Oral Presentation 46th Annual Meeting of the Fetal and Neonatal Physiological Society 2019

Leptin programs an enhanced M1 response in human neonatal monocyte-derived macrophages (#20)

Fabian A. Vega-Tapia 1 , Gustavo Soto 1 , Isidora Lefever 1 , Catalina Letelier 1 , Jose A. Castro-Rodríguez 1 , Bernardo J. Krause 1
  1. Division of Pediatrics, Pontificia Universidad Catolica de Chile, Santiago, SANTIAGO, Chile

Introduction: Offspring from obese women are at high risk to develop chronic diseases related to an altered immune function. Several studies show no changes in circulating levels of inflammatory mediators in neonates of obese women, but a significant increase in leptin, a pro-inflammatory adipokine. We hypothesize that maternal obesity results in a programming of leptin-receptor, IL-10 and TNF genes, and the chronic exposure to leptin during monocyte-to-macrophage results in an enhanced expression of TNFɑ after an inflammatory challenge.

Methods: Cord blood monocytes were isolated from lean (LM, n = 20) and obese mother (ObM, n = 20) neonates. Monocytes DNA were isolated and CpG methylation of LEPR, IL10 and TNF analyzed using an Infinium MethylationEPIC BeadChip. Monocytes were differentiated into macrophages by exposing to M-CSF (100 ng/mL) in presence or absence of leptin (10 or 100 ng/mL), and stimulated for 24 hours with E.coli-LPS (100 ng/mL) and IFN-γ (20 ng/mL). Transcript levels of TNF-α and IL-10 were assessed by qPCR. Parallel experiments on leptin effects were performed in the monocytic cell lines THP-1 and U937.

Results: ObM neonatal monocytes showed no changes in the methylation pattern of IL10 gene, but decreased levels of CpG methylation in LEPR and TNF genes. In vitro exposure to leptin increased basal TNFα levels (10-fold) in monocytes-derived macrophages from LM neonates in a concentration-dependent manner, but not in the ObM group. Leptin enhanced the expression of TNF-α in response to a pro-inflammatory challenge without effects on IL10. Effects of leptin were replicated in THP-1 and U937 cell lines.

Conclusions: These results suggest that increased leptin levels during early life enhances the expression of pro-inflammatory cytokines. This effect may be involved in the developmental effect of pre-gestational obesity in the mother, with high levels of neonatal leptin, and the postnatal risk of developing chronic diseases.