Molecular and Cellular Endocrinology 435 (2016) 2e6

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Molecular and Cellular Endocrinology

j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m/ l o c a t e / m c e

Maternal obesity and prenatal programming

a b, *
Summer Elshenawy , Rebecca Simmons
a Childrens Hospital of Philadelphia, 3516 Civic Center Boulevard, Philadelphia, PA 19104, USA
b Perelman School of Medicine at University of Pennsylvania, 421 Curie Boulevard, Philadelphia, PA 19104, USA

article info abstract

Article history: Obesity is a significant and increasing public health concern in the United States and worldwide. Clinical and epidemiological
Received 28 March 2016 evidence clearly shows that genetic and environmental factors contribute to the increased susceptibility of humans to obesity
Received in revised form and its associated comorbidities; the interplay of these factors is explained by the concept of epigenetics. The impact of
1 July 2016
maternal obesity goes beyond the newborn period; fetal programming during the critical window of pregnancy, can have long
Accepted 1 July 2016
term detrimental effects on the offspring as well as future generations. Emerging evidence is uncovering a link between the
Available online 5 July 2016
clinical and molecular findings in the offspring with epigenetic changes in the setting of maternal obesity. Research targeted
towards reducing the transgenerational propagation and develop-mental programming of obesity is vital in reducing the
Keywords:
increasing rates of disease.
Developmental programming
Maternal obesity Epigenetics
2016 Elsevier Ireland Ltd. All rights reserved.
Obesity in pregnancy
Fetal origins of adult disease

Obesity is a significant and increasing public health concern in the United
States and worldwide (Flegal et al., 2010; Ogden et al., 2006, 2012). In 2010
almost one third of adults and 17% of chil-dren and adolescents were obese
(Ogden et al., 2012). 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 miscarriages (Schmatz et al., 2010; Lu et al., 2001;
Morin, 1998). Understanding obesity on an epidemiologic and molecular
level has become a significant area of focus within the scientific community.
Particularly important, is the under-standing 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 pro-
gramming during the critical window of pregnancy, can have long term
detrimental effects on the offspring and future generations (Nicholas et al.,
2016; Simmons, 2008). Environmental exposures in utero, including
alterations of the nutritional milieu are particularly important during a time of
such rapid growth (Simmons, 2008). The rising prevalence of obesity and its
associated comorbidities, (Bouret et al., 2015), has led to a need for a better
understanding of the impact of obesity on population health, including an
* Corresponding author. Hallam Hurt Professor Pediatrics, Perelman School of Medicine
,Childrens Hospital of Philadelphia, USA.
E-mail address: rsimmons@mail.med.upenn.edu (R. Simmons).
understanding of the impact of maternal obesity on pregnancy and childhood
outcomes. This review will aim to describe clinical data as well as data from
animal models, with a focus on fetal pro-gramming in the setting of maternal
obesity.
1. Birth weight and obesity
Maternal obesity has been linked to macrosomia (Gaudet et al., 2014),
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 vascular factors, and result from differing underlying
molecular mechanisms. Epidemi-ologic studies have shown a trend of
increasing maternal obesity with an associated increase in prevalence of
infants who were born large for gestational age (LGA) (Lu et al., 2001). In a
systematic re-view 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 (Yu et al., 2013). 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
(Tyrrell et al., 2016). 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 9e14 year (Gillman et al., 2003).
When adjusted for
maternal BMI, the increase in risk remained

http://dx.doi.org/10.1016/j.mce.2016.07.002
0303-7207/ 2016 Elsevier Ireland Ltd. All rights reserved.
 S. Elshenawy, R. Simmons / Molecular and Cellular Endocrinology 435 (2016) 2e6
significantly elevated at 30%. A study of Danish military conscripts showed
that even after controlling for birth length and maternal factors, BMI at ages
18e26 strongly correlated with birth weight (Sorensen et al., 1997). 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 (Parsons et al., 2001; Guillaume et al., 1995; Whitaker
et al., 2010; Oken, 2009) suggesting that the intrauterine environment plays
an important role in the later development of obesity. In addition to birth
weight, several clinical studies have shown a direct relation-ship between
maternal obesity and childhood obesity (Parsons et al., 2001; Boerschmann et
al., 2010). In a retrospective cohort study of 8500 low income children in the
US, Whitaker et al. demonstrated a two-fold increase in prevalence of early
childhood obesity in children who were born to obese mothers (Whitaker,
2004). Smith et al. looked at metabolic features of children born before or
after mothers underwent bariatric surgery. They 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, and leptin and increased
ghrelin than offspring born before maternal bariatric surgery (Smith et al.,
2009). 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 (Guenard et al., 2013). Catalano et al. specifically
discusses that pre-pregnancy obesity has a stronger association with metabolic
alterations of the fetus, than gestational weight gain. In one study, they
2 H2B, H3, and H4. The amino termini of histones can be modified by
showed the maternal pre-pregnancy BMI greater than 30 kg/m was asso-
ciated 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, insulin resistance and
leptin levels (Catalano et al., 2009).
2. Epigenetics
Clinical and epidemiological evidence clearly shows that genetic and
environmental factors contribute to the increased suscepti-bility of humans to
obesity and its associated comorbidities; the interplay of these factors is
explained by the concept of epigenetics (Bouret et al., 2015). Epigenetics
explains, as Barker describes, developmental plasticity in which
environment impacts gene expression, particularly during vulnerable times of
development (Barker, 2004). Epigenetics controls differentiation and develop-
ment 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 (Nicholas et al., 2016; Bouret et al., 2015;
Pinney and Simmons, 2012). The 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.
2.1. DNA methylation
DNA methylation is a class of epigenetic regulation, in which a cytosine
base is modified by DNA methyltransferase at the C5 po-sition of cytosine, a
reaction that is carried out by various members of a single family of enzymes.
Approximately 70% of CpG di-nucleotides in human DNA are constitutively
methylated, whereas most of the unmethylated CpGs are located in CpG
islands. CpG
3
islands are CG-rich 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
promoter sequences works as an essential regulatory element by modifying
the binding affinity of transcrip-tion 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 aber-rant
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 known why partic-ular CpG islands are susceptible to aberrant
methylation. DNA methylation is commonly associated with gene silencing
and con-tributes to X-chromosomal inactivation, genomic imprinting, and
transcriptional regulation of tissue-specific genes during cellular
differentiation (Pinney and Simmons, 2012). In the case of maternal obesity
and fetal programming, differential methylation of retinoid X receptor- a
(RXRA) gene in umbilical cord tissue, was shown to be associated with
childhood fat mass, when adjusted for sex (Godfrey et al., 2011).
2.2. Histone modifications
In eukaryotes, the nucleosome consists of DNA wrapped around an
octameric complex of two molecules of each of the four his-tones: H2A,
acetylation, methylation, sumoylation, phosphoryla-tion, glycosylation, and
ADP ribosylation. The most common his-tone 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, providing an additional level of regulation (Pinney and Simmons, 2012).
Histone methylation can influence DNA methylation patterns and vice versa
(Cedar and Bergman, 2009). For example, methylation of lysine 9 on histone
3 (H3) promotes DNA methylation, while CpG methylation stimulates
methylation of lysine 9 on H3 (Schubeler et al., 2000). Recent evi-dence
indicates that this reciprocal relationship between histone methylation and
DNA methylation might be accomplished by direct interactions between
histone and DNA methyltransferases (Cedar and Bergman, 2009). Thus,
chromatin modifications induced by adverse stimuli are self-reinforcing and
can propagate.
2.3. Noncoding RNAs
Noncoding RNAs such as microRNAs (miRNA), small RNAs, and long
or large RNAs, play a significant role in epigenetic gene regu-lation and
chromosomal dynamics and transcription (Bernstein and Allis, 2005). With
the discovery that most of the eukaryotic ge-nomes are transcribed into RNAs
that have no protein-coding po-tential, 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 (Nardelli et al., 2014; Yan et al., 2013; Carreras-Badosa et al., 2015).
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 (Yan et al., 2013). This
demonstrates the role non-coding RNAs may play in regulation of
adipogenesis through differential gene expression. Carreras-Badosa et al.
conducted a study in which plasma circulating miRNAs were measured in
normal pregnancies
4 S. Elshenawy, R. Simmons / Molecular and Cellular Endocrinology 435 (2016) 2e6
as well as pregnancies complicated by pre-gestational and gesta-tional
obesity. In this study 13 circulating miRNAs were differen-tially expressed in
gestational obesity when compared to normal pregnancies, many of which are
associated with altered meta-bolism in the mother including weight gain,
glucose tolerance, in-sulin sensitivity, and serum lipid levels. Specific
miRNAs were also associated with placental weight and birth weight, as well
as growth during infancy, after controlling maternal factors (Carreras-Badosa
et al., 2015).
3. 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 associ-ated with differential regulation of metabolites related
to food and plant component (Isganaitis et al., 2015). Furthermore, while
there is a physiologic increase in fasting triglycerides throughout preg-nancy,
mothers with higher pre-pregnancy BMIs see a greater in-crease in fasting
triglycerides and free fatty acids, demonstrating alteration in lipid metabolism
in the obese mother (Di Cianni et al., 2005). DiCianni et al. showed maternal
fasting triglycerides corre-lated with birth weight (Di Cianni et al., 2005). In a
study looking at differential gene expression in maternal obesity, Carty et al.
found reduced expression of COX7A2 in subcutaneous tissue of 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 (Carty et
al., 2014).
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
mechanism of fetal program-ming. In animal experiments, high fat diet leads
to poor glycemic control and increased adiposity in offspring (Simmons,
2008; Bouret et al., 2015). In a unique study design, Sasson et al. per-formed
a reciprocal early two-cell 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 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 HFD during pre-conceptional period and throughout gestation, had
significantly higher body fat content, but while the females were not
inherently glucose intol-erant, the males were. There were many more genes
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 (Sasson et
al., 2015).
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 reg-ulatory systems in the offspring (Bouret et
al., 2015). Thus varia-tions in different obesogenic diets could explain the
variable presentation seen in population studies. In addition to fat, alter-ations
in glucose 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 (Catalano, 2010;
Schaefer-Graf et al., 2008). These 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 (Bouret et al., 2015; Puro and Agardh, 1984;
Heidenreich and Toledo, 1989a, 1989b). A causal relationship has been
clearly established between maternal glucose intolerance and macrosomia.
Increased maternal concentrations of glucose and amino acids stimulate the
fetal 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 adi-pose tissue and of other
insulin-responsive tissues, often leading to macrosomia (Simmons, 2008).
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 (Radaelli et al.,
2009). 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 (Catalano et al., 2012;
Group, 2010). Macrosomia results from growth of excess fetal adipose tissue
and other insulin responsive tissue in response to increased insulin secretion
from fetal pancreas (Simmons, 2008). Macrosomia can lead to increased
obstetric complications including perinatal asphyxia, shoulder dystocia, and
increased rate of C-sections. Furthermore, in utero exposure to maternal
diabetes is also associated with increased risk of devel-opment of obesity,
diabetes, and metabolic syndrome in childhood and adulthood. Even in
patients with similar birth weights, infants born to mothers with GDM had
increased body fat based anthro-prometric measurements, compared to infants
born to mothers with normal glucose tolerance (Catalano et al., 2003; Sewell
et al., 2006). 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 intra-uterine environment predisposes offspring to obesity
and diabetes (Dabelea et al., 2000). 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 (Law
et al., 1992; Fall et al., 1995). In a study of a cohort consisting of 64 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 (Shekhawat et al., 1998). It is conceivable that programming of leptin
regulatory pathways may be another causal mechanism linking obesity to
exposure to diabetes in pregnancy (Simmons, 2008).
4. Inflammation and developmental programming
Obesity triggers a chronic low-grade state of inflammation characterized
by abnormal cytokines and adipokine production (Hotamisligil, 2006).
Inflammatory markers are systemically elevated in both human and animal
studies of obese subjects (Segovia et al., 2014). The health of a pregnancy
relies on a delicate balance of pro and anti-inflammatory factors. There
is evidence of
 S. Elshenawy, R. Simmons / Molecular and Cellular Endocrinology 435 (2016) 2e6 5

inflammation triggered by obesity in the placenta, in the form of macrophage

infiltration and elevated cytokine expression (Challier et al., 2008). The
placenta is a vital organ in sustaining the fetus and maintaining a health
maternal-fetal interface, thus the inflamma-tory 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 (Schmatz et al., 2010;
Madan et al., 2009). 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 (Sun et al., 2011). Free fatty acids have been shown to activate the
TLR4 signaling, thus creating a link between obesity and the innate immune
system (Schaeffler et al., 2009). Zhu et al. observed elevated free fatty acids,
cholesterol, and tri-glycerides in fetal circulation from obese ewes which were
accompanied by upregulation of toll-like receptor 4 (TLR4), NF- kB, and JNK
(Zhu et al., 2010a) as well as increased mRNA expression fatty acid transport
proteins (FATPs) in the placenta, peroxisome proliferator-activated receptor
(PPAR)-g, which regulates the expression of FATPs (Zhu et al., 2010b).
Additional studies in ro-dents have also implicated (PPAR)- g in metabolic
dysregulation in adipose tissue as well as skeletal muscle the setting of
maternal obesity (Shankar et al., 2008; Samuelsson et al., 2008; Bayol et al.,
2005).

4.1. Adipokines
Adipokines are cytokines released by adipocytes that have im-plications
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 (Simmons, 2008; Pinney and Simmons,
2012; Segovia et al., 2014; Sun et al., 2011). Some of these adipokines
include adiponectin, leptin, and resistin among others (Pinney and Simmons,
2012) with ongoing research resulting in identification of novel adipokines
(Segovia et al., 2014). Leptin is a well-studied adipokine, that serves as a
satiety factor with receptors in the hy-pothalamus; 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 (Zhang et al., 1994). Furthermore, leptin and its receptor are
expressed in murine placenta, indicating it may have a role in fetal growth
and development (Hoggard et al., 1997). Levels of leptin in cord blood are
related to birth weight in offspring (Pinney and Simmons, 2012). Resistin is
highly expressed in visceral fat; it an-tagonizes insulin action leading to
insulin resistance. In the setting of maternal obesity, dietary intake has been
shown to permanently influence metabolism of offspring through epigenetic
mechanisms, with transgenerational effects. Studies have shown alterations of
acetylation and methylation of histone H3K9 in the promoter re-gion of
adiponectin, an adipokine that possesses anti-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 (Nicholas et al.,
2016). Panchenko et al. performed a study looking at the epigenetic effects of
obesity and weight loss during gestation in a mouse model fed a high fat diet
with a phenotype of fetal growth restriction (Panchenko et al., 2016). They
found that maternal obesity was associated with altered expression of some
epigenetic
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
trans-generational 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.
regulators in the fetal liver and placental labyrinth at term. Notably they found
alterations in components of the 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 resi-dues and are implicated in hepatic gluconeogenesis (Panchenko et
al., 2016). 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, he-patic lipid metabolism, regulation of
circadian rhythm, energy expenditure, gluconeogenesis and lipogenesis
(Panchenko et al., 2016).
5. Conclusion
The adverse outcomes associated with maternal obesity arise from
genetic, epigenetic, metabolic and inflammatory alterations with a lasting
impact on fetal development (See Fig. 1). Research targeted towards 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 clinicians to
intervene prior to some of the critical windows of development. These in-
terventions may be able to reverse the programming during these vulnerable
periods, in order to attenuate the effects on future generations (Segovia et al.,
2014).

Funding

T32 (GM008638) NIH/NIGMS Medical Genetics Research

6 S. Elshenawy, R. Simmons / Molecular and Cellular Endocrinology 435 (2016) 2e6
Training Grant.
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