1. γ-Linolenic acid in maternal milk drives cardiac metabolic maturation
- Author
-
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, Huang, Zhiqiang, Hernansanz-Agustín, Pablo, Contreras, Carmen, Martínez, Fernando, Camafeita, Emilio, Vázquez, Jesús, 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, and Ricote, Mercedes
- Abstract
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.
- Published
- 2023
- Full Text
- View/download PDF