Maternal High Fat Diet and Diabetes Disrupts Transcriptomic Pathways That Regulate Cardiac Metabolism and Cell Fate in Newborn Rat Hearts
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Abstract 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.
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A total of 122 genes were significantly reduced while 201 genes were increased in the hearts of newborn rats in the high-fat diet and STZ-induced diabetes model.
“A total of 122 genes were significantly reduced while 201 genes were increased.”
From Recent Experimental Studies of Maternal Obesity, Diabetes during Pregnancy and the Developmental Origins of Cardiovascular Disease (2022) · cites this paper as [123]
The Figure 2 caption in the Results states 122 downregulated and 201 upregulated genes in the combined diabetes and high-fat-diet group, matching the claim. But the accompanying Results text reverses those directions, stating 122 upregulated and 201 downregulated genes. Our copy is internally contradictory on the claimed counts. (LLM, conf=0.78)
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Experimental — accuracy not yet measuredFunctional analysis revealed that downregulation of fibroblast growth factor (FGF) and PI-3-kinase pathways featured prominently in the offspring heart.
“Several pathways were affected, but functional analysis revealed that downregulation of fibroblast growth factor (FGF) and PI-3-kinase pathways and upregulation of peroxisome proliferator-activated receptor coactivator alpha (PGC1α) mitochondrial biogenesis pathway featured prominently in the offspring heart.”
From Recent Experimental Studies of Maternal Obesity, Diabetes during Pregnancy and the Developmental Origins of Cardiovascular Disease (2022) · cites this paper as [123]
Functional analysis revealed that upregulation of peroxisome proliferator-activated receptor coactivator alpha (PGC1α) mitochondrial biogenesis pathway featured prominently in the offspring heart.
“Several pathways were affected, but functional analysis revealed that downregulation of fibroblast growth factor (FGF) and PI-3-kinase pathways and upregulation of peroxisome proliferator-activated receptor coactivator alpha (PGC1α) mitochondrial biogenesis pathway featured prominently in the offspring heart.”
From Recent Experimental Studies of Maternal Obesity, Diabetes during Pregnancy and the Developmental Origins of Cardiovascular Disease (2022) · cites this paper as [123]
32 mitochondrial genes were altered in the offspring of STZ-induced diabetes dams fed a high-fat diet.
“In agreement with the findings regarding mitochondrial function described above, 32 mitochondrial genes were altered in the offspring of STZ-induced diabetes dams fed a high-fat diet [123].”
From Recent Experimental Studies of Maternal Obesity, Diabetes during Pregnancy and the Developmental Origins of Cardiovascular Disease (2022) · cites this paper as [123]
Increased PGC1α protein levels were confirmed in the hearts of the offspring.
“Increased PGC1α protein levels and reduced levels FGF receptor-2 were confirmed in the hearts of the offspring, although levels of phosphorylated Akt were similar [123].”
From Recent Experimental Studies of Maternal Obesity, Diabetes during Pregnancy and the Developmental Origins of Cardiovascular Disease (2022) · cites this paper as [123]
Levels of phosphorylated Akt were similar in the hearts of the offspring.
“Increased PGC1α protein levels and reduced levels FGF receptor-2 were confirmed in the hearts of the offspring, although levels of phosphorylated Akt were similar [123].”
From Recent Experimental Studies of Maternal Obesity, Diabetes during Pregnancy and the Developmental Origins of Cardiovascular Disease (2022) · cites this paper as [123]
Reduced levels of FGF receptor-2 were confirmed in the hearts of the offspring.
“Increased PGC1α protein levels and reduced levels FGF receptor-2 were confirmed in the hearts of the offspring, although levels of phosphorylated Akt were similar [123].”
From Recent Experimental Studies of Maternal Obesity, Diabetes during Pregnancy and the Developmental Origins of Cardiovascular Disease (2022) · cites this paper as [123]
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Age Related Bioenergetics Profiles in Isolated Rat Cardiomyocytes Using Extracellular Flux Analyses
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Self-citation
Flagged first, then by citations
2 of the 112 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
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“Increased PGC1α protein levels and reduced levels FGF receptor-2 were confirmed in the hearts of the offspring, although levels of phosphorylated Akt were similar [123].”
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Effect of Gestational Diabetes in Female Rats on Brain Astrocyte Functions in Their Offspring
Babkina, I., Savinkova, I. G., Artyukhov, A. S., & Горбачева, Л. Р. (2025) · Neurochemical Journal · doi:10.1134/s1819712425700837
- Authors
- Preston, C. C., Larsen, T. D., Eclov, J. A., Louwagie, E. J., Gandy, T. C. T., Faustino, R. S., & Baack, M. L.
- Affiliations
- Sanford Health (US)
- Sanford Research (US)
- University of South Dakota (US)
- Corresponding author
- Baack, Michelle L.
- Venue
- Frontiers in Endocrinology
- Publisher
- Frontiers Media SA
- Published
- 2020-09-17
- Volume
- 11
- Pages
- 570846-570846
- ISSN
- 1664-2392 (ISSN-L)
- PMC
- PMC7527411
- OpenAlex
- W3087264118
- Cited by
- 22
- References
- 112
- Citations by year
- 2025: 6 · 2024: 2 · 2023: 4 · 2022: 5 · 2021: 4 · 2020: 1
- FWCI
- 3.36
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Endocrinology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute of Child Health and Human Development
- National Institute of General Medical Sciences
- Topics
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Health Sciences › Medicine › Obstetrics and Gynecology › Gestational Diabetes Research and Management
- Keywords
- maternal diabetes, maternal high-fat diet, neonatal rat heart, cardiac transcriptome, myocardial metabolism, PI3K/Akt signaling, PGC-1α, mitochondrial biogenesis, glycolysis, glycogen, epigenetic reprogramming, maternal hyperglycemia, hyperlipidemia
- MeSH terms
- Animals, Animals, Newborn, Organelle Biogenesis, Female, Male, Myocardium, Pregnancy, Diabetes, Gestational, Gene Expression Profiling, Maternal Nutritional Physiological Phenomena, Rats, Gene Regulatory Networks, Diet, High-Fat, Transcriptome
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