Abstract
Changes in fetal DNA methylation (DNAm) of the leptin (LEP) gene have been associated with exposure to maternal hyperglycemia, but their links with childhood obesity risk are still unclear. We investigated the association between maternal hyperglycemia, placental LEP DNAm (25 5′-C-phosphate-G-3′ (CpG) sites), neonatal leptinemia, and adiposity (i.e., BMI and skinfold thickness (ST) (subscapular (SS) + triceps (TR) skinfold measures, and the ratio of SS:TR) at 3-years-old, in 259 mother–child dyads, from Gen3G birth cohort. We conducted multivariate linear analyses adjusted for gestational age at birth, sex of the child, age at follow-up, and cellular heterogeneity. We assessed the causal role of DNAm in the association between maternal glycemia and childhood outcomes, using mediation analysis. We found three CpGs associated with neonatal leptinemia (p ≤ 0.002). Of these, cg05136031 and cg15758240 were also associated with BMI (β = −2.69, p = 0.05) and fat distribution (β = −0.581, p = 0.05) at 3-years-old, respectively. Maternal glycemia was associated with DNAm at cg15758240 (β = −0.01, p = 0.04) and neonatal leptinemia (β = 0.19, p = 0.004). DNAm levels at cg15758240 mediates 0.8% of the association between maternal glycemia and neonatal leptinemia (p < 0.001). Our results support that DNAm regulation of the leptin pathway in response to maternal glycemia might be involved in programming adiposity in childhood.
Highlights
Childhood obesity is a growing public health problem [1]
Maternal fasting glucose levels measured at the second trimester of pregnancy were associated with cord blood leptinemia (β = 0.19, p = 0.004) after adjustment for maternal age and Body mass index (BMI) at the first trimester of pregnancy, gestational age at delivery, and sex of the offspring
We showed that an exposure to maternal hyperglycemia during pregnancy likely modulated neonatal leptinemia, partially through changes in cord blood LEP DNA methylation (DNAm) levels
Summary
Childhood obesity is a growing public health problem [1]. It has been linked to various comorbidities, including type 2 diabetes, asthma, dyslipidemia, and psychosocial disorders, which have been increasing recently [2]. It is critical to identify the mechanisms involved in the pathogenesis of childhood obesity, and in the context of studies on the Developmental Origin of Health and Disease (DOHaD) hypothesis. The DOHaD hypothesis postulates that exposure to adverse maternal environment during early development is associated with later onset of numerous chronic disorders over the life course, including obesity [5,6,7,8,9]. DNA methylation (DNAm), the most studied epigenetic modification, has been identified among the potential underlying mechanisms involved in the regulation of many metabolic functions, including leptin (LEP) gene expression regulation in the placenta [12,13,14]. The placenta has been suggested as a relevant tissue in the field, as it plays a crucial role in materno–fetal exchanges optimizing fetal growth, influences maternal physiology by secreting hormones (e.g., leptin), and has on average lower DNAm levels, suggesting that many genes are actively transcribed to support its metabolic activity [15,16,17]
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