γ-Linolenic acid in maternal milk drives cardiac metabolic maturation.
Ana ParedesRaquel Justo-MéndezDaniel Jimenez-BlascoVanessa NúñezIrene CaleroMaría Villalba-OreroAndrea Alegre-MartíThierry FischerAna GradillasViviane Aparecida Rodrigues Sant'AnnaFelipe WereZhiqiang HuangPablo Hernansanz-AgustínCarmen ContrerasFernando Martínez de BenitoEmilio CamafeitaJesus VazquezJesús Ruíz-CabelloEstela Area-GómezFatima Sánchez-CaboEckardt TreuterJuan Pedro BolañosEva Estébanez-PerpiñáFrancisco Javier RupérezCoral BarbasJosé Antonio EnríquezMercedes RicotePublished in: Nature (2023)
Birth presents a metabolic challenge to cardiomyocytes as they reshape fuel preference from glucose to fatty acids for postnatal energy production 1,2 . This adaptation is triggered in part by post-partum environmental changes 3 , 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 receptors 4 (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.
Keyphrases
- fatty acid
- transcription factor
- high glucose
- gene expression
- oxidative stress
- pregnancy outcomes
- left ventricular
- birth weight
- endothelial cells
- pregnant women
- genome wide analysis
- dna damage
- poor prognosis
- diabetic rats
- blood glucose
- preterm infants
- genome wide
- metabolic syndrome
- body mass index
- angiotensin ii
- type diabetes
- human health
- physical activity
- risk assessment
- weight loss
- preterm birth
- heat shock protein