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Maternal obesity and prenatal programming
Accepted Manuscript Maternal obesity and prenatal programming Summer Elshenawy, Rebecca Simmons PII:
S0303-7207(16)30233-7
DOI:
10.1016/j.mce.2016.07.002
Reference:
MCE 9555
To appear in:
Molecular and Cellular Endocrinology
Received Date: 28 March 2016 Revised Date:
1 July 2016
Accepted Date: 1 July 2016
Please cite this article as: Elshenawy, S., Simmons, R., Maternal obesity and prenatal programming, Molecular and Cellular Endocrinology (2016), doi: 10.1016/j.mce.2016.07.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Maternal obesity and prenatal programming
Summer Elshenawy, MD1
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Rebecca Simmons, MD2
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Children's Hospital of Philadelphia, 3516 Civic Center Boulevard, Philadelphia, PA 19104, USA Funding: T32(GM008638) NIH/NIGMS Medical Genetics Research Training Grant Correspondence should be addressed to R.A.S ([email protected])
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Perelman School of Medicine at University of Pennsylvania, 421 Curie Boulevard, Philadelphia, PA 19104, USA
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Correspondence should be addressed to R.A.S ([email protected])
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Dr. Rebecca Simmons Hallam Hurt Professor Pediatrics Perelman School of Medicine Children’s Hospital of Philadelphia
ACCEPTED MANUSCRIPT Obesity is a significant and increasing public health concern in the United States and worldwide[1-3]. In 2010 almost one third of adults and 17% of children and adolescents were obese [3]. Obesity in pregnancy is associated with complications that include gestational diabetes, intrauterine growth restriction, infants born large for gestational age, increased caesarian sections and other obstetric interventions, as well as
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miscarriages [4-6]. Understanding obesity on an epidemiologic and molecular level has become an significant area of focus within the scientific community. Particularly important, is the understanding of how maternal obesity may affect the outcomes of offspring from the neonatal period to adulthood. The impact of maternal obesity goes beyond the newborn period; fetal programming during the critical window of pregnancy, can have
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long term detrimental effects on the offspring and future generations [7, 8]. Environmental exposures in utero, including alterations of the nutritional milieu are particularly important during a time of such rapid growth [8].
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The rising prevalence of obesity and its associated comorbidities, [9], has led to a need for a better understanding of the impact of obesity on population health, including an understanding of the impact of maternal obesity on pregnancy and childhood outcomes. This review will aim to describe clinical data as well
Birth weight and Obesity
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as data from animal models, with a focus on fetal programming in the setting of maternal obesity.
Maternal obesity has been linked to macrosomia [10], which is a risk factor for obesity and metabolic syndrome later in life. The variation in fetal growth in the setting of maternal obesity may be related to diet composition or
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vascular factors, and result from differing underlying molecular mechanisms. Epidemiologic studies have shown a trend of increasing maternal obesity with an associated increase in prevalence of infants who were
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born large for gestational age (LGA) [5]. In a systematic review by Yu et al, pre-pregnancy obesity in women correlated with an increased risk of having LGA baby, and increased risk of obesity later in life [11]. A Mendelian randomization study performed by Tyrell et al, established genetic alleles associated with maternal obesity and elevated blood glucose were linked to higher birth weight in the offspring [12]. There is a clearly established link between birth weight and obesity later in life. In the U.S. Growing Up Today Study, a cohort study of over 14,000 adolescents, a 1-kg increment in birth weight in full term infants was associated with an approximately 50% increase in the risk of overweight at ages 9 to14 year [13]. When adjusted for maternal BMI, the increase in risk remained significantly elevated at 30%. A study of Danish military conscripts showed
ACCEPTED MANUSCRIPT that even after controlling for birth length and maternal factors, BMI at ages 18–26 strongly correlated with birth weight [14]. Both paternal and maternal adiposity are correlated with a higher birth weight of the offspring. However, the association is much stronger for the mother compared to the father [15-18] suggesting that the intrauterine environment plays an important role in the later development of obesity. In addition to birth weight,
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several clinical studies have shown a direct relationship between maternal obesity and childhood obesity [15, 19]. In a retrospective cohort study of 8500 low income children in the US, Whitaker et al demonstrated a twofold increase in prevalence of early childhood obesity in children who were born to obese mothers [20]. Smith et al. looked at metabolic features of children born before or after mothers underwent bariatric surgery. They
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found that children born after maternal bariatric surgery had had lower birth weight, lower prevalence of severe obesity adjusted for age and gender, greater insulin sensitivity, improved lipid profile, lower C-reactive protein,
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and leptin and increased ghrelin than offspring born before maternal bariatric surgery [21]. Guenard et al. also looked at offspring before and after bariatric surgery, finding epigenetic changes in genes involved in glucoregulatory, including insulin sensitivity, inflammatory, and vascular disease genes conferring a more favorable cardiometabolic profile in the offspring born after maternal bariatric surgery [22]. Catalano et al specifically discusses that pre-pregnancy obesity has a stronger association with metabolic alterations of the
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fetus, than gestational weight gain. In one study, they showed the maternal pre-pregnancy BMI greater than 30 kg/m2 was associated with increased body fat percentage at age 8. Furthermore, they demonstrated that at age 8, children of obese mothers had higher systolic blood pressures, waist circumference, triglycerides,
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Epigenetics
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insulin resistance and leptin levels [23].
Clinical and epidemiological evidence clearly shows that genetic and environmental factors contribute to the increased susceptibility of humans to obesity and its associated comorbidities; the interplay of these factors is explained by the concept of epigenetics [9]. Epigenetics explains, as Barker describes, “developmental plasticity” in which environment impacts gene expression, particularly during vulnerable times of development [24]. Epigenetics controls differentiation and development of different cell types by modulating chromatin architecture. It is a dynamic process that is influenced by environmental factors. The mechanisms include DNA methylation, histone modification and the presence of noncoding RNAs and microRNAs [7, 9, 25]. The
ACCEPTED MANUSCRIPT epigenetic modifications can lead to stable propagation with transgenerational effects. Although human data is still limited, emerging evidence is uncovering a link between the clinical and molecular findings in the offspring with epigenetic changes in the setting of maternal obesity.
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DNA methylation: DNA methylation is a class of epigenetic regulation, in which a cytosine base is modified by DNA methyltransferase at the C5 position of cytosine, a reaction that is carried out by various members of a single family of enzymes. Approximately 70% of CpG dinucleotides in human DNA are constitutively methylated, whereas most of the unmethylated CpGs are located in CpG islands. CpG islands are CG-rich
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sequences located near coding sequences and they serve as promoters for their associated genes. Approximately half of mammalian genes have CpG islands. The methylation status of CpG islands within
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promoter sequences works as an essential regulatory element by modifying the binding affinity of transcription factors to DNA binding sites. In normal cells, most CpG islands remain unmethylated; however, under circumstances such as oxidative stress, they can become methylated de novo. This aberrant methylation is accompanied by local changes in histone modification and chromatin structure, such that the CpG island and its embedded promoter take on a repressed conformation that is incompatible with gene transcription. It is not
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known why particular CpG islands are susceptible to aberrant methylation. DNA methylation is commonly associated with gene silencing and contributes to X-chromosomal inactivation, genomic imprinting, and transcriptional regulation of tissue-specific genes during cellular differentiation [25]. In the case of maternal
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obesity and fetal programming, differential methylation of retinoid X receptor-α (RXRA) gene in umbilical cord
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tissue, was shown to be associated with childhood fat mass, when adjusted for sex [26].
Histone modifications: In eukaryotes, the nucleosome consists of DNA wrapped around an octameric complex of two molecules of each of the four histones: H2A, H2B, H3, and H4. The amino termini of histones can be modified by acetylation, methylation, sumoylation, phosphorylation, glycosylation, and ADP ribosylation. The most common histone modifications involve acetylation and methylation of lysine residues in the amino termini of H3 and H4. Increased acetylation induces transcription activation, whereas decreased acetylation usually induces transcription repression. Methylation of histones, on the other hand, is associated with both transcription repression and activation. Moreover, lysine residues can be mono-, di-, or trimethylated in vivo,
ACCEPTED MANUSCRIPT providing an additional level of regulation [25]. Histone methylation can influence DNA methylation patterns and vice versa [27]. For example, methylation of lysine 9 on histone 3 (H3) promotes DNA methylation, while CpG methylation stimulates methylation of lysine 9 on H3 [28]. Recent evidence indicates that this reciprocal relationship between histone methylation and DNA methylation might be accomplished by direct interactions
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between histone and DNA methyltransferases [27]. Thus, chromatin modifications induced by adverse stimuli are self-reinforcing and can propagate.
Noncoding RNAs: Noncoding RNAs such as microRNAs (miRNA), small RNAs, and long or large RNAs, play a
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significant role in epigenetic gene regulation and chromosomal dynamics and transcription [29]. With the discovery that most of the eukaryotic genomes are transcribed into RNAs that have no protein-coding potential,
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evidence has emerged of the different regulatory functions of noncoding RNAs. Studies have shown differential expression of miRNAs in the amnion, plasma, and other tissues of obese mothers [30-32]. Yan et al. demonstrated that the offspring of obese pregnant ewes had decreased expression of miRNA let-7g in skeletal muscle, which correlated with increased adipose deposition in skeletal muscle [31]. This demonstrates the role non-coding RNAs may play in regulation of adipogenesis through differential gene expression.
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Carreras-Badosa et al. conducted a study in which plasma circulating miRNAs were measured in normal pregnancies as well as pregnancies complicated by pre-gestational and gestational obesity. In this study 13 circulating miRNAs were differentially expressed in gestational obesity when compared to normal pregnancies,
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many of which are associated with altered metabolism in the mother including weight gain, glucose tolerance, insulin sensitivity, and serum lipid levels. Specific miRNAs were also associated with placental weight and birth
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weight, as well as growth during infancy, after controlling maternal factors [32].
Macronutrient impact on fetal development The adverse effects of maternal obesity on the fetus are likely multifactorial, involving hormonal, inflammatory, and metabolic alterations. Macronutrient intake influenced by maternal diet and body composition likely plays a role in the metabolic conditioning of the fetus in utero. Metabolomic analysis of umbilical cord blood showed that accelerated early childhood weight gain was associated with differential regulation of metabolites related to food and plant component [33]. Furthermore, while there is a physiologic increase in fasting triglycerides
ACCEPTED MANUSCRIPT throughout pregnancy, mothers with higher pre-pregnancy BMIs see a greater increase in fasting triglycerides and free fatty acids, demonstrating alteration in lipid metabolism in the obese mother [34]. DiCianni et al showed maternal fasting triglycerides correlated with birth weight [34]. In a study looking at differential gene expression in maternal obesity, Carty et al found reduced expression of COX7A2 in subcutaneous tissue of
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obese pregnant women at term. COX7A2 is a mitochondrial protein, with key roles in steroidogenesis and oxidative stress regulation and could provide a link between inflammation and obesity-related pregnancy complications [35].
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Maternal obesity and fetal programming has been studied in multiple animal models. Various models evaluate the impact of different types of diet, and may indicate that the macronutrient content of the diet, may impact the
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mechanism of fetal programming. In animal experiments, high fat diet leads to poor glycemic control and increased adiposity in offspring [8, 9]. In a unique study design, Sasson et al performed a reciprocal early twocell embryo transfer between mice fed different diets prior to and during pregnancy. Pre-gestational exposure to high fat diet resulted in growth restricted fetuses and newborn pups but no effect on adult weight, body fat content or leptin levels. They observed differential gene expression of several imprinted genes in the placenta
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of the pre-pregnancy high fat diet animals suggesting an epigenetic alteration in the germ line in the setting of maternal obesity. Gestational exposure to maternal high fat diet (HFD) resulted in increased body fat, elevated leptin levels, and impaired glucose tolerance in offspring. In contrast, the offspring of mothers who were fed a
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HFD during pre-conceptional period and throughout gestation, had significantly higher body fat content, but while the females were not inherently glucose intolerant, the males were. There were many more genes
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differentially expressed in the HFD/HFD group suggesting a compound effect of the pre-conceptional and gestational exposure. Many of the genes that were differentially expressed in the placenta play a role in inflammation [36].
More recently, animal studies have also looked at a “western diet” model, which is high in simple sugars to more closely mimic human diets, which result in alterations in glucose metabolism, increased adiposity, as well as alterations in central appetite regulatory systems in the offspring [9]. Thus variations in different obesogenic diets could explain the variable presentation seen in population studies. In addition to fat, alterations in glucose
ACCEPTED MANUSCRIPT metabolisms in the setting of gestational diabetes and insulin resistance has been studied in the setting of maternal obesity and as a separate entity. Insulin sensitivity is reduced in the pregnant state, and while placental factors may contribute, emerging evidence has implicated other factors such as elevated cytokines, including TNF alpha, and altered lipid metabolism as culprits to this change during gestation [37, 38]. These
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factors are exacerbated in the setting of maternal obesity leading to more significant insulin resistance. Insulin also plays an important role on neuronal development with implications in central regulation of energy homeostasis [9, 39-41]. A causal relationship has been clearly established between maternal glucose intolerance and macrosomia. Increased maternal concentrations of glucose and amino acids stimulate the fetal
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pancreas to secrete exaggerated amounts of insulin, and the fetal liver to produce higher levels of insulin dependent growth factors. Fetal hyperinsulinism stimulates the growth of fetal adipose tissue and of other
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insulin-responsive tissues, often leading to macrosomia [8]. Furthermore, a gene expression study by Radaelli et al, demonstrated significant alterations in genes involved in lipid metabolism in the placentas of mothers with gestational and type 1 diabetes mellitus [42]. In a large international multicenter observational study consisting of 25,000 women, maternal GDM and obesity were independently associated with increased birth weights as well as other adverse pregnancy outcomes. Their combined effect was greater than either alone [43, 44].
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Macrosomia results from growth of excess fetal adipose tissue and other insulin responsive tissue in response to increased insulin secretion from fetal pancreas [8]. Macrosomia can lead to increased obstetric complications including perinatal asphyxia, shoulder dystocia, and increased rate of C-sections. Furthermore,
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in utero exposure to maternal diabetes is also associated with increased risk of development of obesity, diabetes, and metabolic syndrome in childhood and adulthood. Even in patients with similar birth weights,
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infants born to mothers with GDM had increased body fat based anthroprometric measurements, compared to infants born to mothers with normal glucose tolerance [45, 46]. A study conducted by Dabalea et al looked at families that consisted of at least one sibling before and one sibling born after maternal diagnosis of type 2 diabetes. This study showed increased BMI and increased risk of diabetes in the siblings born after mothers were diagnosed. By looking at siblings of the same parents, this study controlled for genetic factors, suggesting that the intrauterine environment predisposes offspring to obesity and diabetes [47]. In the human infant, birth weight and infant adiposity is positively correlated with leptin levels. Both cord blood and plasma concentrations are increased in infants of diabetic mothers[48, 49]. In a study of a cohort consisting of 64
ACCEPTED MANUSCRIPT mothers, 33 GDM and 31 controls together with their 9-year-old offspring, an elevated child leptin was highly correlated with elevated maternal leptin in GDM mothers [50]. It is conceivable that programming of leptin regulatory pathways may be another causal mechanism linking obesity to exposure to diabetes in pregnancy
Inflammation and developmental programming
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[8].
Obesity triggers a chronic low-grade state of inflammation characterized by abnormal cytokines and adipokine production [51]. Inflammatory markers are systemically elevated in both human and animal studies of obese
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subjects [52]. The health of a pregnancy relies on a delicate balance of pro and anti-inflammatory factors. There is evidence of inflammation triggered by obesity in the placenta, in the form of macrophage infiltration
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and elevated cytokine expression [53]. The placenta is a vital organ in sustaining the fetus and maintaining a health maternal-fetal interface, thus the inflammatory state in the setting of obesity can lead to detrimental effects that can explain adverse outcomes of pregnancy as well as long-term effects on the fetus [4, 54]. Obesity results in adipocyte hypertrophy, which can lead to cell hypoxia and necrosis, triggering an inflammatory cascade of chemokine release and metabolic dysregulation including the transport of fatty acids
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[55]. Free fatty acids have been shown to activate the TLR4 signaling, thus creating a link between obesity and the innate immune system [56]. Zhu et al. observed elevated free fatty acids, cholesterol, and triglycerides in fetal circulation from obese ewes which were accompanied by upregulation of toll-like receptor 4 (TLR4), NF-
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ߢB, and JNK [57] as well as increased mRNA expression fatty acid transport proteins (FATPs) in the placenta, peroxisome proliferator-activated receptor (PPAR)-γ, which regulates the expression of FATPs [58]. Additional
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studies in rodents have also implicated (PPAR)-γ in metabolic dysregulation in adipose tissue as well as skeletal muscle the setting of maternal obesity [59-61].
Adipokines
Adipokines are cytokines released by adipocytes that have implications in regulation of a number of diverse processes including lipogenesis, angiogenesis inflammation, and metabolic processes. Adipose tissue serves to store fat, and had recently been thought to be relatively inert. However, the recognition of adipokines has clearly established the role of adipocyte in maintaining energy homeostasis [8, 25, 52, 55]. Some of these
ACCEPTED MANUSCRIPT adipokines include adiponectin, leptin, and resistin among others [25] with ongoing research resulting in identification of novel adipokines [52]. Leptin is a well-studied adipokine, that serves as a satiety factor with receptors in the hypothalamus; mutations in the leptin gene can lead to an obese phenotype. It can be used as a circulating signal of fat mass, and an indicator of the important regulatory role played by adipocytes [62].
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Furthermore, leptin and its receptor are expressed in murine placenta, indicating it may have a role in fetal growth and development [63]. Levels of leptin in cord blood are related to birth weight in offspring [25]. Resistin is highly expressed in visceral fat; it antagonizes insulin action leading to insulin resistance. In the setting of maternal obesity, dietary intake has been shown to permanently influence metabolism of offspring through
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epigenetic mechanisms, with transgenerational effects. Studies have shown alterations of acetylation and methylation of histone H3K9 in the promoter region of adiponectin, an adipokine that possesses anti-
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inflammatory and insulin sensitizing properties. Adiponectin possesses anti-inflammatory and insulin sensitizing properties and is reduced in obese patients with insulin resistance and type 2 DM. In rodent models, maternal high fat diet lead to epigenetic changes in fat and skeletal muscle. Alterations were seen in the acetylation and methylation of H3K9 of the adiponectin promoter and changes in methylation of histone H4K20 within the leptin promoter [7]. Panchenko et al performed a study looking at the epigenetic effects of
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obesity and weight loss during gestation in a mouse model fed a high fat diet with a phenotype of fetal growth restriction [64]. They found that maternal obesity was associated with altered expression of some epigenetic regulators in the fetal liver and placental labyrinth at term. Notably they found alterations in components of the
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histone acetylation pathway. Transcript levels of arginine methyltransferases Prmt1 and Prmt7 were upregulated in the liver of fetuses born to obese mothers. Prmts catalyze the methylation of arginine histone
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residues and are implicated in hepatic gluconeogenesis [64]. They also saw alterations in the lysine acetylation pathway in offspring of obese mothers. They also found differential expression in KATs and HDACs, which are lysine demethylases, with implications in metabolic processes including adipogenesis, hepatic lipid metabolism, regulation of circadian rhythm, energy expenditure, gluconeogenesis and lipogenesis [64].
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ACCEPTED MANUSCRIPT
Figure 1. The effect of maternal obesity on the offspring is multifactorial and may result from alterations in macronutrient availability (elevated fats, carbohydrates and decreased insulin sensitivity), epigenetic modifications (DNA methylation, histone modification, and noncoding RNAs) and inflammation (adipokine and cytokine release). There is often interplay between these factors resulting in a compounded effect on the offspring. The impact is evident in short term outcomes such as fetal growth as well as long term outcomes including increased risk of childhood obesity and ultimately metabolic syndrome and obesity in the adult. There are also transgenerational effects with an ongoing cycle of offspring of obese mothers going on to have offspring with exposure to the same environmental and epigenetic factors leading to an ongoing epidemic of obesity.
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Conclusion
The adverse outcomes associated with maternal obesity arise from genetic, epigenetic, metabolic and inflammatory alterations with a lasting impact on fetal development (See Figure 1). Research targeted towards
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reducing the transgenerational propagation and developmental programming of obesity is vital in reducing the increasing rates of disease. Recognizing the risk factors for obesity and its associated comorbidities will allow
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clinicians to intervene prior to some of the critical windows of development. These interventions may be able to reverse the programming during these vulnerable periods, in order to attenuate the effects on future generations [52].
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Schaeffler, A., et al., Fatty acid-induced induction of Toll-like receptor-4/nuclear factor-kappaB pathway in adipocytes links nutritional signalling with innate immunity. Immunology, 2009. 126(2): p. 233-45. Zhu, M.J., et al., Maternal obesity up-regulates inflammatory signaling pathways and enhances cytokine expression in the mid-gestation sheep placenta. Placenta, 2010. 31(5): p. 387-91. Zhu, M.J., et al., Maternal obesity markedly increases placental fatty acid transporter expression and fetal blood triglycerides at midgestation in the ewe. Am J Physiol Regul Integr Comp Physiol, 2010. 299(5): p. R1224-31. Shankar, K., et al., Maternal obesity at conception programs obesity in the offspring. Am J Physiol Regul Integr Comp Physiol, 2008. 294(2): p. R528-38. Samuelsson, A.M., et al., Diet-induced obesity in female mice leads to offspring hyperphagia, adiposity, hypertension, and insulin resistance: a novel murine model of developmental programming. Hypertension, 2008. 51(2): p. 383-92. Bayol, S.A., B.H. Simbi, and N.C. Stickland, A maternal cafeteria diet during gestation and lactation promotes adiposity and impairs skeletal muscle development and metabolism in rat offspring at weaning. J Physiol, 2005. 567(Pt 3): p. 951-61. Zhang, Y., et al., Positional cloning of the mouse obese gene and its human homologue. Nature, 1994. 372(6505): p. 425-32. Hoggard, N., et al., Leptin and leptin receptor mRNA and protein expression in the murine fetus and placenta. Proc Natl Acad Sci U S A, 1997. 94(20): p. 11073-8. Panchenko, P.E., et al., Expression of epigenetic machinery genes is sensitive to maternal obesity and weight loss in relation to fetal growth in mice. Clin Epigenetics, 2016. 8: p. 22.
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Highlights Ms. Ref. No.: MCE-D-16-00169 Title: Maternal obesity and prenatal programming Molecular and Cellular Endocrinology
Genetic and environmental factors contribute to the development of obesity.
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Maternal obesity is associated with epigenetic modifications in the offspring.
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Fetal programming has long-term effects on offspring as well as future generations.
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Research targeted towards reducing the developmental programming of obesity is vital.
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S0303-7207(16)30233-7
DOI:
10.1016/j.mce.2016.07.002
Reference:
MCE 9555
To appear in:
Molecular and Cellular Endocrinology
Received Date: 28 March 2016 Revised Date:
1 July 2016
Accepted Date: 1 July 2016
Please cite this article as: Elshenawy, S., Simmons, R., Maternal obesity and prenatal programming, Molecular and Cellular Endocrinology (2016), doi: 10.1016/j.mce.2016.07.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Maternal obesity and prenatal programming
Summer Elshenawy, MD1
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Rebecca Simmons, MD2
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Children's Hospital of Philadelphia, 3516 Civic Center Boulevard, Philadelphia, PA 19104, USA Funding: T32(GM008638) NIH/NIGMS Medical Genetics Research Training Grant Correspondence should be addressed to R.A.S ([email protected])
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Perelman School of Medicine at University of Pennsylvania, 421 Curie Boulevard, Philadelphia, PA 19104, USA
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Correspondence should be addressed to R.A.S ([email protected])
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Dr. Rebecca Simmons Hallam Hurt Professor Pediatrics Perelman School of Medicine Children’s Hospital of Philadelphia
ACCEPTED MANUSCRIPT Obesity is a significant and increasing public health concern in the United States and worldwide[1-3]. In 2010 almost one third of adults and 17% of children and adolescents were obese [3]. Obesity in pregnancy is associated with complications that include gestational diabetes, intrauterine growth restriction, infants born large for gestational age, increased caesarian sections and other obstetric interventions, as well as
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miscarriages [4-6]. Understanding obesity on an epidemiologic and molecular level has become an significant area of focus within the scientific community. Particularly important, is the understanding of how maternal obesity may affect the outcomes of offspring from the neonatal period to adulthood. The impact of maternal obesity goes beyond the newborn period; fetal programming during the critical window of pregnancy, can have
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long term detrimental effects on the offspring and future generations [7, 8]. Environmental exposures in utero, including alterations of the nutritional milieu are particularly important during a time of such rapid growth [8].
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The rising prevalence of obesity and its associated comorbidities, [9], has led to a need for a better understanding of the impact of obesity on population health, including an understanding of the impact of maternal obesity on pregnancy and childhood outcomes. This review will aim to describe clinical data as well
Birth weight and Obesity
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as data from animal models, with a focus on fetal programming in the setting of maternal obesity.
Maternal obesity has been linked to macrosomia [10], which is a risk factor for obesity and metabolic syndrome later in life. The variation in fetal growth in the setting of maternal obesity may be related to diet composition or
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vascular factors, and result from differing underlying molecular mechanisms. Epidemiologic studies have shown a trend of increasing maternal obesity with an associated increase in prevalence of infants who were
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born large for gestational age (LGA) [5]. In a systematic review by Yu et al, pre-pregnancy obesity in women correlated with an increased risk of having LGA baby, and increased risk of obesity later in life [11]. A Mendelian randomization study performed by Tyrell et al, established genetic alleles associated with maternal obesity and elevated blood glucose were linked to higher birth weight in the offspring [12]. There is a clearly established link between birth weight and obesity later in life. In the U.S. Growing Up Today Study, a cohort study of over 14,000 adolescents, a 1-kg increment in birth weight in full term infants was associated with an approximately 50% increase in the risk of overweight at ages 9 to14 year [13]. When adjusted for maternal BMI, the increase in risk remained significantly elevated at 30%. A study of Danish military conscripts showed
ACCEPTED MANUSCRIPT that even after controlling for birth length and maternal factors, BMI at ages 18–26 strongly correlated with birth weight [14]. Both paternal and maternal adiposity are correlated with a higher birth weight of the offspring. However, the association is much stronger for the mother compared to the father [15-18] suggesting that the intrauterine environment plays an important role in the later development of obesity. In addition to birth weight,
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several clinical studies have shown a direct relationship between maternal obesity and childhood obesity [15, 19]. In a retrospective cohort study of 8500 low income children in the US, Whitaker et al demonstrated a twofold increase in prevalence of early childhood obesity in children who were born to obese mothers [20]. Smith et al. looked at metabolic features of children born before or after mothers underwent bariatric surgery. They
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found that children born after maternal bariatric surgery had had lower birth weight, lower prevalence of severe obesity adjusted for age and gender, greater insulin sensitivity, improved lipid profile, lower C-reactive protein,
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and leptin and increased ghrelin than offspring born before maternal bariatric surgery [21]. Guenard et al. also looked at offspring before and after bariatric surgery, finding epigenetic changes in genes involved in glucoregulatory, including insulin sensitivity, inflammatory, and vascular disease genes conferring a more favorable cardiometabolic profile in the offspring born after maternal bariatric surgery [22]. Catalano et al specifically discusses that pre-pregnancy obesity has a stronger association with metabolic alterations of the
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fetus, than gestational weight gain. In one study, they showed the maternal pre-pregnancy BMI greater than 30 kg/m2 was associated with increased body fat percentage at age 8. Furthermore, they demonstrated that at age 8, children of obese mothers had higher systolic blood pressures, waist circumference, triglycerides,
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Epigenetics
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insulin resistance and leptin levels [23].
Clinical and epidemiological evidence clearly shows that genetic and environmental factors contribute to the increased susceptibility of humans to obesity and its associated comorbidities; the interplay of these factors is explained by the concept of epigenetics [9]. Epigenetics explains, as Barker describes, “developmental plasticity” in which environment impacts gene expression, particularly during vulnerable times of development [24]. Epigenetics controls differentiation and development of different cell types by modulating chromatin architecture. It is a dynamic process that is influenced by environmental factors. The mechanisms include DNA methylation, histone modification and the presence of noncoding RNAs and microRNAs [7, 9, 25]. The
ACCEPTED MANUSCRIPT epigenetic modifications can lead to stable propagation with transgenerational effects. Although human data is still limited, emerging evidence is uncovering a link between the clinical and molecular findings in the offspring with epigenetic changes in the setting of maternal obesity.
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DNA methylation: DNA methylation is a class of epigenetic regulation, in which a cytosine base is modified by DNA methyltransferase at the C5 position of cytosine, a reaction that is carried out by various members of a single family of enzymes. Approximately 70% of CpG dinucleotides in human DNA are constitutively methylated, whereas most of the unmethylated CpGs are located in CpG islands. CpG islands are CG-rich
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sequences located near coding sequences and they serve as promoters for their associated genes. Approximately half of mammalian genes have CpG islands. The methylation status of CpG islands within
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promoter sequences works as an essential regulatory element by modifying the binding affinity of transcription factors to DNA binding sites. In normal cells, most CpG islands remain unmethylated; however, under circumstances such as oxidative stress, they can become methylated de novo. This aberrant methylation is accompanied by local changes in histone modification and chromatin structure, such that the CpG island and its embedded promoter take on a repressed conformation that is incompatible with gene transcription. It is not
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known why particular CpG islands are susceptible to aberrant methylation. DNA methylation is commonly associated with gene silencing and contributes to X-chromosomal inactivation, genomic imprinting, and transcriptional regulation of tissue-specific genes during cellular differentiation [25]. In the case of maternal
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obesity and fetal programming, differential methylation of retinoid X receptor-α (RXRA) gene in umbilical cord
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tissue, was shown to be associated with childhood fat mass, when adjusted for sex [26].
Histone modifications: In eukaryotes, the nucleosome consists of DNA wrapped around an octameric complex of two molecules of each of the four histones: H2A, H2B, H3, and H4. The amino termini of histones can be modified by acetylation, methylation, sumoylation, phosphorylation, glycosylation, and ADP ribosylation. The most common histone modifications involve acetylation and methylation of lysine residues in the amino termini of H3 and H4. Increased acetylation induces transcription activation, whereas decreased acetylation usually induces transcription repression. Methylation of histones, on the other hand, is associated with both transcription repression and activation. Moreover, lysine residues can be mono-, di-, or trimethylated in vivo,
ACCEPTED MANUSCRIPT providing an additional level of regulation [25]. Histone methylation can influence DNA methylation patterns and vice versa [27]. For example, methylation of lysine 9 on histone 3 (H3) promotes DNA methylation, while CpG methylation stimulates methylation of lysine 9 on H3 [28]. Recent evidence indicates that this reciprocal relationship between histone methylation and DNA methylation might be accomplished by direct interactions
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between histone and DNA methyltransferases [27]. Thus, chromatin modifications induced by adverse stimuli are self-reinforcing and can propagate.
Noncoding RNAs: Noncoding RNAs such as microRNAs (miRNA), small RNAs, and long or large RNAs, play a
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significant role in epigenetic gene regulation and chromosomal dynamics and transcription [29]. With the discovery that most of the eukaryotic genomes are transcribed into RNAs that have no protein-coding potential,
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evidence has emerged of the different regulatory functions of noncoding RNAs. Studies have shown differential expression of miRNAs in the amnion, plasma, and other tissues of obese mothers [30-32]. Yan et al. demonstrated that the offspring of obese pregnant ewes had decreased expression of miRNA let-7g in skeletal muscle, which correlated with increased adipose deposition in skeletal muscle [31]. This demonstrates the role non-coding RNAs may play in regulation of adipogenesis through differential gene expression.
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Carreras-Badosa et al. conducted a study in which plasma circulating miRNAs were measured in normal pregnancies as well as pregnancies complicated by pre-gestational and gestational obesity. In this study 13 circulating miRNAs were differentially expressed in gestational obesity when compared to normal pregnancies,
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many of which are associated with altered metabolism in the mother including weight gain, glucose tolerance, insulin sensitivity, and serum lipid levels. Specific miRNAs were also associated with placental weight and birth
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weight, as well as growth during infancy, after controlling maternal factors [32].
Macronutrient impact on fetal development The adverse effects of maternal obesity on the fetus are likely multifactorial, involving hormonal, inflammatory, and metabolic alterations. Macronutrient intake influenced by maternal diet and body composition likely plays a role in the metabolic conditioning of the fetus in utero. Metabolomic analysis of umbilical cord blood showed that accelerated early childhood weight gain was associated with differential regulation of metabolites related to food and plant component [33]. Furthermore, while there is a physiologic increase in fasting triglycerides
ACCEPTED MANUSCRIPT throughout pregnancy, mothers with higher pre-pregnancy BMIs see a greater increase in fasting triglycerides and free fatty acids, demonstrating alteration in lipid metabolism in the obese mother [34]. DiCianni et al showed maternal fasting triglycerides correlated with birth weight [34]. In a study looking at differential gene expression in maternal obesity, Carty et al found reduced expression of COX7A2 in subcutaneous tissue of
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obese pregnant women at term. COX7A2 is a mitochondrial protein, with key roles in steroidogenesis and oxidative stress regulation and could provide a link between inflammation and obesity-related pregnancy complications [35].
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Maternal obesity and fetal programming has been studied in multiple animal models. Various models evaluate the impact of different types of diet, and may indicate that the macronutrient content of the diet, may impact the
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mechanism of fetal programming. In animal experiments, high fat diet leads to poor glycemic control and increased adiposity in offspring [8, 9]. In a unique study design, Sasson et al performed a reciprocal early twocell embryo transfer between mice fed different diets prior to and during pregnancy. Pre-gestational exposure to high fat diet resulted in growth restricted fetuses and newborn pups but no effect on adult weight, body fat content or leptin levels. They observed differential gene expression of several imprinted genes in the placenta
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of the pre-pregnancy high fat diet animals suggesting an epigenetic alteration in the germ line in the setting of maternal obesity. Gestational exposure to maternal high fat diet (HFD) resulted in increased body fat, elevated leptin levels, and impaired glucose tolerance in offspring. In contrast, the offspring of mothers who were fed a
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HFD during pre-conceptional period and throughout gestation, had significantly higher body fat content, but while the females were not inherently glucose intolerant, the males were. There were many more genes
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differentially expressed in the HFD/HFD group suggesting a compound effect of the pre-conceptional and gestational exposure. Many of the genes that were differentially expressed in the placenta play a role in inflammation [36].
More recently, animal studies have also looked at a “western diet” model, which is high in simple sugars to more closely mimic human diets, which result in alterations in glucose metabolism, increased adiposity, as well as alterations in central appetite regulatory systems in the offspring [9]. Thus variations in different obesogenic diets could explain the variable presentation seen in population studies. In addition to fat, alterations in glucose
ACCEPTED MANUSCRIPT metabolisms in the setting of gestational diabetes and insulin resistance has been studied in the setting of maternal obesity and as a separate entity. Insulin sensitivity is reduced in the pregnant state, and while placental factors may contribute, emerging evidence has implicated other factors such as elevated cytokines, including TNF alpha, and altered lipid metabolism as culprits to this change during gestation [37, 38]. These
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factors are exacerbated in the setting of maternal obesity leading to more significant insulin resistance. Insulin also plays an important role on neuronal development with implications in central regulation of energy homeostasis [9, 39-41]. A causal relationship has been clearly established between maternal glucose intolerance and macrosomia. Increased maternal concentrations of glucose and amino acids stimulate the fetal
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pancreas to secrete exaggerated amounts of insulin, and the fetal liver to produce higher levels of insulin dependent growth factors. Fetal hyperinsulinism stimulates the growth of fetal adipose tissue and of other
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insulin-responsive tissues, often leading to macrosomia [8]. Furthermore, a gene expression study by Radaelli et al, demonstrated significant alterations in genes involved in lipid metabolism in the placentas of mothers with gestational and type 1 diabetes mellitus [42]. In a large international multicenter observational study consisting of 25,000 women, maternal GDM and obesity were independently associated with increased birth weights as well as other adverse pregnancy outcomes. Their combined effect was greater than either alone [43, 44].
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Macrosomia results from growth of excess fetal adipose tissue and other insulin responsive tissue in response to increased insulin secretion from fetal pancreas [8]. Macrosomia can lead to increased obstetric complications including perinatal asphyxia, shoulder dystocia, and increased rate of C-sections. Furthermore,
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in utero exposure to maternal diabetes is also associated with increased risk of development of obesity, diabetes, and metabolic syndrome in childhood and adulthood. Even in patients with similar birth weights,
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infants born to mothers with GDM had increased body fat based anthroprometric measurements, compared to infants born to mothers with normal glucose tolerance [45, 46]. A study conducted by Dabalea et al looked at families that consisted of at least one sibling before and one sibling born after maternal diagnosis of type 2 diabetes. This study showed increased BMI and increased risk of diabetes in the siblings born after mothers were diagnosed. By looking at siblings of the same parents, this study controlled for genetic factors, suggesting that the intrauterine environment predisposes offspring to obesity and diabetes [47]. In the human infant, birth weight and infant adiposity is positively correlated with leptin levels. Both cord blood and plasma concentrations are increased in infants of diabetic mothers[48, 49]. In a study of a cohort consisting of 64
ACCEPTED MANUSCRIPT mothers, 33 GDM and 31 controls together with their 9-year-old offspring, an elevated child leptin was highly correlated with elevated maternal leptin in GDM mothers [50]. It is conceivable that programming of leptin regulatory pathways may be another causal mechanism linking obesity to exposure to diabetes in pregnancy
Inflammation and developmental programming
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[8].
Obesity triggers a chronic low-grade state of inflammation characterized by abnormal cytokines and adipokine production [51]. Inflammatory markers are systemically elevated in both human and animal studies of obese
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subjects [52]. The health of a pregnancy relies on a delicate balance of pro and anti-inflammatory factors. There is evidence of inflammation triggered by obesity in the placenta, in the form of macrophage infiltration
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and elevated cytokine expression [53]. The placenta is a vital organ in sustaining the fetus and maintaining a health maternal-fetal interface, thus the inflammatory state in the setting of obesity can lead to detrimental effects that can explain adverse outcomes of pregnancy as well as long-term effects on the fetus [4, 54]. Obesity results in adipocyte hypertrophy, which can lead to cell hypoxia and necrosis, triggering an inflammatory cascade of chemokine release and metabolic dysregulation including the transport of fatty acids
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[55]. Free fatty acids have been shown to activate the TLR4 signaling, thus creating a link between obesity and the innate immune system [56]. Zhu et al. observed elevated free fatty acids, cholesterol, and triglycerides in fetal circulation from obese ewes which were accompanied by upregulation of toll-like receptor 4 (TLR4), NF-
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ߢB, and JNK [57] as well as increased mRNA expression fatty acid transport proteins (FATPs) in the placenta, peroxisome proliferator-activated receptor (PPAR)-γ, which regulates the expression of FATPs [58]. Additional
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studies in rodents have also implicated (PPAR)-γ in metabolic dysregulation in adipose tissue as well as skeletal muscle the setting of maternal obesity [59-61].
Adipokines
Adipokines are cytokines released by adipocytes that have implications in regulation of a number of diverse processes including lipogenesis, angiogenesis inflammation, and metabolic processes. Adipose tissue serves to store fat, and had recently been thought to be relatively inert. However, the recognition of adipokines has clearly established the role of adipocyte in maintaining energy homeostasis [8, 25, 52, 55]. Some of these
ACCEPTED MANUSCRIPT adipokines include adiponectin, leptin, and resistin among others [25] with ongoing research resulting in identification of novel adipokines [52]. Leptin is a well-studied adipokine, that serves as a satiety factor with receptors in the hypothalamus; mutations in the leptin gene can lead to an obese phenotype. It can be used as a circulating signal of fat mass, and an indicator of the important regulatory role played by adipocytes [62].
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Furthermore, leptin and its receptor are expressed in murine placenta, indicating it may have a role in fetal growth and development [63]. Levels of leptin in cord blood are related to birth weight in offspring [25]. Resistin is highly expressed in visceral fat; it antagonizes insulin action leading to insulin resistance. In the setting of maternal obesity, dietary intake has been shown to permanently influence metabolism of offspring through
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epigenetic mechanisms, with transgenerational effects. Studies have shown alterations of acetylation and methylation of histone H3K9 in the promoter region of adiponectin, an adipokine that possesses anti-
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inflammatory and insulin sensitizing properties. Adiponectin possesses anti-inflammatory and insulin sensitizing properties and is reduced in obese patients with insulin resistance and type 2 DM. In rodent models, maternal high fat diet lead to epigenetic changes in fat and skeletal muscle. Alterations were seen in the acetylation and methylation of H3K9 of the adiponectin promoter and changes in methylation of histone H4K20 within the leptin promoter [7]. Panchenko et al performed a study looking at the epigenetic effects of
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obesity and weight loss during gestation in a mouse model fed a high fat diet with a phenotype of fetal growth restriction [64]. They found that maternal obesity was associated with altered expression of some epigenetic regulators in the fetal liver and placental labyrinth at term. Notably they found alterations in components of the
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histone acetylation pathway. Transcript levels of arginine methyltransferases Prmt1 and Prmt7 were upregulated in the liver of fetuses born to obese mothers. Prmts catalyze the methylation of arginine histone
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residues and are implicated in hepatic gluconeogenesis [64]. They also saw alterations in the lysine acetylation pathway in offspring of obese mothers. They also found differential expression in KATs and HDACs, which are lysine demethylases, with implications in metabolic processes including adipogenesis, hepatic lipid metabolism, regulation of circadian rhythm, energy expenditure, gluconeogenesis and lipogenesis [64].
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Figure 1. The effect of maternal obesity on the offspring is multifactorial and may result from alterations in macronutrient availability (elevated fats, carbohydrates and decreased insulin sensitivity), epigenetic modifications (DNA methylation, histone modification, and noncoding RNAs) and inflammation (adipokine and cytokine release). There is often interplay between these factors resulting in a compounded effect on the offspring. The impact is evident in short term outcomes such as fetal growth as well as long term outcomes including increased risk of childhood obesity and ultimately metabolic syndrome and obesity in the adult. There are also transgenerational effects with an ongoing cycle of offspring of obese mothers going on to have offspring with exposure to the same environmental and epigenetic factors leading to an ongoing epidemic of obesity.
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Conclusion
The adverse outcomes associated with maternal obesity arise from genetic, epigenetic, metabolic and inflammatory alterations with a lasting impact on fetal development (See Figure 1). Research targeted towards
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reducing the transgenerational propagation and developmental programming of obesity is vital in reducing the increasing rates of disease. Recognizing the risk factors for obesity and its associated comorbidities will allow
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clinicians to intervene prior to some of the critical windows of development. These interventions may be able to reverse the programming during these vulnerable periods, in order to attenuate the effects on future generations [52].
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Highlights Ms. Ref. No.: MCE-D-16-00169 Title: Maternal obesity and prenatal programming Molecular and Cellular Endocrinology
Genetic and environmental factors contribute to the development of obesity.
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Maternal obesity is associated with epigenetic modifications in the offspring.
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Fetal programming has long-term effects on offspring as well as future generations.
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Research targeted towards reducing the developmental programming of obesity is vital.
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