Paredes, AnaJusto-Mendez, RaquelJiménez-Blasco, DanielNunez, VanessaCalero, IreneVillalba-Orero, MariaAlegre-Martí, AndreaFischer, ThierryGradillas, AnaSant'Anna, Viviane Aparecida RodriguesWere, FelipeHuang, ZhiqiangHernansanz-Agustín, PabloContreras, CarmenMartinez, FernandoCamafeita, EmilioVazquez, JesusRuiz-Cabello, JesusArea-Gómez, EstelaSanchez-Cabo, FatimaTreuter, EckardtBolaños, Juan PedroEstébanez-Perpiñá, EvaRupérez, Francisco JavierBarbas, CoralEnriquez, Jose AntonioRicote, Mercedes2024-01-122024-01-122023-06Nature. 2023; 618(7964):365-373.http://hdl.handle.net/20.500.12105/16948Birth 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.engAMhttp://creativecommons.org/licenses/by-nc-nd/4.0/Fatty Acidsgamma-Linolenic AcidGlucoseHeartMilk, HumanFemaleHumansInfant, NewbornPregnancyChromatinGene Expression RegulationHomeostasisIn Vitro TechniquesMitochondriaMyocytes, CardiacRetinoid X ReceptorsTranscription FactorsAttribution-NonCommercial-NoDerivatives 4.0 Internacional37225978618796436510.1038/s41586-023-06068-71476-4687Natureopen access