Maternal gestational diabetes is associated with genome-wide DNA methylation variation in placenta and cord blood of exposed offspring

A predisposing factor for development of the hyperglycaemic state of gestational diabetes mellitus (GDM) is obesity. We previously showed that increasing maternal obesity is associated with significant reductions in placental mitochondrial respiration. MicroRNA (miR)-143 has been previously shown to regulate the metabolic switch from oxidative phosphorylation to aerobic glycolysis in cancer tissues. We hypothesized that mitochondrial respiration is reduced and aerobic glycolysis is up-regulated via changes in miR-143 expression in the placenta of women with GDM. Placental tissue was collected at term from women with A1GDM (controlled by diet), A2GDM (controlled by medication) and body mass index (BMI)-matched controls (CTRL). miR-143 expression was measured by RT-PCR. Expression of mitochondrial complexes, transcription factors peroxisome proliferator-activated receptor-γ co-activator 1α (PGC1α) and peroxisome proliferator-activated receptor γ (PPARγ), components of mammalian target of rapamycin (mTOR) signalling, glucose transporter GLUT1 and glycolytic enzymes [hexokinase-2 (HK-2), phosphofructokinase (PFK) and lactate dehydrogenase (LDH)] were measured by Western blot. Trophoblast respiration was measured by XF24 Analyser. Expression of miR-143, mitochondrial complexes, and PPARγ and PGC1α, which act downstream of miR-143, were significantly decreased in A2GDM placentae compared with A1GDM and CTRL (P<0.01). Placental hPL (human placental lactogen) levels, expression of glycolytic enzymes, GLUT1 and mTOR signalling were also significantly increased by more than 2-fold in A2GDM compared with A1GDM and CTRL (P<0.05). There was a 50% reduction in mitochondrial respiration in trophoblast cells isolated from A2GDM placentae. Overexpression of miR-143 was able to increase mitochondrial respiration, increase protein expression of mitochondrial complexes and decrease expression of glycolytic enzymes by 40% compared with A2GDM. Down-regulation of miR-143 mediates the metabolic switch from oxidative phosphorylation to aerobic glycolysis in placenta of women with A2GDM.

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“…The prevalence of GDM has been estimated at ~7% of pregnancies in the USA [1]. Gestational diabetes affects both the mother and the offspring.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial function and glucose metabolism in the placenta with gestational diabetes mellitus: role of miR-143

2016

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“…Finer et al found that maternal gestational diabetes leads to genome-wide DNA methylation difference in the placenta and cord blood of exposed offspring. Pathways involved in MAPK signaling are enhanced in methylation genes [40]. Nyggf4 , which is a newly discovered obesity candidate gene, may regulate the methylation levels of various isoforms of the MAPK subfamily [41].…”

Section: Discussionmentioning

confidence: 99%

Effects of Maternal Chromium Restriction on the Long-Term Programming in MAPK Signaling Pathway of Lipid Metabolism in Mice

et al. 2016

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It is now broadly accepted that the nutritional environment in early life is a key factor in susceptibility to metabolic diseases. In this study, we evaluated the effects of maternal chromium restriction in vivo on the modulation of lipid metabolism and the mechanisms involved in this process. Sixteen pregnant C57BL mice were randomly divided into two dietary treatments: a control (C) diet group and a low chromium (L) diet group. The diet treatment was maintained through gestation and lactation period. After weaning, some of the pups continued with either the control diet or low chromium diet (CC or LL), whereas other pups switched to another diet (CL or LC). At 32 weeks of age, serum lipid metabolism, proinflammatory indexes, oxidative stress and anti-oxidant markers, and DNA methylation status in adipose tissue were measured. The results indicated that the maternal low chromium diet increased body weight, fat pad weight, serum triglyceride (TG), low-density lipoprotein cholesterol (LDL), tumor necrosis factor-α (TNF-α), malondialdehyde (MDA), and oxidized glutathione (GSSG). There was a decrease in serum reduced/oxidized glutathione (GSH/GSSG) ratio at 32 weeks of age in female offspring. From adipose tissue, we identified 1214 individual hypomethylated CpG sites and 411 individual hypermethylated CpG sites in the LC group when compared to the CC group. Pathway analysis of the differential methylation genes revealed a significant increase in hypomethylated genes in the mitogen-activated protein kinase (MAPK) signaling pathway in the LC group. Our study highlights the importance of the MAPK signaling pathway in epigenetic changes involved in the lipid metabolism of the offspring from chromium-restricted dams.

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“…The study reported a similar methylation pattern for MEST in a group of obese adults compared to that in normal-weight controls. A study on placenta tissue from 27 GDM and 21 healthy pregnancies (67) found 1708 differentially methylated positions (>5%) that reached significance (P < 0.05) after FDR. Pathways that were differently methylated included endocytosis, mitogen-activated protein kinases (MAPK) signaling pathway, cell adhesion molecules (CAMs), focal adhesion, chemokine signaling and insulin signaling pathways.…”

Section: Other Genesmentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Epigenetic modifications and gestational diabetes: a systematic review of published literature

Moen

Sommer

Prasad

et al. 2017

European Journal of Endocrinology

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Objective: To summarize the current knowledge on epigenetic alterations in mother and offspring subjected to gestational diabetes (GDM) and indicate future topics for research. Design: Systematic review. Methods: We performed extensive searches in PubMed, EMBASE and Google scholar, using a combination of the search terms: GDM, gestational diabetes, epigenetic(s), methylation, histone modification, histone methylation, histone acetylation, microRNA and miRNA. Studies that compared women diagnosed with GDM and healthy controls were included. Two authors independently scanned the abstracts, and all included papers were read by at least two authors. The searches were completed on October 31st, 2016. Results: We identified 236 articles, of which 43 were considered relevant for this systematic review. Studies published showed that epigenetic alterations could be found in both mothers with GDM and their offspring. However, differences in methodology, diagnostic criteria for GDM and populations studied, together with a limited number of published studies and small sample sizes, preclude clear conclusions about the role of epigenetic modifications in transmitting risk from GDM mothers to their offspring. Conclusion: The current research literature suggests that GDM may have impact on epigenetic modifications in the mother and offspring. However, larger studies that include multiple cohorts of GDM patients and their offspring are needed.

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Maternal gestational diabetes is associated with genome-wide DNA methylation variation in placenta and cord blood of exposed offspring

Cited by 184 publications

References 39 publications

Mitochondrial function and glucose metabolism in the placenta with gestational diabetes mellitus: role of miR-143

Mitochondrial function and glucose metabolism in the placenta with gestational diabetes mellitus: role of miR-143

Effects of Maternal Chromium Restriction on the Long-Term Programming in MAPK Signaling Pathway of Lipid Metabolism in Mice

MECHANISMS IN ENDOCRINOLOGY: Epigenetic modifications and gestational diabetes: a systematic review of published literature

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