Lipid- -Immune crosstalk Immune crosstalk Lipid at the Maternal- -Fetal Interface Fetal Interface For non commercial use ONLY at the Maternal Sylvie Hauguel-de Mouzon, PhD Case Western Reserve University, Cleveland, USA
What makes the baby fat ? Inflammation : the concepts
Adiponectin Inflammatory Exposome in pregnancy with obesity Lean OW & Obese p Insulin ( U/ml) 6.3 ± 3.7 14.3 ± 5.6 <0.001 13.1 ± 9.1 35.1 ± 20.5 Leptin (ng/ml) 0.001 1.2 ± 0.4 3.2 ± 3.7 IL-6 (ng/ml) 0.05 CRP(mg/dl) 0.4 ± 0.3 0.7 ± 0.4 0.03 ns TNF-alpha (pg/ml) 1.9 ± 1.3 1.8 ± 0.8 ( g/ml) 0.001 11.6 ± 1.3 8.4 ± 1.2
macrophages invade the maternal adipose tissue and the placental stroma ADIPOSE TISSUE PLACENTA CD 68 CD 68
2012 2012 PCA of all microbial communities first trimester third trimester postpartum obese overweight normal weight
Dietary exposome impacts gut microbiota inflammation inflammation LPS inflammation Cani & Delzenne 2009
Lipopolysaccharide (LPS) structure
Toll-like Receptor 4 inflammatory signals 2006, Jason K. Kim TLR4 LPS
Increased LPS in maternal plasma in term Pregnancy 1.0 p=0.004 0.75 plasma (EU/ml) 0.50 0.25 0.0 Lean Obese Basu, Hauguel-de Mouzon Obesity 2010
The lipid-inflammation connection Toll Like Receptor 4 links innate immunity and fatty acid–induced insulin resistance Shi, Flier J. Clin. Invest. 2006 Fat uses a TOLL-road to connect inflammation and diabetes Kim J Cell Metab. 2006
What makes the baby fat ? Lipids – the concepts
Hypothesis Hyperlipemic envrionment at the maternal-fetal interface increases placental inflammation
saturated Dietary exposome: lipids High plasma TG Fatty Acids Cholesterol (apoB)
Meyer et al 2012
Structural Similarity between LPS and Fatty Acids C14:0 FA C12:0 Palmitic acid (C16:0) Oleic acid (C18:1)
Toll-like Receptor 4 inflammatory signals Fatty Acid Lipid A LPS TLR4 CD14 MyD88 NF B IL6-TNF -IL8 Jason K. Kim, 2006 TLRs play a fundamental role in pathogen recognition and activation of innate immunity
HUMAN TERM PRIMARY TROPHOBLAST cells Cytokeratine TLR4 CONTROL PALMITATE 24hrs
Can maternal lipid diet elicit placental inflammation saturated FA PALMITATE C16:0 mono- unsaturated FA OLEATE C18:1
TLR4 gene expression in cultured human trophoblast cells 16 mRNA fold change 12 (n=5) 8 4 1 0 CTL BSA LPS Oleate Palmitate
TLR4 activation in cultured human trophoblast cells 20 * 4 PALMITATE Effect of LPS TLR4 mRNA fold change * 15 3 10 2 5 1 * 1 0 0 CTL 24h 6h CTL 6h 24h
Inflammatory cytokine response to palmitate but not oleate in cultured trophoblast cells mRNA fold change over CTL LPS Oleate Palmitate (n=5) 60 45 30 15 1 0 IL-6 IL-8 TNF-a
Placenta TLR4 localization TLR4 Cytokeratin Dapi m
Placenta TLR4 mRNA 6 Fold change vs basal 4 2 0 Obese Lean Yang, Hauguel-de Mouzon (ongoing studies)
TOM Summary 1- TLR4 inflammatory pathways are activated in placenta of obese women 2- LC-SAFA but not NSFA activate placental TLR4 inflammatory pathways
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