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

  1. Navya Sree Boga
  2. Amit K Banerjee
  3. Saikanth Varma
  4. Archana Molangiri
  5. Syeda Farhana
  6. Santosh Kumar Banjara
  7. Nitasha Bagga
  8. Asim K. Duttaroy
  9. Sanjay Basak
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Abstract

Objective

This retrospective cohort investigated the role of leptin’s 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.

Methods

Global 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.

Results

Preterm 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.

Conclusions

The 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 importance

What is already known?

  • Leptin communicates about the body’s fat deposits to the brain and aids in maintaining energy homeostasis and stable body weight.

  • Preterm exhibit lower body weight and fat mass at birth than term neonates, who often show rapid compensatory catch-up growth.

What does this study add?

  • Leptin gene ( LEP ) promoter methylation was reduced in preterm cord blood compared to term.

  • Higher interleukin-6 ( IL6 ) and tumour necrosis factor-alpha ( TNF α ) 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.

  • LEP -targeting micro-RNAs showed affinities for critical genes associated with fat cell differentiation, energy regulation, and other processes.

How might these results change the direction of research or the focus of clinical practice?

  • Since 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.

  • While 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.

Graphical Abstract

Maternal 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.

Article activity feed

  1. Version published to 10.1101/2024.12.16.24319077v1 on medRxiv