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 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.

出生对心肌细胞提出了代谢挑战，因为它们重塑了产后能量生产的燃料偏好，从葡萄糖到脂肪酸^1,2 。这种适应部分是由产后环境变化触发的³ ，但协调心肌细胞成熟的分子仍然未知。在这里，我们表明，这种转变是由母体提供的 γ-亚麻酸 (GLA) 协调的，γ-亚麻酸是母乳中富含的 18:3 omega-6 脂肪酸。 GLA 结合并激活类视黄醇 X 受体⁴ (RXR)，这是一种配体调节的转录因子，在胚胎阶段的心肌细胞中表达。多方面的全基因组分析表明，胚胎心肌细胞中 RXR 的缺乏导致染色质景观异常，从而阻止了控制线粒体脂肪酸稳态的 RXR 依赖性基因表达特征的诱导。随后的代谢转变缺陷导致线粒体脂质来源的能量产生减弱和葡萄糖消耗增加，导致围产期心脏功能障碍和死亡。最后，GLA 补充在体外和体内诱导心肌细胞中线粒体脂肪酸稳态特征的 RXR 依赖性表达。因此，我们的研究将 GLA-RXR 轴确定为母体控制围产期心脏代谢的关键转录调节机制。