Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/16156
γ-Linolenic acid in maternal milk drives cardiac metabolic maturation.
Paredes, Ana | Justo-Méndez, Raquel | Jiménez-Blasco, Daniel | Núñez, Vanessa | Calero, Irene | Villalba-Orero, María | Alegre-Martí, Andrea | Fischer, Thierry | Gradillas, Ana | Sant'Anna, Viviane Aparecida Rodrigues | Were, Felipe CNIC | Huang, Zhiqiang | Hernansanz-Agustín, Pablo | Contreras, Carmen | Martínez, Fernando | Camafeita, Emilio CNIC | Vázquez, Jesús | Ruiz-Cabello, Jesús | Area-Gómez, Estela | Sánchez-Cabo, Fátima | Treuter, Eckardt | Bolaños, Juan Pedro | Estébanez-Perpiñá, Eva | Rupérez, Francisco Javier | Barbas, Coral | Enriquez, Jose Antonio CNIC | Ricote, Mercedes CNIC
Nature. 2023 Jun;618(7964):365-373
Birth presents a metabolic challenge to cardiomyocytes as they reshape fuel preference from glucose to fatty acids for postnatal energy production1,2. This adaptation is triggered in part by post-partum environmental changes3, 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 receptors4 (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.
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