Maternal obesity and gestational diabetes are associated with placental leptin DNA methylation

Lesseur, Corina; Armstrong, David A.; Paquette, Alison G.; Li, Zhigang; Padbury, Jamés F.; Marsit, Carmen J.

doi:10.1016/j.ajog.2014.06.037

Cited by 99 publications

(71 citation statements)

References 37 publications

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“…18,19 Discrepancies between previous observations might be due to variations in cellularity of placenta tissues 32 and/or to the impact of GDM treatments on their specific epigenetic profiles. These potential confounding factors were not considered in neither of previous studies.…”

Section: Discussioncontrasting

confidence: 44%

“…17 A few observational studies have investigated associations between maternal glycemia and offspring DNAm in LEP genomic region, yet with contradictory findings in direction of effect. 18,19 Observational studies using GDM or maternal glucose levels as exposure are limited by measurement errors and confounding as any other epidemiological studies based on biochemical markers. While it does not allow the establishment of causality with certainty, the Mendelian randomization (MR) approach has the potential to improve causal inference.…”

Section: Introductionmentioning

confidence: 99%

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Mendelian randomization supports causality between maternal hyperglycemia and epigenetic regulation of leptin gene in newborns

et al. 2015

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Leptin is an adipokine that acts in the central nervous system and regulates energy balance. Animal models and human observational studies have suggested that leptin surge in the perinatal period has a critical role in programming long-term risk of obesity. In utero exposure to maternal hyperglycemia has been associated with increased risk of obesity later in life. Epigenetic mechanisms are suspected to be involved in fetal programming of long term metabolic diseases. We investigated whether DNA methylation levels near LEP locus mediate the relation between maternal glycemia and neonatal leptin levels using the 2-step epigenetic Mendelian randomization approach. We used data and samples from up to 485 mother-child dyads from Gen3G, a large prospective population-based cohort. First, we built a genetic risk score to capture maternal glycemia based on 10 known glycemic genetic variants (GRS 10 ) and showed it was an adequate instrumental variable (b D 0.046 mmol/L of maternal fasting glucose per additional risk allele; SE D 0.007; P D 7.8 £ 10 ¡11 ; N D 467). A higher GRS 10 was associated with lower methylation levels at cg12083122 located near LEP (b D ¡0.072 unit per additional risk allele; SE D 0.04; P D 0.05; N D 166). Direction and effect size of association between the instrumental variable GRS 10 and methylation at cg12083122 were consistent with the negative association we observed using measured maternal glycemia. Lower DNA methylation levels at cg12083122 were associated with higher cord blood leptin levels (b D ¡0.17 log of cord blood leptin per unit; SE D 0.07; P D 0.01; N D 170). Our study supports that maternal glycemia is part of causal pathways influencing offspring leptin epigenetic regulation.

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Section: Discussioncontrasting

confidence: 44%

Section: Introductionmentioning

confidence: 99%

Mendelian randomization supports causality between maternal hyperglycemia and epigenetic regulation of leptin gene in newborns

et al. 2015

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“…17 It has been shown that the LEP promoter is subject to epigenetic programming and that the expression of leptin can be modulated by DNA methylation. 18 For example, in utero exposure to famine and gestational diabetes has been associated with offspring LEP promoter hypermethylation in blood of adults 11 and placental LEP hypermethylation, 19 respectively. According to Lesseur et al, 12 cord blood LEP methylation was higher in small for gestational age infants and lower in infants born to pre-pregnancy obese mothers.…”

Section: Discussionmentioning

confidence: 99%

Dietary and supplemental maternal methyl-group donor intake and cord blood DNA methylation

et al. 2016

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Maternal nutrition is critically involved in the development and health of the fetus. We evaluated maternal methyl-group donor intake through diet (methionine, betaine, choline, folate) and supplementation (folic acid) before and during pregnancy in relation to global DNA methylation and hydroxymethylation and gene specific (IGF2 DMR, DNMT1, LEP, RXRA) cord blood methylation. A total of 115 mother-infant pairs were enrolled in the MAternal Nutrition and Offspring's Epigenome (MANOE) study. The intake of methylgroup donors was assessed using a food-frequency questionnaire. LC-MS/MS and pyrosequencing were used to measure global and gene specific methylation, respectively. Dietary intake of methyl-groups before and during pregnancy was associated with changes in LEP, DNMT1, and RXRA cord blood methylation. Statistically significant higher cord blood LEP methylation was observed when mothers started folic acid supplementation more than 6 months before conception compared with 3-6 months before conception (34.6 § 6.3% vs. 30.1 § 3.6%, P D 0.011, LEP CpG1) or no folic acid used before conception (16.2 § 4.4% vs. 13.9 § 3%, P D 0.036 for LEP CpG3 and 24.5 § 3.5% vs. 22.2 § 3.5%, P D 0.045 for LEP mean CpG). Taking folic acid supplements during the entire pregnancy resulted in statistically significantly higher cord blood RXRA methylation as compared with stopping supplementation in the second trimester (12.3 § 1.9% vs. 11.1 § 2%, P D 0.008 for RXRA mean CpG). To conclude, long-term folic acid use before and during pregnancy was associated with higher LEP and RXRA cord blood methylation, respectively. To date, pregnant women are advised to take a folic acid supplement of 400 mg/day from 4 weeks before until 12 weeks of pregnancy. Our results suggest significant epigenetic modifications when taking a folic acid supplement beyond the current advice.

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“…Most An adverse intrauterine environment, complicated by either undernutrition [14] or overfeeding [15], may programme harmful metabolic consequences later in life through epigenetic modifications such as DNA methylation. For instance, maternal gestational glycaemia concentrations correlate with placental DNA methylation adaptations of LEP (leptin) [16,17], ADIPOQ (adiponectin, C1Q and collagen domain-containing) [18] and ABCA1 (ATPbinding cassette transporter A1) [19] genes. Although the tenet of fetal metabolic programming has been extensively explored in animal models [20,21], only a small number of studies on epigenetic modification have been conducted in humans, especially in those with GDM.…”

Section: Introductionmentioning

confidence: 99%

Placental DNA methylation of peroxisome-proliferator-activated receptor-γ co-activator-1α promoter is associated with maternal gestational glucose level

et al. 2015

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Intrauterine exposure to hyperglycaemia may increase the risk of later-life metabolic disorders. Although the underlying mechanism is not fully understood, epigenetic dysregulation in fetal programming has been implicated. With regard to energy homoeostasis, PGC-1α (peroxisome-proliferator-activated receptor γ co-activator-1α, encoded by the PPARGC1A gene) plays a regulatory role in several biochemical processes. We hypothesized that maternal gestational glucose levels would positively correlate with DNA methylation of the PPARGC1A promoter in placental tissue. We undertook a cross-sectional study of 58 mothers who underwent uncomplicated Caesarean delivery in a university hospital. Maternal gestational glucose concentration was determined after a 75-g OGTT (oral glucose tolerance test) at 24-28 weeks of gestation. Placenta tissue and cord blood were collected immediately after delivery. Genomic DNA was extracted and thereafter bisulfite conversion was performed. After PCR amplification, the DNA methylation of the PPARGC1A promoter was quantified using a pyrosequencing technique. The protein level of PGC-1α was evaluated by Western blotting. For all participants as a whole, including the GDM (gestational diabetes mellitus) and normoglycaemia groups, the maternal gestational glucose level was positively correlated with placental DNA methylation, and negatively correlated with cord blood DNA methylation of the PPARGC1A promoter in a CpG site-specific manner. In the GDM group alone, the placental CpG site-specific methylation of the PPARGC1A promoter strongly correlated with gestational 2-h post-OGTT glycaemia. Epigenetic alteration of the PPAGRC1A promoter may be one of the potential mechanisms underlying the metabolic programming in offspring exposed to intrauterine hyperglycaemia.

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Maternal obesity and gestational diabetes are associated with placental leptin DNA methylation

Cited by 99 publications

References 37 publications

Mendelian randomization supports causality between maternal hyperglycemia and epigenetic regulation of leptin gene in newborns

Mendelian randomization supports causality between maternal hyperglycemia and epigenetic regulation of leptin gene in newborns

Dietary and supplemental maternal methyl-group donor intake and cord blood DNA methylation

Placental DNA methylation of peroxisome-proliferator-activated receptor-γ co-activator-1α promoter is associated with maternal gestational glucose level

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