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

Abstract

Background: Children born to diabetic or obese mothers have a higher risk of heart disease at birth and later in life. Using chromatin immunoprecipitation sequencing, we previously demonstrated that late-gestation diabetes, maternal high fat (HF) diet, and the combination causes 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 maternal diabetes and maternal H diet. Methods: Microarray gene expression profiling of hearts from diabetes exposed, HF diet exposed, and combination exposed newborn rats was compared to controls. Functional annotation, pathway and network analysis of differentially expressed genes were performed in combination exposed and control newborn rat hearts. Further downstream metabolic assessments included measurement of total and phosphorylated AKT2 and GSK3β, as well as quantification of glycolytic capacity by extracellular flux analysis and glycogen staining. Results: Transcriptional analysis identified significant fuel-mediated changes in offspring cardiac gene expression. Specifically, functional pathways analysis identified two key signaling cascades that were functionally prioritized in combination exposed offspring hearts: (1) downregulation of fibroblast growth factor (FGF) activated PI3K/AKT pathway and (2) upregulation of peroxisome proliferator-activated receptor gamma coactivator alpha (PGC1α) mitochondrial biogenesis signaling. Functional metabolic and histochemical assays supported these transcriptome changes, corroborating diabetes-and diet-induced cardiac transcriptome remodeling and cardiac metabolism in offspring. Conclusion: 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 regulation of heart health.

Mitochondrial Transfer Improves Cardiomyocyte Bioenergetics and Viability in Male Rats Exposed to Pregestational Diabetes

“…It is well known that offspring of diabetic mothers develop responsive hyperinsulinemia in utero, which may "program" mitochondrial dysfunction including oxidative phosphorylation and viability. In our own studies, we have shown disruptions in cardiac insulin signaling pathways and relative insulin resistance in myocardium of offspring exposed to LGDM and maternal HF diet [11], so it is plausible that the hyperinsulinemia in our PGDM-exposed offspring is driving the mitochondrial effects shown here.…”

“…Finally, studies should further investigate whether developmentally programmed changes in mitochondria are inherited or acquired following exposure to in utero conditions. Reflecting metabolic memory mentioned above, we have previously found distinct, epigenetic signatures with maternal LGDM and HF diet that vary by solo and combination exposure [11,12]. The work of Miller and Orchard disputes the concept that short-term exposure to hyperglycemia alone causes disease attributed to metabolic memory; disease can instead be attributed to cumulative hyperglycemia exposure [57].…”

“…Yet, our studies suggest that beyond transient hyperglycemia, developmentally programmed heart disease is more complex as lipids and insulin, rather than just hyperglycemia, appear to play important roles. Indeed, our own LGDM and HF diet model demonstrate significant diet-mediated changes in the myocardial epigenome and transcriptome [8,11], particularly alongside lipid-associated oxidative stress [10]. Given our previous findings, we hypothesized that maternal PGDM alongside a maternal HF diet would expose the developing offspring to hyperglycemia during ovulation, fertilization, implantation, and organogenesis to cause even worse mitochondrial dysfunction in developing CM (compared to LGDM exposure) potentially contributing to cardiac birth defects as well as neonatal cardiomyopathy by higher rates of mitochondria-mediated cell death.…”

“…Diabetes and obesity during pregnancy expose the fetus to excess circulating glucose and lipids, inciting fetal hyperinsulinemia and fuel-mediated heart disease at birth [1][2][3][4] and later in life [5][6][7], yet prevention is hindered because mechanisms are not well understood. Work from our lab [8][9][10][11][12] and others [13][14][15] suggests that mitochondria play a central, pathogenic role, specifically in offspring exposed to late-gestation diabetes mellitus (LGDM) and maternal high-fat (HF) diet. This study aimed to answer key remaining questions.…”

Intrauterine Programming of Cardiovascular Diseases in Maternal Diabetes

“…A transcriptomic study performed in neonatal heart from dams treated with a combination of high-fat diet and STZ at day 14 of pregnancy, showed many changes in key genes of metabolic cardiac pathways. Among them, a downregulation of fibroblast growth factor ( FGF ), which in turn downregulates PI3K/AKT pathway activation that lead to increased glycogen synthase kinase 3 β ( GSK3β ) and peroxisome proliferator-activated receptor gamma coactivator alpha ( PGC1α ; Preston et al, 2020 ). PI3K/AKT is an insulin sensitive pathway that modulates metabolic pathways as gluconeogenesis (modulated by GSK3β) and mitochondrial function and biogenesis (modulated by PGC1α), between others.…”