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Maternal High Fat Diet and Diabetes Disrupts Transcriptomic Pathways That Regulate Cardiac Metabolism and Cell Fate
Claudia C Preston1, Tricia D Larsen2, Julie A Eclov2
1Genetics and Genomics Group, Sanford Research, Sioux Falls, SD, United States.
Insights
Maternal diabetes and high-fat diet alter offspring heart gene expression, impacting key signaling pathways. This research reveals how combined maternal conditions affect fetal heart development and metabolism.
Area of Science:
- Cardiovascular Biology
- Developmental Biology
- Metabolic Disease
Background:
- Offspring of diabetic or obese mothers face increased congenital and later-life heart disease risk.
- Previous studies showed distinct epigenetic reprogramming in fetal rat hearts due to maternal diabetes, high-fat diet, or both.
- This study investigates the comprehensive transcriptional changes in newborn rat hearts exposed to these maternal conditions.
Purpose of the Study:
- To determine the overall transcriptional signature of newborn offspring hearts exposed to maternal diabetes and/or a high-fat diet.
- To identify specific signaling pathways and metabolic alterations in offspring hearts.
- To elucidate the combined impact of maternal hyperglycemia and hyperlipidemia on cardiac development.
Main Methods:
- Microarray gene expression profiling of newborn rat hearts (diabetes, high-fat diet, combination, and control groups).
- Functional annotation, pathway, and network analyses of differentially expressed genes.
- Metabolic assessments including AKT2/GSK3β phosphorylation, glycolytic capacity, and glycogen staining.
Main Results:
- Significant fuel-mediated alterations in offspring cardiac gene expression were identified.
- Key signaling pathways affected in combination-exposed offspring included downregulation of the FGF-activated PI3K/AKT pathway and upregulation of PGC1α mitochondrial biogenesis.
- Metabolic and histochemical assays confirmed transcriptome changes, supporting diabetes- and diet-induced cardiac remodeling.
Conclusions:
- This study presents novel data on the combined effects of maternal hyperglycemia and hyperlipidemia on the fetal cardiac transcriptome.
- It elucidates specific molecular mechanisms by which maternal metabolic conditions influence offspring heart development and metabolism.
- Findings highlight nuanced impacts on cardiac regulation, offering insights into heart health in offspring of mothers with diabetes or obesity.
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.
