Abstract Wed073: Understanding cardiac metabolomic adaptation in normal vs obese maternal heart

Maternal mortality rates in the US have been steadily rising, with cardiovascular disease (CVD) as the leading cause. Obesity significantly increases risk of maternal deaths, particularly deaths from CVD. While normal pregnancy induces transient physiological cardiac hypertrophy (CH), obese pregnancy exacerbates CH, leading to cardiac dysfunction and impaired energetics in human patients, and signs of pathological remodeling revealed by animal models. The aim of this study is to investigate the metabolic maladaptations and molecular mechanisms underlying the obesity-induced cardiac maladaptation during pregnancy. To study the effect of obese pregnancy, mice were fed on Western Diet for 14-16 weeks to induce obesity in C57BL6/J mice. Bulk RNA-seq was performed on heart tissues to investigate the transcriptional changes during pregnancy with or without obesity. RNA-seq revealed robust upregulation of genes in fatty acid (FA) oxidation in obese pregnancy. Using PCSF network analysis, I identified FoxO1 as a critical regulatory hub in the trajectories from normal to obese pregnancy, which is a transcriptional factor that regulates biological processes including metabolism, particularly fatty acid utilization, through downstream genes PDK4 and CD36. To understand the role of FoxO1 in the pathological responses in obese pregnancy, I used AAV9-FoxO1 shRNA to inhibit FoxO1 expression during pregnancy in obese mice. To understand whether obese pregnancy leads to cardiac metabolomic maladaptation, I used in vivo isotope tracing approach to assess the fuel preference—utilization of fatty acid vs. glucose in the normal and obese maternal heart. Results: I found that FoxO1 is over-activated at protein level in maternal heart in obese pregnancy. FoxO1 inhibition led to attenuated pathological cardiac hypertrophy phenotype, as evident by smaller cardiomyocyte cross-sectional area, less fibrosis accumulation and lower fetal gene expression. Normal pregnancy leads to a mild switch in fuel preference towards fatty acid. Meanwhile, obese pregnancy leads to a more robust metabolic imbalance between fatty acid vs glucose. Our findings suggest that obese pregnancy leads to over-activation of FoxO1. FoxO1 inhibition attenuated the pathological cardiac hypertrophy phenotype caused by obese pregnancy. Obese pregnancy leads to imbalance metabolic fuel preference in the maternal heart. The rescue effect of FoxO1 is potentially through the rewiring of fuel preference.