γ-Linolenic acid in maternal milk drives cardiac metabolic maturation

Ana Paredes, Raquel Justo-Méndez, Daniel Jiménez-Blasco, Vanessa Núñez, Irene Calero, María Villalba-Orero, Andrea Alegre-Martí, Thierry Fischer, Ana Gradillas, Viviane Aparecida Rodrigues Sant’Anna, Felipe Were, Zhiqiang Huang, Pablo Hernansanz-Agustín, Carmen Contreras, Fernando Martínez, Emilio Camafeita, Jesús Vázquez, Jesús Ruiz-Cabello, Estela Area-Gómez, Fátima Sánchez-Cabo, Eckardt Treuter, Juan Pedro Bolaños, Eva Estébanez-Perpiñá, Francisco Javier Rupérez, Coral Barbas, José Antonio Enríquez and Mercedes Ricote ()
Additional contact information
Ana Paredes: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Raquel Justo-Méndez: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Daniel Jiménez-Blasco: University of Salamanca, CSIC
Vanessa Núñez: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Irene Calero: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
María Villalba-Orero: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Andrea Alegre-Martí: Institute of Biomedicine (IBUB) of the University of Barcelona (UB)
Thierry Fischer: Centro Nacional de Biotecnología-Consejo Superior de Investigaciones Científicas (CNB/CSIC), Campus Universidad Autónoma de Madrid (UAM)
Ana Gradillas: Universidad San Pablo-CEU, CEU Universities
Viviane Aparecida Rodrigues Sant’Anna: Universidad San Pablo-CEU, CEU Universities
Felipe Were: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Zhiqiang Huang: Karolinska Institutet
Pablo Hernansanz-Agustín: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Carmen Contreras: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Fernando Martínez: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Emilio Camafeita: CIBER de Enfermedades Cardiovasculares (CIBERCV)
Jesús Vázquez: CIBER de Enfermedades Cardiovasculares (CIBERCV)
Jesús Ruiz-Cabello: Basque Research and Technology Alliance (BRTA)
Estela Area-Gómez: Centro de Investigaciones Biológicas Margarita Salas-CSIC
Fátima Sánchez-Cabo: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Eckardt Treuter: Karolinska Institutet
Juan Pedro Bolaños: University of Salamanca, CSIC
Eva Estébanez-Perpiñá: Institute of Biomedicine (IBUB) of the University of Barcelona (UB)
Francisco Javier Rupérez: Universidad San Pablo-CEU, CEU Universities
Coral Barbas: Universidad San Pablo-CEU, CEU Universities
José Antonio Enríquez: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Mercedes Ricote: Centro Nacional de Investigaciones Cardiovasculares (CNIC)

Nature, 2023, vol. 618, issue 7964, 365-373

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41586-023-06068-7

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