Current topicInflammation in maternal obesity and gestational diabetes mellitus
Introduction
Obesity in pregnancy is rapidly becoming more common worldwide and constitutes a major medical problem. In the United States, 35% of women of reproductive age are obese (body mass index, BMI > 30 kgm/m2) [1]. Maternal obesity has a significant economic impact, estimated to cost $106.8 million annually in the US alone [2]. Obesity during pregnancy is associated with increased mortality and morbidity for both mother and offspring. Obese women are at greater risk for developing pregnancy complications such as preeclampsia, thromboembolism, and gestational diabetes mellitus (GDM), as well as cardiovascular and metabolic disorders in later life [3], [4]. The risk of developing GDM is increased 1.3–3.8 times in obese women compared to women of normal BMI [5], and ∼70% of women with GDM may go on to develop type 2 diabetes up to 28 years post-partum [6].
Infants of obese mothers have a higher incidence of congenital abnormalities and are more likely to be large for gestational age (LGA) at birth [4], [7], [8]. Children of obese mothers, in particular if they are born LGA, are prone to develop metabolic disease [9], [10], [11], [12]. The hypothesis that the fetal environment may influence the development of disease in adulthood, now termed the ‘developmental origins of adult disease’, was proposed by Barker and based on the observation that low birthweight correlated positively with the development of cardiovascular disease in later life [13]. Considerable epidemiological evidence has accumulated demonstrating that maternal obesity is predictive for the development of obesity [14], cardiovascular disease [15], and type 2 diabetes in offspring [10]. Children of obese women with GDM are more likely to have increased adiposity and be insulin resistant, propagating the vicious cycle of metabolic disorders into the next generation [16]. There are currently limited options for early prevention of the metabolic syndrome in children born to obese women. Improving the metabolic environment of the obese pregnant mother to break this vicious cycle may be an attractive approach to decrease the future economical, societal, and personal burden of obesity. However, to make progress in this area, better understanding of the mechanisms linking obesity in pregnancy to adverse outcomes in the infant is necessary.
In recent years, there has been increased interest in the role of inflammation as a mediator of programming of metabolic disorders following exposure to the adverse intrauterine environment in maternal obesity. In the non-pregnant state, obesity is associated with a chronic, low-grade inflammatory state, termed ‘metainflammation’, or metabolically induced inflammation [17]. Metainflammation is distinct from an acute pro-inflammatory response and is triggered primarily by metabolites and nutrients, leading to systemic insulin resistance [17].
Placental inflammation has been observed in pregnancies complicated by obesity [18] and GDM [19], and may play a central role in determining the fetal environment in these pregnancies. Normal pregnancy is associated with a highly regulated inflammatory response that is vital to the process of placentation, from implantation through to labor at term [20]. Maternal obesity and GDM have been associated with changes in placental nutrient transporter expression and activity [21], [22]. These changes in placental function may be caused by altered inflammatory profiles in the mother, placenta and fetus in obesity and GDM, leading to the co-morbidities observed in these pregnancies [23], [24]. This article summarizes the literature reporting inflammatory profiles in the maternal, placental and fetal compartments in association to maternal obesity and GDM. Unless otherwise stated, we have focused specifically on studies documenting inflammation in women. While vascular and endothelial changes, oxidative stress, and tissue damage do occur in response to inflammation, we have focused on primary changes in inflammatory mediators and immune cells and pathways in obese pregnancies and GDM. A better understanding of how maternal obesity and metainflammation relates to the fetal intrauterine environment may lead to the development of better therapeutic interventions to prevent the development of metabolic disorders in later life.
Section snippets
Metainflammation, obesity and insulin resistance in the non-pregnant state
The acute inflammatory response induced by infection or trauma is typically a rapid response, characterized by vasodilation, infiltration of tissue by neutrophils, accumulation of macrophages and lymphocytes, and resolution. Acute inflammation is also characterized by an increased basal metabolic rate due to the focused and rapid response to the insult. Once the insult is neutralized, inflammation subsides. Inflammation induced by obesity in non-pregnant individuals is distinct from the
Maternal inflammation
Pregnancy itself is characterized by an altered inflammatory profile compared to the non-pregnant state. A tightly regulated balance between pro- and anti-inflammatory cytokines may be necessary for normal implantation, trophoblast invasion and placentation. A pro-inflammatory response localized to the uterine site of implantation may be necessary for this process [32]. In contrast, the post-implantation period is associated with an ‘immunosuppressive’ bias towards producing Th2 cytokines,
The placenta as an inflammatory organ: not just a silent observer
It is well established that placental cytokine production is critical for the maintenance of pregnancy. Cytotrophoblasts, syncytiotrophoblast and Hofbauer cells are known to secrete cytokines necessary at various stages of pregnancy from implantation to delivery [20]. It has been suggested that the placenta plays an active role in mediating inflammation in women with obesity and GDM. Placental structure and function may be altered in an adaptive response to obesity, and the placenta may act as
Inflammation and developmental programming
Inflammatory mediators may act in utero to program fetal adipose tissue, liver and skeletal muscle for insulin resistance later in life. Because it is not possible to examine fetal and neonatal tissues in humans, animal models have been utilized to investigate inflammation in specific tissues in offspring of obese dams. Maternal obesity is associated with adipogenesis, increased adiposity and insulin resistance in fetal tissues in several animal models [71]. In one study, activation of the
Conclusions and future directions
In conclusion, metainflammation, or chronic, low-grade metabolically induced inflammation may play a role in maternal obesity and GDM, leading to developmental programming in utero. The maternal inflammatory profile associated with GDM may be more pronounced than in obese women pregnant women without GDM. Studies investigating inflammatory mediators in the maternal, placental and fetal compartments in obesity and GDM are not always concordant. There is insufficient evidence that maternal
Conflict of interest
None.
Acknowledgements
This work was funded by NIH grant DK89989 to TLP.
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