The energy-rich condition of obesity is associated with the activation of inflammatory pathways present in adipose tissue. The combined metabolic and immune dysregulation results in an increased in circulating chemokines, cytokines and inflammatory mediators. In pregnancy complicated with obesity the maternal adipose tissue and the placenta both contribute to increase systemic inflammation (60
). The chronic inflammatory milieu in pregnancy, associated with obesity and GDM, has provided the basis for the hypothesis: that if the mother is in an inflammatory condition, must not the fetus also be exposed to such an environment?
We propose that the maternal metabolic inflammation of obese women does not directly translate into inflammation in the fetal compartment. Experimental data from our group and others do not support this concept. In pregnancy complicated by obesity, the concentration of inflammatory markers and mediators is typically increased in the maternal but not in the fetal circulation (61
). Most maternal cytokines are not readily transferred across the placenta in humans (62
). Several cytokines such as Il-6 or leptin, synthesized within the placenta itself, are preferentially released into the maternal rather than into the fetal circulation (63
).The environment of elevated IL-6 in systemic maternal and cord blood, as well as in maternal adipose tissue and the placenta, may play a role in metabolic inflammation. The role of hyperinsulinemia as a stimulus of Il-6 production by adipose tissue of obese women further underlies the close interactions of immune and metabolic systems (64
). This is in contrast to other cytokines such as TNF-alpha which may primarily act locally ().
The metabolic inflammation of pregnancy (sometimes termed as meta-inflammation) is not to the degree associated with severe infection or sepsis. Hence meta-inflammation may play an indirect role at the maternal fetal interface to modify the availability of energy substrates for fetal needs. The pattern of low grade chronic metabolic inflammation, being a common denominator for obesity and other diseases associated with insulin resistance, has emerged from the molecular cross-talks between metabolic and immune systems (65
). Adipose tissue is actively involved in innate sensing. For example, adipose tissue is the major source of systemic IL-6 when systemic inflammation is induced by lipopolysaccharides (LPS) injection in mice (66
) Toll like receptors, a family of membrane receptors recruited in innate sensing are the first line of pathogen recognition activated by environmental stimuli, such as (LPS) (67
). Toll like receptor 4 (TLR4) responds to LPS by activation of intracellular signals which result in the increased synthesis of IL-6 and other pro-inflammatory cytokines (68
). The ability of FFA to also activate TLR4 in adipose cells, also underlines the relationship between the immune and metabolic systems in disorders of lipid metabolism (69
In pregnancies complicated by obesity, there is an increased expression and activation of TLR4 in maternal adipose tissue suggesting a response to immune stimuli (70
). The contribution of the placenta to the increased inflammatory environment of obese pregnancy is supported by the observation that placenta perfused with LPS release increased amounts of cytokines (71
). How or why circulating LPS is increased in obesity is not yet clear. There are correlations between gut pathogens, obesity and inflammation (72
). Changes in diet and associated microbiota have recently been proposed as potential contributors to increased LPS and metabolic inflammation through TLR4 (73
). We have reported that obese women have increased circulating levels of LPS and that LPS induces TLR4 receptors in adipose tissue (70
). These data are consistent with changes in the microbiota of obese vs. lean pregnant women, which would enrich the environment with LPS (74
Based on the metabolic and immune interactions between maternal adipose tissue and the placenta, we hypothesize that obesogenic-diabetogenic challenges in the mother result in excess of either glucose or lipid availability for fetal adipose tissue lipogenesis (). Depending on whether the maternal environment has evidence of increased glucose plus insulin or elevated lipid concentrations, either source of substrates may contribute to fetal fat accretion. Increased in fetal IL-6 may also contribute to increase insulin resistance before birth. Definite proof of our integrative hypothesis is awaiting experimental support.
homeostatic regulation of fetal adipose tissue growth