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.

PurposeWe initiated the Genetics of Glucose regulation in Gestation and Growth (Gen3G) prospective cohort to increase our understanding of biological, environmental and genetic determinants of glucose regulation during pregnancy and their impact on fetal development.ParticipantsBetween January 2010 and June 2013, we invited pregnant women aged ≥18 years old who visited the blood sampling in pregnancy clinic in Sherbrooke for their first trimester clinical blood samples: 1034 women accepted to participate in our cohort study.Findings to dateAt first and second trimester, we collected demographics and lifestyle questionnaires, anthropometry measures (including fat and lean mass estimated using bioimpedance), blood pressure, and blood samples. At second trimester, women completed a full 75 g oral glucose tolerance test and we collected additional blood samples. At delivery, we collected cord blood and placenta samples; obstetrical and neonatal clinical data were abstracted from electronic medical records. We also collected buffy coats and extracted DNA from maternal and/or offspring samples (placenta and blood cells) to pursue genetic and epigenetic hypotheses. So far, we have found that low adiponectin and low vitamin D maternal levels in first trimester predict higher risk of developing gestational diabetes.Future plansWe are now in the phase of prospective follow-up of mothers and offspring 3 and 5 years postdelivery to investigate the consequences of maternal dysglycaemia during pregnancy on offspring adiposity and metabolic profile.Trial registration numberNCT01623934.

Background: Excessive gestational weight gain (GWG) is associated with adverse pregnancy outcomes. In non-pregnant populations, low leptin levels stimulate positive energy balance. In pregnancy, both the placenta and adipose tissue contribute to circulating leptin levels. We tested whether maternal leptin levels are associated with subsequent GWG and whether this association varies depending on stage of pregnancy and on maternal body mass index (BMI). Methods: This prospective cohort study included 675 pregnant women followed from 1 st trimester until delivery. We collected anthropometric measurements, blood samples at 1 st and 2 nd trimester, and clinical data until delivery. Maternal leptin was measured by ELISA (Luminex technology). We classified women by BMI measured at 1

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Higher insulin resistance is associated with higher levels of circulating TNFα at first and second trimesters of pregnancy. TNFα level dynamics during an OGTT at second trimester vary according to insulin-resistance state.

Indigenous women and children experience some of the most profound health disparities globally. These disparities are grounded in historical and contemporary trauma secondary to colonial atrocities perpetuated by settler society. The health disparities that exist for chronic diseases may have their origins in early-life exposures that Indigenous women and children face. Mechanistically, there is evidence that these adverse exposures epigenetically modify genes associated with cardiometabolic disease risk. Interventions designed to support a resilient pregnancy and first 1000 days of life should abrogate disparities in early-life socioeconomic status. Breastfeeding, prenatal care and early child education are key targets for governments and health care providers to start addressing current health disparities in cardiometabolic diseases among Indigenous youth. Programmes grounded in cultural safety and co-developed with communities have successfully reduced health disparities. More works of this kind are needed to reduce inequities in cardiometabolic diseases among Indigenous women and children worldwide.