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Título: | γ-Linolenic acid in maternal milk drives cardiac metabolic maturation |
Autor: | Paredes, Ana; Justo-Méndez, Raquel; Jimenez-Blasco, Daniel CSIC ORCID; Núñez, Vanessa; Calero, Irene; Villalba-Orero, María; Alegre-Martí, Andrea; Fischer, Thierry; Gradillas, Ana; Rodrigues Sant’Anna, Viviane Aparecida; Were, Felipe; Huang, Zhiqiang; Hernansanz-Agustín, Pablo; Contreras, Carmen; Martínez, Fernando CSIC ORCID; Camafeita, Emilio; Vázquez, Jesús CSIC ORCID CVN; Ruiz-Cabello, Jesús; Area-Gómez, Estela; Sánchez-Cabo, Fátima; Treuter, Eckardt; Bolaños, Juan Pedro; Estébanez-Perpiñá, Eva; Rupérez, Francisco Javier; Barbas, Coral; Enríquez, José Antonio; Ricote, Mercedes | Fecha de publicación: | 8-jun-2023 | Editor: | Nature Publishing Group | Citación: | Nature 618: 365-373 (2023) | Resumen: | Birth presents a metabolic challenge to cardiomyocytes as they reshape fuel preference from glucose to fatty acids for postnatal energy production. This adaptation is triggered in part by post-partum environmental changes, but the molecules orchestrating cardiomyocyte maturation remain unknown. Here we show that this transition is coordinated by maternally supplied γ-linolenic acid (GLA), an 18:3 omega-6 fatty acid enriched in the maternal milk. GLA binds and activates retinoid X receptors (RXRs), ligand-regulated transcription factors that are expressed in cardiomyocytes from embryonic stages. Multifaceted genome-wide analysis revealed that the lack of RXR in embryonic cardiomyocytes caused an aberrant chromatin landscape that prevented the induction of an RXR-dependent gene expression signature controlling mitochondrial fatty acid homeostasis. The ensuing defective metabolic transition featured blunted mitochondrial lipid-derived energy production and enhanced glucose consumption, leading to perinatal cardiac dysfunction and death. Finally, GLA supplementation induced RXR-dependent expression of the mitochondrial fatty acid homeostasis signature in cardiomyocytes, both in vitro and in vivo. Thus, our study identifies the GLA–RXR axis as a key transcriptional regulatory mechanism underlying the maternal control of perinatal cardiac metabolism. | Versión del editor: | http://dx.doi.org/10.1038/s41586-023-06068-7 | URI: | http://hdl.handle.net/10261/341328 | DOI: | 10.1038/s41586-023-06068-7 | Identificadores: | doi: 10.1038/s41586-023-06068-7 e-issn: 1476-4687 other CEX2020-001041-S |
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