Maternal High Fat Diet and Diabetes Disrupts Transcriptomic Pathways That Regulate Cardiac Metabolism and Cell Fate in Newborn Rat Hearts
Open Access
- 17 September 2020
- journal article
- research article
- Published by Frontiers Media SA in Frontiers in Endocrinology
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.Keywords
Funding Information
- National Institute of Child Health and Human Development
- National Institute of General Medical Sciences
This publication has 111 references indexed in Scilit:
- p32 protein levels are integral to mitochondrial and endoplasmic reticulum morphology, cell metabolism and survivalBiochemical Journal, 2013
- Toll-Like Receptor 4 Knockout Mice Are Protected against Endoplasmic Reticulum Stress Induced by a High-Fat DietPLOS ONE, 2013
- Quantification of carbonic anhydrase gene expression in ventricle of hypertrophic and failing human heartBMC Cardiovascular Disorders, 2013
- Heparin-Binding EGF-Like Growth Factor Induces Heart Interstitial Fibrosis via an Akt/mTor/p70s6k PathwayPLOS ONE, 2012
- p32/gC1qR is indispensable for fetal development and mitochondrial translation: importance of its RNA-binding abilityNucleic Acids Research, 2012
- Lipid Metabolism and Toxicity in the HeartCell Metabolism, 2012
- Mapping of the Saccharomyces cerevisiae Oxa1-Mitochondrial Ribosome Interface and Identification of MrpL40, a Ribosomal Protein in Close Proximity to Oxa1 and Critical for Oxidative Phosphorylation Complex AssemblyEukaryotic Cell, 2009
- A Multicenter, Randomized Trial of Treatment for Mild Gestational DiabetesNew England Journal of Medicine, 2009
- Dynamic organization of mitochondria in human heart and in myocardial diseaseThe International Journal of Biochemistry & Cell Biology, 2009
- Quantitative analysis of Akt phosphorylation and activity in response to EGF and insulin treatmentBiochemical and Biophysical Research Communications, 2007