| First Author | Paredes A | Year | 2023 |
| Journal | Nature | Volume | 618 |
| Issue | 7964 | Pages | 365-373 |
| PubMed ID | 37225978 | Mgi Jnum | J:340032 |
| Mgi Id | MGI:7525585 | Doi | 10.1038/s41586-023-06068-7 |
| Citation | Paredes A, et al. (2023) gamma-Linolenic acid in maternal milk drives cardiac metabolic maturation. Nature 618(7964):365-373 |
| abstractText | 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 gamma-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. |
