Maternal High Fat Diet and Diabetes Disrupts Transcriptomic Pathways that Regulate Cardiac Metabolism and Cell Fate in Newborn Rat Hearts

Background Children born to diabetic or obese mothers have a higher risk of heart disease at birth and later in life. Our previous work using chromatin immunoprecipitation sequencing revealed that late-gestation diabetes in combination with maternal high fat (HF) diet cause a distinct fuel-mediated epigenetic reprogramming of rat cardiac tissue during fetal cardiogenesis. The objective of the present study was to investigate the overall transcriptional signature of newborn offspring exposed to the combination of maternal diabetes and maternal HF diet. Methods Gene expression profiling from hearts of diabetes exposed, HF diet exposed, combination exposed and control newborn rats was compared for differential transcriptome expression. Functional annotation, pathway and network analysis was performed on statistically significant differentially expressed genes from the combination exposed group compared with controls. Downstream metabolic assessments included measurement of total and phosphorylated AKT2 and GSK3β assays, as well as quantification of glycolytic capacity by extracellular flux analysis and glycogen staining. Results Transcriptome analysis of newborn rat hearts showed significant changes in cardiac gene expression following exposure to maternal diabetes or HF diet individually, as well as the combination of diabetes + HF compared with controls. Reactome analyses identified expression changes in two key signaling cascades functionally prioritized in male control and combination exposed offspring hearts. These pathways included downregulation of the fibroblast growth factor (FGF) pathway and concomitant downstream PI3K/AKT activation canonically recognized as a regulator of cell metabolism, growth, and development. In contrast, the second pathway exhibited significant upregulation of mitoribosomal signaling that regulates mitochondrial biogenesis, mitophagy and cell fate. Focused bioinformatic analysis on mitochondrial genes enriched in the combination exposed dataset revealed genes associated with diverse aspects of mitochondrial structure, function, and dynamism. Functional biochemical, metabolic, and histochemical assays supported these transcriptome changes, confirming the essential role of mitochondrial energetics in facilitating diabetes- and diet-induced cardiac transcriptome remodeling and phenotype in offspring. Conclusions This study provides the first data accounting for the compounding effects of maternal hyperglycemia and hyperlipidemia on the developmental cardiac transcriptome, and elucidates nuanced and novel features of maternal diabetes and diet on intergenerational regulation of heart health.