Philips, E. A.; Alharithi, Y.; Wilson, T. D.; Broberg, C.; Davis, B. A.; Koch, S.; Carbone, L.; Rubinstein, J.; Gurley, S. B.; Rugonyi, S.; Kumar, S.; Maloyan, A.

Maternal obesity during pregnancy significantly increases the offspring risk of later-life cardiovascular disease. This study investigated cardiometabolic perturbations by utilizing a mouse model of maternal high-fat diet (HFD)-induced obesity that recapitulates metabolic abnormalities observed in humans. We report that offspring of HFD-fed mothers (Off-HFD) exhibit a progression of obesity, hypertension, dyslipidemia, and metabolic inflexibility when compared with offspring of regular diet-fed mothers (Off-RD). Deeper investigation of cardiac function further identified significant functional, metabolic, and immune perturbations in adult offspring of mothers on HFD. Specifically, Off-HFD mice presented progressing cardiac hypertrophy with reduced ejection fraction, increased accumulation of fibrotic tissue, mitochondrial dysfunction, and altered immune complexity including increases in cardiac resident and infiltrated macrophages, and decreases in CD4 and CD8 T-cell subpopulations. While these alterations may not be immediately catastrophic, they likely predispose the offspring to heightened sensitivity to nutritional, psychological, or environmental stressors. Analysis of DNA methylation in the hearts of newly-weaned offspring from RD and HFD mothers revealed numerous differentially methylated CpGs and regions within genes associated with cardiac development, hypertrophy, mitochondrial function, and immune response. Thus, our study shows epigenetic remodelling early in development, which is likely responsible for the cardiovascular dysregulation observed in adult life. These findings uncover potential windows of opportunity for preventive therapy and early therapeutic interventions.