Obesity and pregnancy are associated with a combination of insulin resistance and inflammatory changes which exacerbate in combination. Based on the similarity between the inflammatory transcriptomes of adipose tissue and placenta, we hypothesized that the placenta develops exaggerated inflammation in response to obesity. The aim of this study was to characterize placental inflammatory mediators and macrophage accumulation in relation to peripheral inflammation in obesity.Placental macrophages and maternal peripheral mononuclear cells from 20 obese and 15 lean women were functionally and phenotypically characterized using immunohistochemistry, flow cytometry and expression for macrophage markers and inflammatory cytokines. The number of resident CD68+ and CD14+ cells was increased 2-3 fold in placenta of obese as compared to lean women. The enhanced macrophage population was characterized by a marked phenotypic heterogeneity with complex subsets of CD14+, CD68+ and CD11b+ cells and by an increased expression of the pro-inflammatory mediators IL-1, TNF-alpha, IL-6. Placental inflammation was associated with an activation of peripheral blood mononuclear cells with high amount of CD14, TNF-alpha, IL-6 and the chemokine receptors CCR2 and IL8-R in maternal but not fetal circulation. Additionally, plasma CRP and IL-6 concentrations were higher in obese compared to lean women.In conclusion, the chronic inflammation state of pre-gravid obesity is extending to in utero life with accumulation of an heterogeneous macrophage population and proinflammatory mediators in the placenta. The resulting inflammatory milieu in which the fetus develops may have critical consequences for short and long term programming of obesity. KeywordsObesity; pregnancy; placenta; inflammation; cytokines; fetus; programming The association between excess neonatal adiposity and high pre-gravid BMI and the alarming rise in the number of overweight women of reproductive age, call for elucidating the adverse consequences of obesity in pregnancy (1,2). In non gravid individuals, obesity is described as a low grade inflammatory condition associated with increased production of pro-inflammatory factors which originate from the macrophages infiltrating the adipose tissue (3,4). During pregnancy, however, the placenta becomes a significant source of a variety of cytokines and adipocytokines whose expression is dysregulated by maternal diabetes and obesity (5-7).Pregnancy is considered as a natural inflammatory state evident in activation of maternal leucocytes and increased systemic concentration of acute phase reactants and cytokines (8).The physiological inflammatory state of pregnancy becomes exaggerated when pregnancy is complicated by pre-eclampsia and gestational diabetes and returns to baseline levels after delivery (9-11). Products of inflammatory stress secreted by the placenta and microparticules shedding from the syncytial surface of the placenta into the systemic circulation have been proposed as mechanisms driving adaptive immunity (1...

Obese pregnant women develop severe insulin resistance and enhanced systemic and placental inflammation, suggesting associated modifications of endocrine and immune functions. Activation of innate immunity by endotoxins/lipopolysaccharides (LPS) has been proposed as a mechanism for enhancing metabolic alterations in disorders with insulin resistance. The aim of this study was to characterize the immune responses developed by the adipose tissue AT and their potential links to maternal endotoxemia in pregnancy with obesity. Blood and subcutaneous abdominal AT were obtained from 120 lean and obese women (term pregnancy) recruited at delivery. Gene expression was assessed in AT and stromal vascular cells isolated from a subset of 24 subjects from the same cohort. Doubling of plasma endotoxin concentrations indicated subclinical endotoxemia in obese compared with lean women. This was associated with significant increase in systemic CRP and IL-6 but not TNF-alpha concentrations. AT inflammation was characterized by accumulation of CD68+ macrophages with a 3-fold increased gene expression of the macrophage markers CD68, EMR1 and CD14. Gene expression for cytokines IL-6, TNF-α, IL-8, and MCP1 and for LPS - sensing CD14, TLR4, TRAM2 was 2.5-5 fold higher in stromal cells of obese compared to lean. LPS-treated cultured stromal cells of obese women expressed a 5-16 fold stimulation of the same cytokines up-regulated in vivo. Our data demonstrate that subclinical endotoxemia is associated with systemic and AT inflammation in obese pregnant women. Recognition of bacterial pathogens may contribute to the combined dysfunction of innate immunity and the metabolic systems in AT.

Objective Changes in metabolic homeostasis in pregnant diabetic women are potential determinants of increased adiposity of the fetus. The aim of this study was to characterize diabetes-induced changes in genes for fetal-placental energy metabolism in relation to fetal adiposity. Research Design and Methods Placentas of women with type 1 diabetes (T1DM), gestational diabetes (GDM) or no complications were analyzed using microarray profiling. Pattern of gene expression were assessed in primary placental cell cultures. Results Diabetes was associated with 49 alterations in gene expression at key steps in placental energy metabolism with 67 % related to lipid and 9 % related to glucose pathways. Preferential activation of lipid genes was observed in pregnancy with GDM. T1DM induced fewer lipid modifications but an enhancement of glycosylation and acylation pathways. Oleate enhanced expression of genes for fatty acid esterification and the formation of lipid droplets 3 times as much as glucose in cultured placental cells. Conclusions These results point to fatty acids as preferential lipogenic substrates for placental cells and, suggest that genes for fetal-placental lipid metabolism are selectively enhanced in GDM. The recruited genes may be instrumental in increasing transplacental lipid fluxes hence delivery of lipid substrates for fetal use.