Fetal Cardiac Lipid Sensing Triggers an Early and Sex-Related Metabolic Energy Switch in Intrauterine Growth Restriction.

Context Intrauterine growth restriction (IUGR) is an immediate outcome of an adverse womb environment, exposing newborns to developing cardiometabolic disorders later in life. This study investigates the cardiac metabolic consequences and underlying mechanism of energy expenditure in developing fetuses under conditions of IUGR. Methods Using an animal model of IUGR characterized by uteroplacental vascular insufficiency, mitochondrial function, gene profiling, lipidomic analysis, and transcriptional assay were determined in fetal cardiac tissue and cardiomyocytes. Results IUGR fetuses exhibited an upregulation of key genes associated with fatty acid breakdown and β-oxidation (Acadvl, Acadl, Acaa2), and mitochondrial carnitine shuttle (Cpt1a, Cpt2), instigating a metabolic gene reprogramming in the heart. Induction of Ech1, Acox1, Acox3, Acsl1, and Pex11a indicated a coordinated interplay with peroxisomal β-oxidation and biogenesis mainly observed in females, suggesting sexual dimorphism in peroxisomal activation. Concurring with the sex-related changes, mitochondrial respiration rates were stronger in IUGR female fetal cardiomyocytes, accounting for enhanced ATP production. Mitochondrial biogenesis was induced in fetal hearts with elevated expression of Ppargc1a transcript specifically in IUGR females. Lipidomic analysis identified accumulation of arachidonic, eicosapentaenoic, and docosapentaenoic polyunsaturated long-chain fatty acids in IUGR fetal hearts, which lead to nuclear receptor PPARα transcriptional activation in cardiomyocytes. Also, enrichment of H3K27ac chromatin marks to PPARα responsive metabolic genes in IUGR fetal hearts outlines an epigenetic control in the early metabolic energy switch. Conclusion These data are consistent with a premature and sex-related remodeling of cardiac metabolism in response to an unfavorable intrauterine environment, with specific long-chain fatty acids that may serve as predictive effectors leading to IUGR.