Maternal obesity and high leptin levels prime pro-inflammatory pathways in human cord blood leukocytes
Bernardo J Krause1, Fabian A Vega-Tapia2, Gustavo Soto-Carrasco3
1Institute of Health Sciences, Universidad de O'Higgins, Rancagua, Chile.
Insights
Maternal obesity impacts offspring immune cells, altering leptin gene expression and methylation. Leptin further amplifies inflammatory responses in neonatal monocytes from mothers with obesity.
Area of Science:
- Immunology
- Developmental Biology
- Metabolic Disorders
Background:
- Maternal obesity is linked to altered immune function in offspring.
- Pro-inflammatory pathways may influence leptin-related gene expression in neonatal monocytes.
Purpose of the Study:
- To investigate the effects of maternal obesity on leptin-related gene expression and DNA methylation in neonatal monocytes.
- To determine how leptin influences inflammatory responses in neonatal monocytes.
Main Methods:
- Analyzed transcriptional profiles of cord blood leukocytes (CBL) and DNA methylation of cord blood monocytes (CBM).
- Assayed differentially expressed genes (DEG) and differentially methylated probes (DMP) in neonates from mothers with normal or obese BMI.
- Cultured CBM-derived macrophages with leptin and stimulated with lipopolysaccharide (LPS) and interferon-gamma to assess cytokine induction.
Main Results:
- Cord blood leukocytes from pregnancies with obesity (CBL-Ob) exhibited significant changes in leptin pathway genes.
- Obese CBM showed distinct DNA methylation profiles enriched in insulin- and leptin-related genes, predicting maternal BMI and leptin levels.
- Leptin exposure enhanced TNF-α and decreased IL-10 in control monocytes, but this effect was blunted in monocytes from mothers with obesity.
Conclusions:
- Pregnancy obesity is associated with unique leptin gene expression and methylation patterns in neonatal monocytes.
- Leptin exacerbates pro-inflammatory cytokine expression in response to M1-skewing stimuli in neonatal monocytes.
Introduction:
Maternal obesity alters the immune function in the offspring. We hypothesize that maternal obesity and pro-inflammatory pathways induce leptin-related genes in neonatal monocytes, whereby high leptin levels enhance their inflammatory response.
Methods:
Transcriptional profiles of cord blood leukocytes (CBL) in basal and pro-inflammatory conditions were studied to determine differentially expressed genes (DEG). The DNA methylation profile of CB monocytes (CBM) of neonates born to control BMI mothers and women with obesity was assayed to identify differentially methylated probes (DMP). CBM-derived macrophages were cultured with or without leptin (10-100 ng/ml) and then stimulated with lipopolysaccharide (LPS, 100 ng/ml) and interferon-gamma (20 ng/ml) to assess the induction of TNF-α and IL-10 transcripts.
Results:
CBL from pregnancies with obesity (CBL-Ob) showed 12,183 DEG, affecting 49 out of 78 from the leptin pathway. Control CBM exposed to LPS showed 45 leptin-related DEG, an effect prevented by the co-exposure to LPS and IL-10. Conversely, CBM-Ob showed 5279 DMP enriched in insulin- and leptin-related genes, and Lasso regression of leptin-related DMP showed high predictive value for plasma leptin levels (r2 = 0.9897) and maternal BMI categories (AUC = 1). Chronic exposure to leptin increased TNF-α and decreased IL-10 levels in control BMI samples but not in Ob-CBM. Enhanced TNF-α induction after proinflammatory stimulation was observed in leptin-treated control BMI samples.
Discussion:
Obesity in pregnancy is associated with a distinctive expression and DNA methylation profile of leptin-related genes in cord blood monocytes, meanwhile, leptin enhances the expression of pro-inflammatory cytokines upon stimulation with M1-skewing agents.
