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

Abstract

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.

Developmental programming: adverse sexually dimorphic transcriptional programming of gestational testosterone excess in cardiac left ventricle of fetal sheep

“…We also note sex specific modulation in pathways associated with mitochondrial function in day 90 fetal LV only in females with prenatal T excess. Sex specific metabolic reprogramming has been noted in a rodent model of IUGR with late gestation female fetuses manifesting upregulation in genes associated with mitochondrial function 51 . Although low birth weight is also a characteristic of prenatal T-treated female sheep 52 , in contrast to the aforementioned study, pathways associated with mitochondrial function were downregulated.…”

Intrauterine Growth Restriction Induces Adulthood Chronic Metabolic Disorder in Cardiac and Skeletal Muscles

“…It results in perinatal cardiomyocyte injuries, inflammation in microglial cells, and metabolic alteration of skeletal muscle (27). Notably, to date, most studies have focused on the short-term perinatal damage due to IUGR (18,27). In clinical research, IUGR has been linked with a long-term risk of cardiovascular complications (17).…”

“…Several studies indicate that IUGR can cause cardiac and skeletal muscle dysfunction of metabolism during the perinatal period and early life (16,17). In a recent study, Maréchal et al (18) detected an alteration in lipid metabolic gene reprogramming and changes in long-chain fatty acid profile with increased oxidative stress in cardiac muscle samples from IUGR rats at birth, which provided an essential molecular basis secondary to IUGR. Notably, however, whether such metabolic alteration remains long-term is currently unknown.…”

Fetal growth restriction and stillbirth: Biomarkers for identifying at risk fetuses

“…We have previously shown that fetal weight was strongly associated with impaired tolerance to severe hypoxia in preterm fetal sheep, particularly in males, and that the pattern of impaired failure of tolerance to hypoxia was sex dependent (Bennet et al, 2007). Others report that FGR reduces cardiac myocyte endowment in a sex-specific manner (Botting et al, 2018) and alters cardiac energy management (Maréchal et al, 2021).…”

“…Critically, pre-clinical studies in a variety of species demonstrate that FGR is also associated with effects on other organs such as the kidney, with reduced nephron endowment and associated reduced filtration capacity (Mitchell et al, 2004), and heart, with reduced cardiac myocyte endowment, impaired maturation, remodeling of cardiac vasculature and a switch in energy substrate use (Louey et al, 2007;Wang et al, 2013;Botting et al, 2018;Masoumy et al, 2018;Maréchal et al, 2021;Drake et al, 2022). Altered renal and cardiac development are strongly linked with later-life risks for cardiovascular disease (Masoumy et al, 2018;Fung and Zinkhan, 2021).…”