: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##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2017-83813-C3-1-Rinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-114953RB-C21info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-094727-B-I00info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2017-88108-Rinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-114977RB-I00info:eu-repo/grantAgreement/AEI//RYC2019-028501-Iinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-101838-J-I00info:eu-repo/grantAgreement/MINECO//IJCI-2016-28313The underlying dataset has been published as supplementary material of the article in the publisher platform at http://dx.doi.org/10.1186/s13293-023-00498-8http://dx.doi.org/10.1186/s13293-023-00498-8Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3373832026-05-22T06:33:51Z |
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