Pregravid Obesity Associates With Increased Maternal Endotoxemia and Metabolic Inflammation

Abstract

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.

Pre‐pregnancy body mass index, weight change during pregnancy, and risk of intellectual disability in children

“…These include insulin resistance/hyperinsulinaemia and systemic inflammation, as well as epigenetic effects on fetal DNA. 39 Obese pregnant women exhibit low-grade endotoxemia and increased systemic C-reactive protein and interleukin-6 concentrations, as well as increased gene expression for a number of pro-inflammatory cytokines in adipose tissue, 40 and they also exhibit increased macrophage accumulation and inflammation in the placenta. 41 Furthermore, there is evidence that prepubescent children of women who were obese during pregnancy were dramatically more likely to have detectable C-reactive protein levels than children of non-obese mothers, even after controlling for the child's BMI and other potential confounding factors.…”

“…1 Limitation in intellectual ability corresponds to an intelligence quotient (IQ) of <70, described as mild (IQ 55-70), moderate (IQ [40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55], or severe to profound (IQ of <40). 2 The prevalence of ID in the general population is estimated to be approximately 1%, and among those with ID 85% are characterised as having mild ID.…”

Inflammatory links between obesity and metabolic disease

“…Since pregnancy represents a physiologic inflammatory state involving the innate and acquired immune system, inflammatory mechanisms may contribute to the in utero programming of nutrient metabolism (72). Maternal obesity is associated with endotoxemia and ATM accumulation that may affect the developing fetus (73). Placental inflammation is a characteristic of maternal obesity, a risk factor for obesity in offspring, and involves inflammatory macrophage infiltration that can alter the maternal-fetal circulation (74).…”

Peroxisome Proliferator-Activated Receptor γ 2 Modulates Late-Pregnancy Homeostatic Metabolic Adaptations

“…Gestation coexists with a state of generalized mild chronic inflammation, which is characterized by increased levels of circulating inflammatory cytokines, and locally by an increase in infiltration of macrophages into adipose tissue (9,10,(36)(37)(38). The inflammatory process is physiological at the end of normal pregnancy (36); however, it is pathological in pregnancy associated with obesity and GDM (10,37). Given its anatomical location close to the fetus and its higher lipolytic capacity, perigonadal WAT has been proposed as the fat depot that supplies more nutrients to the fetus (39).…”