Maternal obesity programs cardiac remodeling in offspring via epigenetic, metabolic, and immune dysregulation

Maternal obesity during pregnancy significantly increases the offspring's risk of later-life cardiovascular disease. This study investigated cardiometabolic perturbations utilizing a mouse model of maternal high-fat diet (HFD)-induced obesity that recapitulates metabolic abnormalities observed in humans. We have previously shown 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). The present investigation of cardiac function further identified significant functional, metabolic, and immune perturbations in adult Off-HFD mice. Specifically, Off-HFD mice presented progressing cardiac hypertrophy with reduced ejection fraction and fractional shortening, increased accumulation of fibrotic tissue, mitochondrial dysfunction, and altered immune complexity including increases in cardiac resident macrophages and decreases in CD4+ and Cd8+ T-cells. While these alterations may not be immediately catastrophic, they likely predispose offspring to heightened sensitivity to nutritional, psychological, or environmental stressors. To explore the timing and mechanisms by which maternal environment impacts offspring cardiac function, we examined DNA methylation in the hearts of newly-weaned Off-RD and Off-HFD mice. This analysis revealed numerous differentially methylated CpGs and regions within genes associated with cardiac development, hypertrophy, mitochondrial function, and immune response. Thus, our study reveals that cardiovascular dysregulations in offspring of obese mothers originate early in development and persist into adult life. These findings uncover potential windows of opportunity for preventive therapy and early therapeutic interventions. Overall design: RRBS methylation profiling of mouse heart tissue from newly-weaned offspring from High Fat Diet (HFD) or Regular Diet (RD) mothers.