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...

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Autores: Zagmutt, Sebastián, Martin, Beatriz, Esteve-Codina, Anna, Serra, Dolors
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2023
País:España
Institución:Universitat Pompeu Fabra
Repositorio:Repositorio Digital de la UPF
OAI Identifier:oai:repositori.upf.edu:10230/57167
Acceso en línea:http://hdl.handle.net/10230/57167
http://dx.doi.org/10.1186/s13293-023-00498-8
Access Level:acceso abierto
Palabra clave:AgRP neurons
CPT1A
Energy balance
Fatty acid metabolism
Food intake
Thirst
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network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv 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
AgRP neurons
CPT1A
Energy balance
Fatty acid metabolism
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
Martin, Beatriz
Esteve-Codina, Anna
Serra, Dolors
author Zagmutt, Sebastián
author_facet Zagmutt, Sebastián
Martin, Beatriz
Esteve-Codina, Anna
Serra, Dolors
author_role author
author2 Martin, Beatriz
Esteve-Codina, Anna
Serra, Dolors
author2_role author
author
author
dc.subject.none.fl_str_mv AgRP neurons
CPT1A
Energy balance
Fatty acid metabolism
Food intake
Thirst
topic AgRP neurons
CPT1A
Energy balance
Fatty acid metabolism
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(flox/flox) mice were crossed with tamoxifen-inducible AgRPCreERT2 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
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/57167
http://dx.doi.org/10.1186/s13293-023-00498-8
url http://hdl.handle.net/10230/57167
http://dx.doi.org/10.1186/s13293-023-00498-8
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Biol Sex Differ. 2023 Mar 25;14(1):14
info:eu-repo/grantAgreement/EC/H2020/638106
info:eu-repo/grantAgreement/ES/2PE/SAF2017-83813-C3-1-R
info:eu-repo/grantAgreement/ES/2PE/PID2020-114953RB-C21
info:eu-repo/grantAgreement/ES/2PE/RTI2018-094727-B-I00
info:eu-repo/grantAgreement/ES/2PE/SAF2017-88108-R
info:eu-repo/grantAgreement/ES/2PE/PID2020-114977RB-I00
info:eu-repo/grantAgreement/ES/2PE/RTI2018-101838-J-I00
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dc.publisher.none.fl_str_mv BioMed Central
publisher.none.fl_str_mv BioMed Central
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spelling CPT1A in AgRP neurons is required for sex-dependent regulation of feeding and thirstZagmutt, SebastiánMartin, BeatrizEsteve-Codina, AnnaSerra, DolorsAgRP neuronsCPT1AEnergy balanceFatty acid metabolismFood 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(flox/flox) mice were crossed with tamoxifen-inducible AgRPCreERT2 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 Central202320232023info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/57167http://dx.doi.org/10.1186/s13293-023-00498-8reponame:Repositorio Digital de la UPFinstname:Universitat Pompeu FabraInglésBiol Sex Differ. 2023 Mar 25;14(1):14info:eu-repo/grantAgreement/EC/H2020/638106info:eu-repo/grantAgreement/ES/2PE/SAF2017-83813-C3-1-Rinfo:eu-repo/grantAgreement/ES/2PE/PID2020-114953RB-C21info:eu-repo/grantAgreement/ES/2PE/RTI2018-094727-B-I00info:eu-repo/grantAgreement/ES/2PE/SAF2017-88108-Rinfo:eu-repo/grantAgreement/ES/2PE/PID2020-114977RB-I00info:eu-repo/grantAgreement/ES/2PE/RTI2018-101838-J-I00© The Author(s) 2023. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.http://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repositori.upf.edu:10230/571672026-06-12T07:21:37Z
score 15,812429

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