γ-Linolenic acid in maternal milk drives cardiac metabolic maturation

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. The switch from glucose- to fatty acid-dependent metabolism in cardiomyocytes of newborn mice is governed by γ-linolenic acid in maternal milk, which binds to retinoid X receptors, thereby causing a transcription-dependent metabolic transition.