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.

Obese women, on average, give birth to babies with high fat mass. Placental lipid metabolism alters fetal lipid delivery, potentially moderating neonatal adiposity, yet how it is affected by maternal obesity is poorly understood. We hypothesized that fatty acid (FA) accumulation (esterification) is higher and FA β-oxidation (FAO) is lower in placentas from obese, compared with lean women. We assessed acylcarnitine profiles (lipid oxidation intermediates) in mother-baby-placenta triads, in addition to lipid content, and messenger RNA (mRNA)/protein expression of key regulators of FA metabolism pathways in placentas of lean and obese women with normal glucose tolerance recruited at scheduled term Cesarean delivery. In isolated trophoblasts, we measured [3H]-palmitate metabolism. Placentas of obese women had 17.5% (95% confidence interval: 6.1, 28.7%) more lipid than placentas of lean women, and higher mRNA and protein expression of FA esterification regulators (e.g., peroxisome proliferator-activated receptor γ, acetyl-CoA carboxylase, steroyl-CoA desaturase 1, and diacylglycerol O-acyltransferase-1). [3H]-palmitate esterification rates were increased in trophoblasts from obese compared with lean women. Placentas of obese women had fewer mitochondria and a lower concentration of acylcarnitines, suggesting a decrease in mitochondrial FAO capacity. Conversely, peroxisomal FAO was greater in placentas of obese women. Altogether, these changes in placental lipid metabolism may serve to limit the amount of maternal lipid transferred to the fetus, restraining excess fetal adiposity in this population of glucose-tolerant women.

ObjectiveLong-chain omega 3 fatty acids, eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3) exert potent anti-inflammatory properties in humans. This study characterized the effects of omega-3 ω-3 fatty acids supplements (ω-3 FA) on the inflammatory status in the placenta and adipose tissue of overweight/obese pregnant women.Study DesignA randomized, double-masked controlled trial was conducted in overweight/obese pregnant women that were randomly assigned to receive DHA plus EPA (2g/day) or the equivalent of a placebo twice a day from week 10–16 to term. Inflammatory pathways were characterized in: 1) adipose tissue and placenta of treated vs. untreated women; and 2) adipose and trophoblast cells cultured with long chain FAs.ResultsThe sum of plasma DHA and EPA increased by 5.8 fold and ω-3 FA/ ω-6 FA ratio was 1.5 in treated vs. untreated women (p< 0.005). Plasma CRP concentrations were reduced (p<0.001). The adipose tissue and placenta of treated women exhibited a significant decrease in TLR4 adipose and placental expression as well as IL6, IL8, and TNFα In vitro, EPA and DHA suppressed the activation of TLR4, IL6, IL8 induced by palmitate in culture of adipose and trophoblast cells.ConclusionSupplementation of overweight/obese pregnant women with dietary ω-3 FAs for >25 weeks reduced inflammation in maternal adipose and the placental tissue. TLR4 appears as a central target of the anti-inflammatory effects at the cellular level.Trial RegistrationClinicalTrials.gov NCT00957476