Abstract
Maternal obesity increases the risk of health complications in both the mother and the infant. In turn, the offspring of obese mothers are inclined to develop obesity, cardiovascular disease, and type 2 diabetes as adults, establishing a vicious cycle of metabolic disease. Obese mothers exhibit dyslipidemia, inflammation, and insulin resistance, factors which can negatively influence fetal development via effects on placental function. Optimal nutrient delivery to the fetus is a critical function of the placenta, and impairments in this process may modulate fetal growth and/or compromise fetal tissue development. Additionally, nutrients, in particular fatty acids, function as bioactive molecules to alter placental inflammatory status. Recent findings demonstrate increased posttranslational processing of IL-1β by an inflammatory process known as the inflammasome, in placentas of obese mothers. Inflammasome activation results in caspase-1-mediated maturation of IL-1β prior to cellular release. High circulating levels of saturated fatty acids activate and polyunsaturated fatty acids inhibit the inflammasome. In addition to its role as an immunogenic molecule, IL-1β impairs placental insulin signaling and function, thereby altering the metabolic function of the placenta. Hence placental inflammasomes may represent one of the key inflammatory mechanisms linking maternal nutrient excess to aberrant placental function and fetal development.
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Keywords
- Gestational Diabetes
- Fetal Growth Restriction
- Inflammasome Activation
- Maternal Obesity
- Placental Function
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
1 Introduction
In the United States, over two-thirds of women of reproductive age have a high body mass index (BMI >25 kg/m2), and more than one-third are obese (BMI >30 kg/m2) [1]. Maternal obesity represents significant health risks for both mother and child. Pregnant mothers who are obese have an increased risk of developing hypertension, preeclampsia, and gestational diabetes. Infants born to obese and gestational diabetic mothers are likely to have greater adiposity, elevated levels of proinflammatory cytokines, and insulin resistance [2]. Children of obese mothers are susceptible to childhood obesity and to develop cardiovascular disease, type 2 diabetes, and obesity as adults [3]. Animal models and clinical studies suggest that the intrauterine environment plays a critical role in mediating the adverse effects of maternal obesity on the offspring and therefore offers a unique window of opportunity for intervention. However, few strategies are currently available for the prevention of obesity or metabolic dysfunction in children of obese mothers. Recent studies demonstrate that children born to women who had undergone bariatric surgery and weight loss had a lower prevalence of obesity compared to their siblings born before surgical weight loss [4]. Although bariatric surgery is limited to morbidly obese patients, this finding establishes the importance of the maternal metabolic environment on the in utero transmission of obesity to the next generation.
In the past decade, the search for potentially unifying mechanisms underlying the pathogenesis of obesity-associated diseases has revealed a surprisingly close relationship between signaling pathways regulating cellular immune response and metabolic homeostasis. This has given rise to the concept of “metaflammation” (metabolically induced inflammation) which refers to a distinct set of inflammatory responses principally triggered by nutrients and metabolites [5]. In contrast to the acute innate immune response induced by microbial stimuli, metaflammation is characterized by multisystemic chronic low-grade inflammation leading to insulin resistance in several tissues including the adipose, liver, and muscle [6]. While pregnancy itself represents a physiologic inflammatory state, women entering pregnancy with preexisting obesity exhibit enhanced systemic inflammation associated with peripheral insulin resistance [7], which may lead to the development of gestational diabetes. In recent years, placental inflammation has emerged as a common observation in these pregnancy disorders [8–12], although the mechanisms regulating placental inflammatory processes in maternal obesity have been a matter for debate [8, 10, 11].
The human placenta is the direct interface between maternal and fetal circulations. The placenta performs many indispensable tasks including hormone production, nutrient transfer, and gas exchange. Optimal placental function is thus paramount to support the growth and development of a healthy infant. Maternal diet and disease can influence placental development and function, leading to changes in the supply of nutrients, hormones, and oxygen to the fetus. The placenta therefore plays a central role in determining the impact of maternal obesity on fetal development and the long-term health of the infant. Clinical studies now indicate that maternal obesity is associated with changes in placental function [13–17]. In particular, placental circulation [17, 18], nutrient transporters [13, 19, 20], and metabolic function [14, 15] have been reported to be influenced by maternal adiposity. Whether these changes are associated with or caused by placental inflammatory processes is currently unclear.
2 Inflammatory Mechanisms Involved in Metabolic Disorders
All tissues possess inflammatory mechanisms which mediate a highly coordinated homeostatic response to harmful stimuli. The short-term adaptive inflammatory response is a crucial component of tissue repair involving the integration of multiple signals in distinct cells and tissues. However, if left unresolved, long-term inflammation may result in permanent organ damage. The chronic nature of obesity produces low-grade inflammation that disrupts metabolic homeostasis over time. An adverse in utero environment may place individuals at risk of lifelong metaflammation predisposing the infant to the development of metabolic syndrome in later life.
Insulin resistance is a hallmark of the metabolic syndrome, occurring as a result of decreased insulin sensitivity in the adipose, liver, and muscle. To maintain homeostasis, insulin secretion from pancreatic β-cells is increased. Over time, β-cells may fail to meet the increasing demand for insulin, resulting in hyperglycemia and diabetes. A link between inflammation and insulin resistance was first established by the demonstration that TNFα knockout mice were protected against obesity-induced insulin resistance [21]. Compared to wild-type obese mice, TNFα-null obese mice exhibited increased insulin signaling in adipose and muscle tissues, improved glucose metabolism, and reduced circulating levels of free fatty acids. Indeed, TNFα levels during pregnancy predicted maternal insulin resistance even in euglycemic women [22], and a proinflammatory maternal milieu is associated with a number of pregnancy disorders.
Inflammation is initiated by cytokines and pathogen-associated molecular patterns (PAMPs), such as carbohydrates, lipoproteins, and lipopolysaccharide components of bacterial and fungal cell walls, that stimulate plasma membrane-bound cytokine receptors or toll-like receptors (TLR) to initiate an inflammatory signaling cascade. These signaling pathways in turn activate transcription factors which drive the expression of genes which collectively assist in the recruitment and activation of immune cells and removal of pathogens and accelerate tissue repair. In recent years, TLR4 has emerged as a sensor for both microbial products and nutrients. The archetypal TLR4 agonist is lipopolysaccharide (LPS), a component of Gram-negative bacteria cell wall. Interestingly, saturated fatty acids (SFAs) acylated in the lipid A moiety of LPS were sufficient to invoke TLR4-mediated biological effects [23], implicating a role for circulating fatty acids in the inflammatory response. The effect of fatty acids on TLR4 activity depends on chain length and saturation [24]. Saturated fatty acids such as palmitic (C16:0) and stearic (C18:0) acid promote TLR4-mediated inflammatory response, whereas the omega-3 polyunsaturated fatty acid (n-3 PUFA) docosahexaenoic acid (C22:6) attenuates TLR4 signaling. Additionally, TLR4 is activated by other endogenous molecules especially in response to stress. Otherwise known as danger-associated molecular patterns (DAMPs), these endogenous TLR4 agonists include heat shock proteins, oxidized lipids and sterols, and breakdown products of the extracellular matrix [25–27].
TLR4 activates two major signaling pathways, the mitogen-associated protein kinase (MAPK) pathways (p38 MAPK and c-Jun N-terminal kinases (JNK)) and nuclear factor kappa B (NF-κB). Activation of JNK results in nuclear translocation where it regulates the activity of activating protein-1 (AP-1), a heterodimeric protein composed of multiple transcription factors belonging to c-Fos, c-Jun, ATF, and JDP families that regulate a vast array of genes. Conversely, NF-κB activation results in nuclear translocation of one of its five subunits which directly controls gene transcription. Moreover, reports of AP-1 regulation of NF-κB and vice versa suggest significant crosstalk between these signaling pathways [28, 29]. Collectively, activation of these signaling pathways results in increased transcription of cytokines, such as IL-6, IL-1β, and TNFα, which inhibit insulin signaling in many tissues. Research in the last decade provides significant evidence for the involvement of these pathways in the initiation, propagation, and development of metabolic diseases [30, 31]. Figure 6.1 illustrates an overview of the major inflammatory mechanisms implicated in metabolic disorders.
3 Placental Inflammation in Maternal Obesity
While there have been numerous animal models of maternal obesity in pregnancy demonstrating placental inflammation [18, 32–34], we have limited our discussion to human studies. Several studies show increased expression of proinflammatory cytokines IL-6, IL-1β, and TNFα in placental tissues of obese mothers [8, 10–12]. The mechanism(s) of placental inflammation in maternal obesity, however, has been a source of contention. Analogous to adipose tissues, increased accumulation of maternal macrophages in placentas of obese mothers has been reported by some investigators [9, 10], while others were unable to show any differences [11]. Similarly, Saben et al. have implicated placental JNK and NF-κB with maternal obesity [12, 35], while we could not find any changes in these pathways, but discovered increased STAT3 and p38 MAPK activity in placentas of obese mothers [8]. One possible explanation for these differences may be related to subject selection, since maternal obesity is also associated with several comorbidities including hypertension and gestational diabetes, conditions potentially more likely to invoke a greater multisystemic inflammatory response than obesity per se.
While activation of placental inflammatory processes in maternal obesity has been described [8, 12, 35, 36], the physiological significance of placental inflammation has not been addressed in adequate detail. Inflammation of the fetal membranes (chorioamnionitis) is a major risk factor for preterm birth, which may result in premature rupture of the membranes (PROM). Recent epidemiological studies demonstrate increased risk of preterm deliveries in obese mothers [37, 38]. However, it is currently unclear if placental inflammation associated with maternal obesity increases the risk of PROM. Systemic or placental inflammation may also result in endothelial dysfunction. Pre-gravid obesity increases maternal levels of markers of endothelial dysfunction [39] and is associated with impaired vascular function in placental arteries [17]. Consequently, this may impact upon fetal heart development, because uteroplacental circulation has been linked with fetal vascular function [40].
Previous work from our lab demonstrated that proinflammatory cytokines influence placental nutrient transport functions [41, 42]. Using concentrations similar to circulating cytokine concentrations in obese women, IL-6 and TNFα were shown to stimulate amino acid transport activity [41], while higher concentrations were required to stimulate fatty acid uptake into primary trophoblasts [42]. STAT3 activity was required for IL-6 (and leptin)-stimulated amino acid uptake [41, 43], while our preliminary data suggests a role for p38 MAPK in regulating the TNFα response (Aye et al, 2015 unpublished observations). In addition to cytokines, insulin and leptin (hormones elevated in maternal obesity) also significantly increase placental amino acid transport [44, 45]. Interestingly, IL-1β which is also upregulated in the placentas of obese mothers [8, 10, 11] was shown to inhibit insulin-dependent [46] and insulin-independent [47, 48] amino acid transport in placental primary trophoblasts and trophoblast cell lines. These findings suggest complex interactions between proinflammatory cytokines and maternal hormones in the regulation of placental nutrient transfer to the fetus.
4 The Emerging Role of Placental Inflammasomes in Pregnancy Disorders
Inflammasomes are multi-protein complexes composed of a cytoplasmic receptor, an apoptosis-associated speck-like protein (ASC) containing a caspase activation and recruitment domain (CARD) adaptor, and pro-caspase-1, which associate upon cellular exposure to microbial or endogenous danger signals. Upon activation, the inflammasome complex formation results in caspase-1 maturation leading to proteolytic cleavage of pro-IL-1β into mature IL-1β (Fig. 6.2). This is then followed by either secretion of IL-1β into the circulation which may lead to systemic inflammatory effects or more locally induced pyroptosis. Currently, six members of the nod-like receptor (NLR) family are known to function as “pathogen” or “danger” sensors to initiate inflammasome complex formation. Of these, NLRP3 is best characterized for its role in both immune and metabolic disorders.
The placenta expresses the cytosolic NLRP1, NLRP3, and NLRC4 [49], which respond to multiple factors associated with both pathogenic and sterile inflammation. Activation of inflammasomes in gestational tissues has been reported in a number of pregnancy complications including preterm birth [50–52], preeclampsia [53–55], and microbial infections [56]. The resulting release of mature IL-1β mediates a myriad of effects in gestational tissues including induction of IGFBP-1 expression in decidual tissues thereby decreasing the bioavailability of IGF-I in the feto-maternal interface and in the maternal circulation [57] and stimulating placental production of progesterone [58], hCG [59], and activin-A [60]. Furthermore, IL-1β is a highly apoptotic agent in human gestational tissues [61]. Hence knowledge of the mechanisms governing IL-1β production in the placenta plays a critical role in understanding the pathogenesis of several pregnancy disorders.
We recently identified increased caspase-1 activation in placentas of women with high BMI ([62] and Fig. 6.2), despite no changes in placental NF-κB DNA-binding activity. Likewise, expression of the mature IL-1β protein (17 kDa) in placental tissues was also positively correlated with maternal BMI, whereas pro-IL-1β (32 kDa) was not significantly altered by maternal BMI. These findings indicate a novel mechanism in which IL-1β is regulated at the posttranslational level by maternal obesity. We further determined the impact of IL-1β on placental function and demonstrated that IL-1β inhibits insulin signaling and function (as measured by insulin-mediated amino acid transport) in primary human trophoblasts [46]. Inhibition of insulin signaling was mediated at the level of the insulin receptor substrate-1 (IRS-1), where IL-1β increased the inhibitory serine phosphorylation of IRS-1 (Ser307), decreased tyrosine phosphorylation-mediated activation of IRS-1 (Tyr612), and reduced total IRS-1 levels. Decreased IRS-1 activity led to inactivation of both the PI3K and GRB2 signaling pathways downstream of IRS-1. Taken together, these findings suggest that the increased inflammasome activation in placentas of high BMI mothers may lead to decreased placental insulin sensitivity. However, the signals activating inflammasomes in these placentas are currently unclear.
Because the classical inflammatory pathways associated with the microbial response (namely, NF-κB and JNK) were not altered in the placenta in pregnancies complicated by maternal obesity, we hypothesized that placental inflammasome activation is a result of DAMPs or nutritional and/or oxidative stress. Robust activation of the inflammasomes requires two signals: a first “priming” signal, which promotes NF-κB activity leading to pro-IL-1β expression, and a second “activating” signal that activates caspase-1. In the placenta, constitutive NF-κB activity is likely to contribute to pro-IL-1β expression, whereas caspase-1 activation requires a specific event. DAMPs including cholesterol crystals, ATP, potassium efflux, and ceramide initiate caspase-1 maturation in many cell types [63]. However, it is currently unclear if DAMPs provide the mechanistic link to placental inflammasome activation because these factors have not been implicated in maternal obesity. On the other hand, maternal obesity is associated with oxidative stress, which may provide the necessary signal required for caspase-1 activation [12, 14, 64]. Dietary SFAs activate inflammasomes in a cell-specific manner [65, 66]. In immune cells palmitic acid, but not oleic acid, triggered inflammasome activation [67]. In contrast, both these saturated fatty acids increased caspase-1 activity and IL-1β maturation in cultured primary human trophoblast cells (Fig. 6.2). This discrepancy is particularly relevant in pregnancy because obese mothers typically have high circulating levels of SFA, especially palmitic acid and monounsaturated fatty acid (MUFA) such as oleic acid [68]. Interestingly, both palmitic and oleic acids are capable of activating TLR4 [35, 69], suggesting that these fatty acids stimulate both the necessary pathways required for robust inflammasome activation. Moreover, most Western diets have low levels of long-chain n-3 PUFA – in particular docosahexaenoic acid (DHA) [70], which has previously been shown to prevent inflammasome activation in macrophages [71–73]. Consistent with these reports, our preliminary data demonstrates that DHA decreases (pro-)caspase-1 expression thereby attenuating IL-1β maturation (Fig. 6.2). The high dietary SFA and MUFA combined with low n-3 PUFA may therefore favor inflammasome activation in the placentas of high BMI mothers (Fig. 6.3).
The clinical significance of increased inflammasome activation leading to IL-1β-mediated insulin resistance in the placenta may be substantial. Although, increased placental amino acid transport activity has been reported in obese [13] or diabetic mothers [74], other studies demonstrate either no changes [75] or reduced transport activity [76, 77]. The discrepancy between these reports may be due to the inflammatory status of these placentas. It is possible that an increased placental inflammatory response associated with maternal obesity [8, 10–12, 35] or diabetes [78–81] may limit placental insulin-mediated transport, featuring an adaptive mechanism to limit excessive fetal growth in the presence of maternal hyperinsulinemia. Providing circumstantial support for this concept are reports demonstrating that the inflammatory processes associated with fetal growth restriction also inhibit placental transport activity in pregnancies complicated by malaria, a condition which increases the risk of fetal growth restriction [48].
Glyburide is a sulfonylurea agent which stimulates insulin release in the pancreas. The use of glyburide in the management of gestational diabetes has been actively explored, due to its glucose-lowering effects. While generally considered a safe alternative to insulin treatment in gestational diabetes pregnancies [82], a recent meta-analysis demonstrated that glyburide use in pregnancy is associated with increased fetal growth [83]. Although it is currently unclear if the association represents a cause and effect, it is interesting to note that glyburide is a potent inhibitor of inflammasome activation [84]. Hence inhibition of inflammasomes by glyburide may reduce IL-1β maturation, resulting in unrestricted insulin signaling in the placenta. Because insulin stimulates placental amino acid transport [45, 85], this may result in increased nutrient transfer to the fetus. In vitro studies testing this hypothesis will establish a mechanistic link between glyburide use in pregnancy and fetal growth.
5 Conclusions
The incidence of maternal obesity and its comorbidities (diabetes and cardiovascular disease) continues to surge, with major public health ramifications. Maternal obesity not only affects newborn health, but it also impacts the long-term health of the child leading to increased risk of childhood obesity and diabetes. Given all the evidence for the critical role of the in utero environment for lifelong health, understanding the impact of obesity in pregnancy represents a significant challenge, but also an intriguing opportunity to improve the health of future generations. Obesity is associated with the triad of metabolic complications: insulin resistance, dyslipidemia, and inflammation. Studies in recent years have demonstrated intimate links between these metabolic pathways, for example, inflammation causes insulin resistance and dyslipidemia, and dyslipidemia causes inflammation and insulin resistance. Excess nutrients, in particular dietary fatty acids, have emerged as a common instigator of these metabolic complications influencing insulin signaling and inflammatory pathways. As an organ of exchange, the placenta is a critical mediator of fetal health and is highly responsive to maternal health and diet. We recently reported inflammasome activation in the placentas of high BMI mothers, which inhibits placental insulin signaling and nutrient transport function. In vitro data suggests that placental inflammasomes are highly responsive to dietary fatty acids, with SFA and MUFA promoting inflammasome activation and n-3 PUFA inhibiting its activity. Future clinical studies are warranted to determine whether dietary interventions during pregnancy can impact upon infant and placental health by altering placental inflammatory pathways.
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Aye, I.L.M.H., Lager, S., Powell, T.L. (2015). The Role of Placental Inflammasomes in Linking the Adverse Effects of Maternal Obesity on Fetal Development. In: Ferrazzi, E., Sears, B. (eds) Metabolic Syndrome and Complications of Pregnancy. Springer, Cham. https://doi.org/10.1007/978-3-319-16853-1_6
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