Can leptin-specific epigenetic modulation of preterm cord blood predispose obesity?

ObjectiveThis retrospective cohort investigated the role of leptins promoter methylation and microRNA targeting profile in developing adiposity and inflammation in neonates, using umbilical cord blood from preterm (n=67) and term (n=71) mothers. MethodsGlobal DNA methylation and leptin promoter methylation were performed. ELISA determined leptin and IGF1 levels. Real-time PCR measured mRNA levels. MicroRNA target prediction on the human leptin gene (LEP) was done in silico using network analysis. ResultsPreterm cord blood significantly reduced genome-wide (p<0.001) and LEP promoter methylation (p=0.001), increased LEP & LEPR expression (p=0.04), and circulatory leptin (p=0.41). Neonatal birth weight positively correlated with leptin and IGF1 levels in preterm (r=0.47, p=0.04) but not in the term. IL6 expression showed a positive correlation with circulatory leptin (r= 0.687, p=0.008), LEP (r= 0.763, p=0.009), and an inverse association with LEP promoter methylation (r= -0.636, p=0.04) in preterm. The obtained LEP targeting miRNAs showed their affinities for critical genes associated with body fat distribution, fat cell differentiation, and energy regulation, implicating a close association in the LEP-miRNA-obesity axis. ConclusionsThe strong correlation between LEP methylation and pro-inflammatory cytokine influences each other in developing chronic inflammation in preterm neonates, which might predispose them to obesity in later life. Study importanceWhat is already known? O_LILeptin communicates about the bodys fat deposits to the brain and aids in maintaining energy homeostasis and stable body weight. C_LIO_LIPreterm exhibit lower body weight and fat mass at birth than term neonates, who often show rapid compensatory catch-up growth. C_LI What does this study add? O_LILeptin gene (LEP) promoter methylation was reduced in preterm cord blood compared to term. C_LIO_LIHigher interleukin-6 (IL6) and tumour necrosis factor-alpha (TNF) expression in preterm but not in term. IL6 correlated positively with circulatory leptin and LEP expression while inversely associated with LEP-specific promoter methylation, indicating that a dysregulated epigenetic control can promote low-grade inflammation in preterm neonates. C_LIO_LILEP-targeting micro-RNAs showed affinities for critical genes associated with fat cell differentiation, energy regulation, and other processes. C_LI How might these results change the direction of research or the focus of clinical practice? O_LISince others observed dysregulated LEP methylation in the adipose tissue of obese subjects, these data imply that leptin could mediate the risk for obesity during preterm birth. C_LIO_LIWhile short-term outcomes of preterm birth are well addressed, its effect on long-term metabolic health is of concern as it might elevate the risk of obesity. C_LI Graphical AbstractMaternal factors leading to preterm birth and cord blood leptin dysregulation in predicting obesity. Elevated blood pressure, infection, and lower haemoglobin in preterm disrupted epigenetic control of leptin and activated inflammation that might induce leptin resistance. The latter is known to reduce satiety and increase body mass, elevating the risk of obesity. Solid arrows depict present data, and dotted lines indicate possible pathways. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=52 SRC="FIGDIR/small/24319077v1_ufig1.gif" ALT="Figure 1"> View larger version (11K): org.highwire.dtl.DTLVardef@1f3604corg.highwire.dtl.DTLVardef@13723b5org.highwire.dtl.DTLVardef@1094bfborg.highwire.dtl.DTLVardef@15b5ebc_HPS_FORMAT_FIGEXP M_FIG C_FIG