Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/16948
Title
γ-Linolenic acid in maternal milk drives cardiac metabolic maturation.
Author(s)
Paredes, Ana | Justo-Mendez, Raquel CNIC | Jiménez-Blasco, Daniel | Nunez, Vanessa CNIC | Calero, Irene | Villalba-Orero, Maria CNIC | Alegre-Martí, Andrea | Fischer, Thierry | Gradillas, Ana | Sant'Anna, Viviane Aparecida Rodrigues | Were, Felipe CNIC | Huang, Zhiqiang | Hernansanz-Agustín, Pablo | Contreras, Carmen | Martinez, Fernando CNIC | Camafeita, Emilio CNIC | Vazquez, Jesus CNIC | Ruiz-Cabello, Jesus CNIC | Area-Gómez, Estela | Sanchez-Cabo, Fatima CNIC | Treuter, Eckardt | Bolaños, Juan Pedro | Estébanez-Perpiñá, Eva | Rupérez, Francisco Javier | Barbas, Coral | Enriquez, Jose Antonio CNIC | Ricote, Mercedes CNIC
Date issued
2023-06
Citation
Nature. 2023; 618(7964):365-373.
Language
Inglés
Document type
research article
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.
MESH
Fatty Acids | gamma-Linolenic Acid | Glucose | Heart | Milk, Human | Female | Humans | Infant, Newborn | Pregnancy | Chromatin | Gene Expression Regulation | Homeostasis | In Vitro Techniques | Mitochondria | Myocytes, Cardiac | Retinoid X Receptors | Transcription Factors
DOI
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