Paredes, AnaVillalba Orero, MaríaRuiz-Cabello Osuna, JesúsRicote, Mercedes2024-02-012024-02-012023Paredes, A., Justo-Méndez, R., Jiménez-Blasco, D. et al. γ-Linolenic acid in maternal milk drives cardiac metabolic maturation. Nature 618, 365–373 (2023). https://doi.org/10.1038/s41586-023-06068-70028-083610.1038/s41586-023-06068-7https://hdl.handle.net/20.500.14352/97794Birth 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.engjournal article1476-4687https://doi.org/10.1038/s41586-023-06068-737225978https://pubmed.ncbi.nlm.nih.gov/37225978/#full-view-affiliation-1restricted accessMedicina24 Ciencias de la Vida