Key words obesity - pregnancy - adipose tissue - perinatal programming - prevention
Schlüsselwörter Adipositas - Schwangerschaft - Fettgewebe - perinatale Programmierung - Prävention
Introduction
The prevalence of overweight and obesity has risen dramatically in the past 20 years also including women of child-bearing age. According to the German National Consumption Study, in 2005 and 2006 29 % of 20 to 29-year-old German women were overweight and 8.7 % were obese. In women of 30 to 39 years even 35.3 % were overweight and in addition, 14.3 % were obese [1 ]. There is still an increasing trend representing a challenge for future generations.
Overweight and obesity have an impact on a variety of physiological changes and molecular biological processes during pregnancy. In Part 1 of our two publications we concentrate on the pathophysiological and molecular mechanisms of a high BMI and its effects on maternal metabolism and epigenetic effects on the fetus. We have to be aware of the associated short and long-term risks.
In Part 2, we evaluate evidence-based studies and international guidelines to document steps in diagnosis, prevention and risk reduction. The WHO-classification of overweight and obesity is explained in Part 2, Tab. 2. Experimental and epidemiological data may complement each other and reflect the reality.
Overweight and Obesity during Pregnancy
Overweight and Obesity during Pregnancy
Pregnancy, overweight and obesity all cause increased insulin resistance, an initial hyperinsulinism and a reduced insulin secretion by pancreatic beta cells, leading to type-2 diabetes (T2D) [2 ], [3 ]. In pregnancy, mild changes may be physiologic [4 ]. In overweight and obese pregnant women there is a high risk that physiological changes turn into a pathological condition of gestational diabetes (GDM) [5 ]. In observational studies, a close correlation was found between
overweight (BMI 25–29.9 kg/m2 ) or obesity (BMI ≥ 30 kg/m2 ) and the risk of GDM [6 ], [7 ]. GDM is present in only 2.3 % of pregnant women within a BMI between 18.5 and 24.9 kg/m2 , but in 9.5 % of obese patients [8 ]. A meta-analysis found a 3.76-fold increased risk for GDM in obese compared to non-obese pregnant women, with an 0.82 % increase in prevalence per BMI-gain of 1 kg/m2
[9 ].
Insulin resistance in obesity has been related to (pro-)inflammatory processes and subclinical inflammation [10 ], [11 ]. These are associated with vascular dysfunction, explaining the increased risk of pre-eclampsia in obese pregnant women [12 ], [13 ], [14 ].
Molecular Biological Mechanisms
Molecular Biological Mechanisms
The molecular basis of endocrine changes is explained by the fact that adipose tissue stores triglycerides and represents a metabolically highly-active tissue [15 ], [16 ], [17 ], [18 ], [19 ], [20 ]. An increase in adipose tissue is associated with an inflammatory reaction inducing insulin resistance and cardiovascular disorders [18 ] ([Fig. 1 ]).
Fig. 1 Adipokines, obesity and risk factors. Fatty acids are stored as triglycerides (TG) by adipocytes. Hypertrophy of adipocytes results in obesity. This increases secretion of monocyte chemotactic protein 1 (MCP-1) and an accumulation of macrophages leading to a pro-inflammatory status with an increase in adipokines secreted by macrophages (TNF-α, IL-6 and -1). Chronic inflammation with high ectopic levels of muscular lipids, disruptions in mitochondrial β-oxidation and insulin-stimulated glucose transportation are the consequence. Adipokines increase the
production of endothelial adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1) and of C-reactive protein (hs CRP) contributing to endothelial dysfunction and atherosclerosis (modified in accordance with [18 ]).
Adipose tissue consists of adipocytes (fat cells) and connective tissue stroma cells, which include endothelial cells, fibroblasts and haematopoetic cells. Immature adipose tissue develops in the fetus between 14 and 16 gestational weeks. Pre-adipocytes gradually differentiate from mesenchymal cell clusters, developing into fat lobules with characteristic lipid vacuoles in the cytoplasm. These fat lobules are surrounded by dense septae of perilobular mesenchymal tissue [21 ], [22 ].
Fetal adipose tissue starts to be visible in the head and throat, and later as part of the fetal body and the upper and lower extremities [23 ]. At around 28 gestational weeks, the adipose tissue formation is completed including the number of fat lobules. Thereafter, adipose lobules increase in size (hypertrophy). However, if obesity during childhood develops, even the number of fat cells (hyperplasia) may increase [24 ]. Only in extreme obesity during adulthood, the number of fat cells may still increase [25 ].
Two types of adipose tissue can be differentiated: white and brown adipose tissue, which have specific functions in fat storage, metabolic activity and thermogenesis respectively [26 ]. In humans, visceral (VAT) and subcutaneous adipose tissue (SAT) are formed. The VAT plays a key role in the development of a metabolic syndrome [16 ], [17 ], [21 ], [27 ].
In 1993, Hotamisligil et al. demonstrated that fat cells in the adipose tissue of mice produce tumour necrosis factor (TNF)-alpha and that obese mice have a greater TNF-alpha expression and higher TNF-alpha levels [28 ]. They also discovered the association between the TNF-alpha production in adipose tissue and insulin resistance. Only one year later, leptin, the product of the ob gene, was identified as the main secreted product of adipose tissue [15 ]. Excessive TNF-alpha production in human obesity leads to a subclinical
inflammation; leptin regulates metabolic processes [29 ], [30 ]. Additionally, signalling cascades of the cellular metabolism are functionally disturbed. Anti-inflammatory cytokines such as adiponectin which, paradoxically, is reduced in obesity, and interleukin (IL)-10 are produced in the VAT [16 ], [31 ], [32 ]. In obesity, adipokines and their receptors are upregulated rather in the VAT than in the SAT [33 ], [34 ] which explains that excessive VAT is more closely associated with a metabolic syndrome than excessive SAT [35 ]. Adipokines from the VAT are directly absorbed by the liver via drainage through the portal veins. Thereby, the VAT has a direct impact on hepatic glucose homeostasis and insulin sensitivity [36 ]. Pro-inflammatory cytokines in adipose tissue are positively correlated with liver fat content and systemic arterial dysfunction and negatively correlated with insulin sensitivity [37 ], [38 ].
TNF alpha, IL-6, IL-10, leptin and adiponectin are part of more than 50 different “adipokines”, peptides which are produced from the white adipose tissue. They circulate in the maternal blood and play an important role in obesity-specific morbidity [16 ], [17 ], [28 ], [31 ], [39 ] ([Table 1 ]).
Table 1 Physiological and pathophysiological effects of selected adipokines [16 ], [18 ], [39 ]).
TNF-alpha
Inflammation, apoptosis, impact on insulin resistance, stimulation of endothelial dysfunction and atherogenesis
IL-6
Inflammation, immune regulation (modulation of the insulin receptor), insulin resistance, atherogenesis
Adiponectin
Stimulation of insulin secretion, increase in insulin sensitivity, stimulation of glucose uptake in the muscle, inflammation reduction, plasma lipid reduction, atheroprotective effect
Leptin
Saturation, increase in energy utilization, weight control, modulation of insulin sensitivity, reduction of insulin secretion, angiogenesis
The placenta produces adipokines similar to the white adipose tissue, only lacking adiponectin, a marker for increased insulin sensitivity [40 ], [41 ]. Challier et al. [42 ] demonstrated that the number of CD14+ and CD68+ macrophages in the placenta of obese women was three-fold increased compared to normal weight women. These macrophages produce pro-inflammatory cytokines as TNF-alpha and IL-6. Local inflammatory changes in obese pregnant women are also reflected in increased plasma concentrations of
C-reactive peptide (CrP) and IL-6. Interestingly, the CD14+ macrophages were of a maternal but not fetal origin [43 ].
Up to now few studies have investigated the effect of overweight and obesity on inflammation during pregnancy. Ramsay et al. [13 ] found higher serum concentrations of leptin, CrP and IL-6 in obese compared to normal weight women. These circulating pro-inflammatory cytokines were also correlated to higher levels of TNF-alpha- and IL-6-mRNA produced by maternal peripheral mononuclear cells [42 ]. However, the invasion of macrophages into the VAT have up to now only been demonstrated in non-pregnant obese adults [44 ], [45 ]. In obese baboons, Farley et al. demonstrated a marked macrophage infiltration into the adipose tissue [46 ]. With increasing degree of obesity macrophages increasingly produce transcription factors, adipokines and inflammatory molecules [47 ] which also results in insulin resistance [44 ].
Visceral obesity associated with glucose intolerance and insulin resistance [13 ], [48 ], may lead to GDM in obese women [20 ]. Unfortunately, there is a paucity of research related to biochemical pathways of GDM in pregnant women. According to Kirwan et al. [49 ] TNF-alpha levels in normal weight pregnant women can predict insulin resistance during later stages of pregnancy. Disturbances in the insulin signalling cascade in obese pregnant women with normal glucose tolerance
could be demonstrated in both the adipose tissue as well as in the skeletal muscle [50 ]. The negative effects of overweight and obesity become more obvious in glucose intolerance and insulin resistance [21 ], [51 ], [52 ]. The inflammatory processes are closely related to the prevalence of pregnancy-induced hypertension or pre-eclampsia in obese pregnant women [53 ].
Maternal obesity associated with GDM and hypertension is thus related to an inflammatory reaction in the white adipose tissue, in the plasma and the placenta. This “pro-inflammatory state” is supposed to be the primary mechanism underlying the insulin resistance and hypertension in obese pregnant women [20 ].
Perinatal Programming of Overweight and Obesity
Perinatal Programming of Overweight and Obesity
“Perinatal programming” has meanwhile been established as a field of research for dealing with the impact of the intrauterine and early postnatal environment on fundamental mechanisms of health and disease [54 ], [55 ], [56 ], [57 ], [58 ], [59 ] ([Fig. 2 ]). The main focus is the phenomenon of an epigenetic, maternal-fetal transmission of acquired conditions.
Fig. 2 Pathogenetic mechanisms, and consequences of perinatal malprogramming. Aetiology of pre- and neonatal overfeeding and hyperinsulinism for excessive weight gain, overweight/obesity, type-2 diabetes mellitus and subsequent cardiovascular diseases in later life (modified in accordance with [58 ]).
Results from epidemiological, clinical and animal experimental studies indicate the impact of nutrition during the pre-natal and early post-natal development and its impact on the occurrence of overweight, obesity, T2D and cardiovascular diseases in later life [60 ], [61 ]. The metabolic state during pregnancy and the kind of nutrition in the neonatal period (e.g. breast-feeding and its long-term effect) may both have negative or positive sequelae for the growing child up to adulthood [62 ], [63 ], [64 ], [65 ].
Günter Dörner at Charité postulated in the 1970s that T2D is “transmitted” more frequently from the maternal line than from the paternal line [66 ]. He developed the concept of “perinatal programming” and established a “functional teratology” [67 ]. In the 1990s the groups of Hales and Barker described the concept of “prenatal origin of adult disease” in growth-retarded fetuses and newborns [68 ].
Apart from genetic factors, maternal diet and nutritional status during pregnancy have a critical impact on intrauterine growth and birthweight. In developed countries, overall birthweight increased by 126 g during the last 20 to 30 years. Accordingly, the rate of macrosomia rose by 25 % per decade [69 ], [70 ], [71 ], [72 ] whereby epigenetic causes are supposed to be the underlying mechanism.
The risk of macrosomia (birthweight > 4000 g) is more than doubled or even tripled in children of obese or morbid obese women [73 ], and mainly combined with excessive weight gain [69 ], [76 ]. In Part 2, we explain the clinical consequences and complications [74 ]. Regardless of the pre-conceptional weight, maternal weight gain during pregnancy positively correlates with the birthweight [69 ], [75 ].
Epidemiological studies showed a positive correlation between birthweight and the body weight in adulthood signifying that maternal obesity-related fetal macrosomia is associated with obesity in later life [77 ], [78 ]. A meta-analysis of a total of 643 902 individuals between 1 and 75 years of age from 26 countries revealed a positive linear connection between birth weight and the later overweight in 59/66 (89.4 %) of studies. In four of the studies (6.1 %), no correlation was observed. In three studies (4.5 %) a U-shaped
relation was described, i.e. a similar risk increase in low and high birth weight. However, no linear inverse relation was described. Based on adjusted estimation, it was shown that the risk of overweight in later life in children with high birth weight was almost doubled (OR 1.96, 95 % CI 1.43–2.67) compared to children of normal birthweight (2500–4000 g) [78 ].
A meta-analysis on the correlation between birth weight and the subsequent risk of T2D accordingly revealed a U-shaped relation in all published studies explaining that children with low birth and high birth weight exhibit an increased risk for T2D in later life [79 ].
It seems to be a vicious circle that obesity during pregnancy causes maternal GDM and an increased birth weight and obesity in the offspring who then develop associated diabetic metabolic disorders, e.g., GDM in females [80 ], [81 ], [82 ], [83 ], [84 ].
Similarly, animal studies showed that not only maternal overweight and obesity but also the nutrition during pregnancy have an impact on the offspring: Pregnant female Japanese macaques that received either a high-fat (35 % fat) or a normal diet (13 % fat) during pregnancy showed differences in the juvenile microbiome of the gastro-intestinal tract during the first year of life [85 ]. Campylobacter was not detectable in the juvenile microbiome after the high-fat-diet. These changes were very stable and could not even be corrected postnatally by a normal
diet.
Maternal obesity and a high-fat diet during pregnancy seem to lead to a malprogramming of the hepatic fatty acid metabolism resulting in upregulated lipogenesis and obesity in the offspring which is indicated by an increased desaturation index (DI), e.g. a ratio of unsaturated (C16 and C18) versus saturated fatty acids. Rats that either received a high-fat or a normal diet did not differ in birth weight, however showed a reduced DI in the offspring of obese rats [86 ]. At the age of six months, the male offspring were significantly heavier (800 vs.
659 g), more obese (26 vs. 20 %) and showed an increased DI in the plasma (0.1 vs. 0.06) and in the liver (0.09 vs. 0.06). A high-fat diet during pregnancy initially suppresses the DI of the newborns but subsequently upregulates the DI despite a normal postnatal diet. Bytautiene et al. demonstrated significantly shorter telomeres and a reduced expression of the Klotho gene in the female and male offspring of obese mice in comparison to normal weight mice, which is a surrogate parameter of an accelerated ageing process [87 ]. A dysfunctional VAT
in the offspring of obese mice was described by the same group [88 ]. Obesity before conception was generated by a high-fat diet. The offspring received a normal diet until the age of six months. A reduced expression of the hypoxia-inducible factor 1 alpha (HIF-1 α) and of the angiotensin 2 receptor as well as an increased expression of angiotensin (ANG) were found in the VAT of the offspring of obese mice. These alterations may disturb developmental cascades leading to fetal programmed hypertension and a metabolic syndrome in later life even in
following generations.
Perinatal mal-programming may also involve the central nervous regulatory centres of metabolism and body weight control. Thus, maternal overweight and/or maternal diabetes (hyperglycaemia) during pregnancy and early postnatal overnutrition lead to increased insulin, glucose, protein and/or leptin levels during critical development stages (e.g. fetal hyperinsulinism). Malprogramming via epigenetic mechanisms results in a life-long disposition for overweight, obesity and diabetic metabolic disorders across generations [54 ], [58 ], [63 ], [89 ], [90 ].
Epigenetic mechanisms are DNA-methylation, the modification of histones and the regulation of microRNAs. Methylation of cytidine bases in cytosine-guanosine nucleotide dimers (CpG) (DNA methylation) has been investigated [91 ]. Highly-methylated DNA (especially the so-called promoter regions) reduces the gene expression [91 ]. Only a few studies have investigated the contribution of epigenetic mechanisms to fetal metabolic programming on a molecular level [92 ], [93 ], [94 ], [95 ], [96 ]. In placentas of women with gestational diabetes, modifications in the methylation of the leptin and adiponectin genes (LEP and ADIPOQ ) have been found. LEP and ADIPOQ are classified as candidate genes for obesity and GDM [93 ], [96 ]. Furthermore, it was shown that total methylation in the placentas of obese women is significantly higher than in normal-weight women [97 ]. These
changes have lasting effects on the regulation of the metabolism of the offspring if they reflect DNA methylation in other tissues, thus triggering the development of chronic metabolic disorders.
In maternal obesity without glucose intolerance the microRNA expression remains unchanged. In a study on 16 obese and 20 normal-weight pregnant women, with a normal glucose tolerance, the microRNA expression in the umbilical cord blood did not differ significantly [98 ]. The authors concluded that in fetal programming other mechanisms are more relevant.
Future prevention should start before conception to avoid maternal obesity, GDM, and the epigenetic modifications. In pregnant rats it was demonstrated that an exercise programme during pregnancy could have positive effects on the metabolic phenotype of the offspring [99 ]. The percentage of fat-free body mass in the male offspring was increased and the fat mass reduced. Interventions and longitudinal studies might help to detect whether we can also modify epigenetics and perinatal programming of GDM, overweight or obesity.
Conclusions
Overweight and obesity lead to an increase in maternal and perinatal morbidity and mortality. The molecular biological mechanisms as gestational diabetes or metabolic syndrome, have not yet been sufficiently investigated. Local and systemic inflammatory processes, triggered by the adipose tissue, seem to play a key role. Despite the increasing prevalence of overweight and obesity in pregnant women in Western countries including Germany, clinical research on mechanisms and interventions are scarce although the diagnosis is easy. Further investigations of the biology of adipose
tissue and its association with insulin resistance, the formation of adipokines and endothelial dysfunction are necessary.
Primary prevention programmes have to be implemented. Avoiding overweight and obesity in childhood and adolescence and appropriate weight gain during pregnancy [100 ] are essential. Educational programs prior to conception are important. The promotion of breast-feeding for newborns should also be considered.
