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Title: CPT1A in AgRP neurons is required for sex-dependent regulation of feeding and thirst
Author: Zagmutt Caroxa, Sebastián
Mera Nanín, Paula
González-García, Ismael
Ibeas, Kevin
Romero, María Del Mar
Obri, Arnaud
Martin, Beatriz
Esteve Codina, Anna
Soler Vázquez, M. Carmen
Bastías-Pérez, Marianela
Cañes Esteve, Laia
Augé Marí, Elisabet
Pelegrí i Gabaldà, Carme
Vilaplana i Hortensi, Jordi
Ariza Piquer, Xavier
García Gómez, Jordi
Martínez González, José
Casals, Núria
López, Miguel
Palmiter, Richard
Sanz, Elisenda
Quintana, Albert
Herrero Rodríguez, Laura
Serra i Cucurull, Dolors
Keywords: Àcids grassos
Fatty acids
Issue Date: 25-Mar-2023
Publisher: BioMed Central
Abstract: 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 hypo‐ thalamus; (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
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It is part of: Biology of Sex Differences, 2023, vol. 14, p. 14
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ISSN: 2042-6410
Appears in Collections:Articles publicats en revistes (Bioquímica i Fisiologia)
Articles publicats en revistes (Química Inorgànica i Orgànica)

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