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 ?-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.

Automated summary

Birth poses a metabolic challenge to cardiomyocytes, requiring a transition from glucose to fatty acids as the main source of energy production. This transition is regulated by a fatty acid called ?-linolenic acid (GLA), present in maternal milk, which activates retinoid X receptors (RXRs) in embryonic cardiomyocytes. The lack of RXR leads to defective gene expression and abnormal mitochondrial fatty acid homeostasis, resulting in cardiac dysfunction and perinatal death. Supplementation of GLA induces RXR-dependent expression of mitochondrial fatty acid homeostasis genes in cardiomyocytes, both in vitro and in vivo.