Review article
Developmental programming by maternal obesity in 2015: Outcomes,
mechanisms, and potential interventions
Naomi C. Penfold ⁎, Susan E. Ozanne
University of Cambridge, Metabolic Research Laboratories MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ,
United Kingdom
a b s t r a c ta r t i c l e i n f o
Available online 2 July 2015
Keywords:
Developmental programming
Maternal obesity
Leptin
Insulin
Ghrelin
Appetite
Reward
Glucose homeostasis
Intervention
Obesity
This article is part of a Special Issue “SBN 2014”.
Obesity in women of child-bearing age is a growing problem in developed and developing countries. Evidence
from human studies indicates that maternal BMI correlates with offspring adiposity from an early age and predisposes
to metabolic disease in later life. Thus the early life environment is an attractive target for intervention
to improve public health. Animal models have been used to investigate the specific physiological outcomes and
mechanisms of developmental programming that result from exposure to maternal obesity in utero. From this
research, targeted intervention strategies can be designed. In this review we summarise recent progress in this
field, with a focus on cardiometabolic disease and central control of appetite and behaviour. We highlight key
factors that may mediate programming by maternal obesity, including leptin, insulin, and ghrelin. Finally, we
explore potential lifestyle and pharmacological interventions in humans and the current state of evidence
from animal models.
© 2015 Elsevier Inc. All rights reserved.
Contents
Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
Animal models have revealed mechanisms underlying programming by maternal obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
Insulin and glucose homeostasis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
Cardiovascular system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
Ectopic lipid deposition. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
Central control of food intake: programming the hypothalamus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
Maternal obesity predisposes to diet-induced obesity: the role of the reward system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
Programming learning and memory: leptin and the hippocampus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
Candidate programming mechanisms and factors in maternal obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
Interventions to improve outcomes of offspring exposed to maternal obesity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
Introduction
The importance of normal foetal growth was first highlighted by
associations between low birth weight and the increased risk of heart
disease and type 2 diabetes in adulthood (Barker et al., 1989; Hales
et al., 1991). Subsequent studies of maternal under-nutrition and,
more recently, maternal over-nutrition have demonstrated that the
maternal nutritional environment and foetal and neonatal growth,
collectively known as the first 1000 days of life, are key determinants
of health in the next generation (de Rooij et al., 2006; Lumey and
Stein, 1997; Ravelli et al., 1976, 1999). In humans, maternal obesity is
associated with low and high birth weight (Cedergren, 2004; Gaudet
et al., 2014) and increased risk of obesity and metabolic dysfunction in
the offspring both in childhood (Boney et al., 2005; Whitaker, 2004) as
well as in adulthood (Brisbois et al., 2012; Cooper et al., 2010). Maternal
Hormones and Behavior 76 (2015) 143–152
⁎ Corresponding author.
E-mail address: np325@medschl.cam.ac.uk (N.C. Penfold).
http://dx.doi.org/10.1016/j.yhbeh.2015.06.015
0018-506X/© 2015 Elsevier Inc. All rights reserved.
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journal homepage: www.elsevier.com/locate/yhbeh
obesity is also associated with increased risk of offspring cardiovascular
disease (Drake and Reynolds, 2010), type 2 diabetes (Berends and
Ozanne, 2012), and neurodevelopmental and psychiatric disorders,
including ADHD, autism, schizophrenia, and mood disorders (Mehta
et al., 2014; Rodriguez, 2010).
The prevalence of overweight and obesity has soared in the last
30 years globally (Ng et al., 2014). Worryingly, the number of children
classified as overweight or obese has increased 150% worldwide in
this timeframe (Ng et al., 2014) and the rate of obesity in women of
child-bearing age is still rising (Fisher et al., 2013). Whilst genetic
factors that predispose to obesity in an obesogenic environment, have
likely contributed to the current global obesity epidemic, the short timescale
of this increase implicates non-genetic factors including the
impact of the intrauterine and neonatal environment on adult health
and disease (McAllister et al., 2009). It is vital that we understand the
mechanisms underlying such developmental programming of disease
by maternal obesity in order to develop effective interventions to help
mitigate the current rise in obesity, cardiovascular and metabolic diseases
as well as mental health disorders. Bariatric surgery to induce
weight loss lowers the risk of gestational diabetes mellitus (GDM),
foetal macrosomia and the rate of obesity in the offspring as well as improving
offspring insulin sensitivity, demonstrating that improving the
maternal metabolic state prior to pregnancy is an effective intervention
that improves the health of both mother and child (Kral et al., 2006; Shai
et al., 2014; Smith et al., 2009). However, bariatric surgery is intrusive,
high-risk, costly and can cause nutrient deficiency, the latter of which
led to severe neural defects in some children conceived very soon
after surgery (Pelizzo et al., 2014). A clearer understanding of the mechanisms
mediating the increased risk of metabolic disease in offspring of
obese women is required in order to develop less intrusive, better
targeted interventions. This review will explore recent progress made
in the understanding of the developmental programming by maternal
obesity and potential avenues for intervention.
Animal models have revealed mechanisms underlying programming
by maternal obesity
Animal studies have confirmed that maternal obesity programs
metabolic syndrome—like outcomes in the offspring including impaired
insulin action and glucose homeostasis (Martin-Gronert et al., 2010;
Samuelsson et al., 2008; Shankar et al., 2010; Shelley et al., 2009),
hypertension, and cardiovascular dysfunction (Blackmore et al., 2014;
Fernandez-Twinn et al., 2012; Samuelsson et al., 2008), as well as
increased adiposity (Bayol et al., 2008; Samuelsson et al., 2008; Song
et al., 2015), and an increased susceptibility to diet-induced obesity
(DIO) (Bayol et al., 2007; Howie et al., 2009; Kirk et al., 2009; Nivoit
et al., 2009; Samuelsson et al., 2008; Shankar et al., 2008; Torrens
et al., 2012). The choice of animal model is often a compromise between
practicality of the research and translatability to humans. Whilst nonhuman
primates (NHPs) share the closest resemblance to human developmental
trajectories and pregnancies, they have a long gestation length
and time to maturity of the offspring, leading to high research costs.
Sheep and pigs are used due to their similarities in placental structure
and function to humans, whilst rabbits are a medium-sized mammal
with intermediary similarities and differences to humans. These larger
mammals are conducive to repeated sampling of blood and tissue,
allowing for longitudinal studies and within-subject analysis. Models
with larger litter sizes, such as pigs and rodents, allow for the easier investigation
of sex differences in programming. Rodent models have been
used extensively due to their short gestation (three weeks) and maturity
intervals (five weeks to puberty) and the ease with which to generate a
well-powered experiment of animals of ages across the lifecourse.
Furthermore, they enable genetic engineering to elucidate mechanisms.
A disadvantage is that these smaller mammals are limited to one
sampling point, precluding true longitudinal analysis. In addition,
there are several differences in developmental timings of key tissues
between rodents and humans. An overarching observation is that the
third trimester in humans is roughly equivalent to the first postnatal
weeks in the rodent. Notably adipose tissue develops from early in
gestation in humans whereas subcutaneous and visceral depots develop
from late gestation and early postnatal life, respectively, in rodents
(Rosen and Spiegelman, 2014). Cardiomyocyte proliferation and growth
is mostly complete by birth in the human and sheep (Morrison et al.,
2007), whereas cardiomyocyte division ends at postnatal day 3 to 4 in
the rat, with growth occurring over the first two weeks of life (Li et al.,
1996). In addition, the development of key intra-hypothalamic connections
occurs during the second postnatal week in rodents but these connections
are established by birth in humans and NHPs (Bouret, 2012;
Coupe and Bouret, 2013; Liu et al., 2013). The choice of animal model
will affect the translatability of the results, however the outcomes seen
in these models often recapitulate phenotypes reported in humans, signifying
the validity of the use of a range of animals to investigate the mechanisms
underlying developmental programming.
Insulin and glucose homeostasis
Maternal obesity programs offspring adiposity, decreased glucose
tolerance, and impaired insulin sensitivity (Fernandez-Twinn et al.,
2012; Samuelsson et al., 2008; Yan et al., 2011). The mechanisms underlying
programming of insulin resistance and glucose homeostasis by
maternal obesity include alterations in peripheral insulin signalling
and insulin secretion [reviewed in (Berends and Ozanne, 2012) and
(Duque-Guimaraes and Ozanne, 2013)]. Adult offspring exposed to
maternal obesity are hyperinsulinaemic and have alterations in the
expression of key insulin signalling and glucose handling molecules
in skeletal muscle, the liver and adipose tissue that indicate a predisposition
for insulin resistance and impaired glucose tolerance
(Martin-Gronert et al., 2010; Nicholas et al., 2013a; Rattanatray et al.,
2010; Shelley et al., 2009; Yan et al., 2011). At least some of the programming
of insulin signalling protein expression appears to occur
through post-transcriptional mechanisms via changes in microRNA
(miR-) levels. Maternal obesity at conception in sheep increases hepatic
miR-29b, miR-130, and miR-107 levels (Nicholas et al., 2013b). Increased
miR-126 expression in adipose tissue of mice exposed to maternal
obesity is associated with down-regulated expression of target
genes involved in insulin signalling including insulin receptor substrate
1 (IRS-1) (Fernandez-Twinn et al., 2014). These programmed changes
in IRS-1 and miR-126 were maintained following differentiation of
pre-adipocytes in vitro, indicating that maternal obesity programs
altered insulin signalling in the offspring adipose tissue in a cellautonomous
fashion.
In addition to peripheral insulin signalling, recent evidence suggests
that the central control of glucose homeostasis is vulnerable to the
hyperinsulinaemic obese maternal environment. Genetically-induced
maternal hyperinsulinaemia and insulin resistance is associated
with disrupted glucose homeostasis and hyperinsulinaemia in male
wild-type offspring despite normal body weight and glycaemia in the
mother (Isganaitis et al., 2014). Furthermore, a recent study demonstrated
that genetic abrogation of insulin signalling specifically in proopiomelanocortin
(POMC) neurons of offspring exposed to a maternal
high-fat diet (HFD) restores POMC innervation of pre-autonomic
paraventricular nucleus (PVH) neurons and normalises the impaired
glucose tolerance otherwise seen (Vogt et al., 2014). This is associated
with an improvement in pancreatic beta cell glucose-stimulated insulin
secretion and parasympathetic innervation of beta cells.
Maternal hyperinsulinaemia with insulin resistance might program
altered offspring development via the concomitant maternal
hyperglycaemia, since insulin does not cross the placenta whereas
glucose does (Dabelea, 2007). In humans, impaired glucose tolerance
during pregnancy is often associated with increased birth weight and
increased risk of childhood obesity (Catalano et al., 2003; Cottrell and
Ozanne, 2007; Hillier et al., 2007; Liu et al., 2014; Plagemann et al.,
144 N.C. Penfold, S.E. Ozanne / Hormones and Behavior 76 (2015) 143–152
2002). Treating GDM mothers to lower their blood glucose reduces this
risk, particularly in male offspring (Bahado-Singh et al., 2012; Gillman
et al., 2010). In a recent study in mice, genetically-induced maternal
hyperglycaemia is associated with increased body weight and impaired
glucose tolerance in wild-type male offspring (Nadif et al., 2015). Therefore
control of glycaemia during pregnancy is not only important for
maternal health but also for the long term health of the offspring.
Cardiovascular system
Hypertension and cardiac hypertrophy are common phenotypes
observed in offspring exposed to maternal obesity (Fernandez-Twinn
et al., 2012; Samuelsson et al., 2008). Studies in rabbits and rats have
suggested that changes in sympathetic tone may be an important
mediator of these effects. Maternal HFD in rabbits increases renal
sympathetic nerve activity in the offspring (Prior et al., 2014). Likewise
studies suggest that maternal obesity in rats induces hypertension in
the offspring via increased sympathetic drive in early development
(Samuelsson et al., 2010), which may be mediated by altered early life
leptin signalling.
Leptin action in the nucleus of the solitary tract (NTS) and the ventromedial
nucleus of the hypothalamus (VMH) increases sympathetic outflow
via the renal nerve (Li et al., 2013; Mark et al., 2009; Marsh et al.,
2003). Umbilical cord leptin levels are elevated in obese pregnancies
(Ferretti et al., 2014; Karakosta et al., 2013; Walsh et al., 2014) and neonatal
circulating leptin is elevated in offspring of obese mice (Samuelsson
et al., 2008). Therefore, early life hyperleptinaemia may drive sympathetic
hyperstimulation in the developing renal-cardiovascular system, leading
to hypertension and cardiovascular dysfunction in adulthood (Briffa
et al., 2014). Indeed, neonatal leptin administration in rats results in
cardiac hypertrophy and dysfunction in adulthood (Marques et al.,
2014b). In addition, rat offspring exposed to maternal obesity show an
exaggerated hypertensive response to peripheral leptin administration
in adulthood (Samuelsson et al., 2010). This is unlikely to be due to impaired
central leptin signalling, as maternal obesity-mediated programming
of leptin resistance is hypothalamic nuclei-specific (Kirk et al.,
2009) and diet-induced obesity in adulthood does not impair central
leptin-mediated sympathetic activity via the renal nerve (Rahmouni
et al., 2005). Therefore it has been postulated that the hyperleptinaemia
seen in adult offspring of maternal obesity animal models drives the accompanying
hypertension via the concomitant increase in central activation
of the sympathetic nervous system (Samuelsson et al., 2010;
Simonds et al., 2014). Notably, it has recently been shown that the increased
risk of hypertension in obese individuals is dependent on functional
leptin signalling (Simonds et al., 2014).
Our studies in a mouse model of maternal DIO have shown that male
offspring of obese dams display cardiac hypertrophy associated with
hyperinsulinaemia and increased oxidative stress prior to a change in
body weight or adiposity, indicating that the programming of increased
risk of cardiovascular disease is independent from mechanisms relating
to obesity (Blackmore et al., 2014; Fernandez-Twinn et al., 2012).
Furthermore, frank cardiac dysfunction with increased sympathetic
dominance akin to the early stages of heart failure is evident in these
mice by young adulthood (Blackmore et al., 2014). This dysfunction
may relate to pathological cardiac hypertrophy and cardiac stress as
early as weaning. Oxidative stress, inflammation and epigenetic mechanisms
may all be involved in the programming of cardiovascular dysfunction
by maternal obesity (Blackmore and Ozanne, 2013, 2014). Given that
obesity itself increases the risk of heart disease, cardiac dysfunction may
be exaggerated in high-fat-fed offspring exposed to maternal obesity.
Indeed, the combination of maternal HFD and post-weaning exposure
to HFD culminates in reduced vasorelaxation in both mice and nonhuman
primates (Fan et al., 2013; Torrens et al., 2012), with increased
oxidative stress in the femoral arteries of adult male offspring (Torrens
et al., 2012).
In summary, early life exposure to hyperleptinaemia as a consequence
of maternal obesity may drive increased sympathetic tone leading to hypertension
and accelerate the onset of cardiac hypertrophy and heart
failure.
Ectopic lipid deposition
Maternal obesity programs increased adiposity and adipose tissue
function in the offspring via alterations in adipocyte morphology
and signalling (Alfaradhi and Ozanne, 2011; Benkalfat et al., 2011;
Murabayashi et al., 2013) as well as changes in food intake. As well as
increased adiposity, ectopic lipid deposition has also been observed in
the liver and pancreas of offspring exposed to maternal obesity
(Alfaradhi et al., 2014; Oben et al., 2010a,b), in association with altered
hepatic mRNA and protein expression profiles indicative of increased
lipogenesis (Bruce et al., 2009), elevated markers of oxidative damage
(Alfaradhi et al., 2014; Bringhenti et al., 2014; Torrens et al., 2012), inflammation,
fibrosis and increased sympathetic nervous system activation
(Oben et al., 2010a). These results provide evidence for an increased
risk of non-alcoholic fatty liver and pancreas diseases (NAFLD and
NAFPD, respectively) in offspring of obese mothers, a pathology which
commonly occurs in obesity when the normal capacity of white adipose
tissue for lipid storage has been exceeded. Recent evidence from a
mouse model of maternal DIO suggests that the predisposition for
NAFPD in high-fat-fed offspring is associated with a programmed shift
in the cellular circadian clock (Carter et al., 2014). Perturbation in internal
biological rhythms is a recent addition to the list of offspring physiologies
affected by maternal nutrition (Martin-Gronert and Ozanne, 2013) and
represents an exciting avenue for investigation, given the new understanding
of circadian biology in health and disease (Bailey et al., 2014).
Interestingly, recent evidence from a swine model of maternal obesity
suggests that increased risk of liver disease can be programmed
transgenerationally, since early postnatal increases in adiposity and
markers of paediatric liver disease are found in male piglets of obese
grandmothers (Gonzalez-Bulnes et al., 2014).
Central control of food intake: programming the hypothalamus
The increased incidence of offspring obesity is frequently associated
with hyperphagia in maternal over-nutrition models (Bayol et al., 2007;
Kirk et al., 2009; Long et al., 2011; Nivoit et al., 2009; Samuelsson et al.,
2008). This increased caloric intake is accompanied by alterations in
hypothalamic expression of key neuropeptides, their receptors and
molecules involved in signalling by peripheral factors (Chen and
Morris, 2009; Chen et al., 2009; Ferezou-Viala et al., 2007; Gupta et al.,
2009; Morris and Chen, 2009; Page et al., 2009) as well as altered hypothalamic
development (Chang et al., 2008; Kirk et al., 2009). Alterations
in gene expression may be due to epigenetic alterations such as changes
in DNA methylation within the gene promoters, as observed in offspring
exposed to early life over-nutrition (Plagemann et al., 2009, 2010). The
impaired development of hypothalamic circuitry in rodents is likely
due to alterations in the hormonal environment in early postnatal
life. Insulin has been implicated in the programming of hypothalamic
circuits in response to maternal diabetes and maternal over-nutrition
(Steculorum et al., 2013; Vogt et al., 2014). Maternal hypoinsulinaemic
hyperglycaemia increases the ratio of orexigenic neurons to anorexigenic
neurons in the neonatal arcuate nucleus (Arc) (Franke et al.,
2005; Steculorum and Bouret, 2011b) and impairs Arc-PVH Agoutirelated
peptide (AgRP) and POMC projections (Steculorum and
Bouret, 2011b). These changes are associated with elevated circulating
glucose, insulin and leptin in the neonate and central leptin resistance,
hyperphagia and obesity in adult life (Steculorum and Bouret, 2011b).
In addition, maternal over-nutrition can alter the timing, amplitude of,
and response to the postnatal surge in neonatal leptin concentrations
that is critical for the development of hypothalamic circuitry (Ahima
et al., 1998; Bouret et al., 2004a; Long et al., 2011; Toste et al., 2006).
145N.C. Penfold, S.E. Ozanne / Hormones and Behavior 76 (2015) 143–152
Leptin promotes neurite outgrowth from the Arc during neonatal life
(Bouret et al., 2004b, 2012) and abnormal neonatal leptin signalling impairs
the formation of the Arc-derived hypothalamic projections (Attig
et al., 2008; Delahaye et al., 2008; Yura et al., 2005). It has recently
emerged that ghrelin also contributes to the early life programming of
obesity. Neonatal ghrelin administration increases Arc neuronal number
and increases the ratio of orexigenic to anorexigenic gene expression
(Steculorum and Bouret, 2011a). Chronic postnatal ghrelin impairs the
formation of Arc projections in association with metabolic dysfunction
and impaired leptin sensitivity in adulthood (Steculorum et al., 2015).
Neonatal over-nutrition, by reducing litter size and thus increasing access
to the mother's milk, predisposes offspring to hyperphagia and obesity in
adulthood (Collden et al., 2015; Plagemann et al., 1999). This is associated
with decreased serum ghrelin in neonates, due to a loss of the normal
up-regulation of ghrelin mRNA in the neonatal stomach, and with abrogation
of ghrelin-induced gene expression in the Arc, potentially due to
impaired transport of ghrelin into the ventromedial hypothalamus
(Collden et al., 2015). Impairment of central ghrelin action in neonates
increases Arc projection density and leads to obesity, hyperglycaemia
and impaired leptin sensitivity in adulthood (Steculorum et al., 2015).
Thus alteration of central insulin, leptin, and ghrelin signalling in
neonates exposed to maternal obesity, with insulin resistance, hyperglycaemia
and hyperleptinaemia, may underlie the programming of
altered hypothalamic development and subsequent metabolic dysfunction
in the adult offspring.
Maternal obesity predisposes to diet-induced obesity: the role of the
reward system
Studies in rodents have demonstrated that offspring exposed to maternal
obesity and/or HFD during gestation and lactation are predisposed
to a greater increase in adiposity and metabolic dysregulation than those
from control dams when the offspring themselves are challenged with a
HFD after weaning (Benkalfat et al., 2011; Howie et al., 2009; Page et al.,
2009; Parente et al., 2008; Rajia et al., 2010). Post-weaning exposure to
a HFD further alters hypothalamic mRNA and protein expression (Page
et al., 2009; Rajia et al., 2010), which may mediate the increased caloric
intake and drive the increased adiposity. Alternatively, the increased
propensity for DIO in offspring of obese mothers may be mediated via
programmed dysregulation of the central mechanisms involved in palatable
food intake: namely the mesocorticolimbic dopamine pathway from
the ventral tegmental area (VTA) to the nucleus accumbens (NAcc).
Dopaminergic signalling in the NAcc is thought to control incentive
salience, or the motivated “wanting” of palatable foods, whilst opioidergic
inputs onto the same pathway are thought to signal the pleasure associated
with eating tasty foods and so influence food preferences or the
“liking” of palatable foods (Blum et al., 2012; Egecioglu et al., 2011;
Volkow et al., 2011). Connections between the reward system and the
hypothalamus are critical for the regulation of reward-related feeding
(Dietrich et al., 2012; Leinninger et al., 2011).
In humans and rodents, reward signalling is altered in obesity
(Batterink et al., 2010; Burger and Stice, 2011; Finger et al., 2012;
Johnson and Kenny, 2010; Shin and Berthoud, 2011; Stoeckel et al.,
2008), due at least in part to chronic HFD-mediated epigenetic dysregulation
of key dopaminergic and opioidergic signalling molecules (Vucetic
et al., 2011, 2012). In addition, dysregulated reward signalling may predispose
to diet-induced obesity (Blum et al., 2014; Volkow et al., 2008).
Thus, the central reward system may be vulnerable to early life exposure
to maternal obesity and programmed alterations may underlie the
increased propensity for obesity when offspring are exposed to a highly
palatable diet in adulthood.
Indeed, in animal models of maternal HFD or obesity, offspring
consume more high-fat and high-sugar foods than controls (Bayol
et al., 2007; Bocarsly et al., 2012; Ong and Muhlhausler, 2011, 2014;
Tamashiro et al., 2009; Walker et al., 2008). This may be due to an increased
preference for these macronutrients (Vucetic et al., 2010) but
is not associated with altered orosensory stimulation by their taste
(Treesukosol et al., 2014). Whilst food preferences can be programmed
by maternal nutrition (reviewed in (Gugusheff et al., 2014)), maternal
obesity is also associated with altered motivation for palatable foods
in multiple rodent models (Grissom et al., 2014b; Naef et al., 2011;
Rodriguez et al., 2012). The programmed increases in preference for
fat and sugar and altered motivation to work for such foods are associated
with changes in dopaminergic tone (Naef et al., 2011, 2013) as well
as in expression of key dopaminergic and opioidergic signalling genes
(Naef et al., 2011; Ong and Muhlhausler, 2011; Vucetic et al., 2010),
with evidence for epigenetic regulation at some loci (Grissom et al.,
2014a; Vucetic et al., 2010). In fact, maternal obesity at conception is
sufficient to program opioid dysregulation in the offspring (Grissom
et al., 2014c). Therefore, maternal obesity may predispose the offspring
to DIO via programmed changes in the mesocorticolimbic reward pathway.
Importantly, the mesocorticolimbic dopamine pathway develops
in utero in rodents with VTA efferents innervating the accumbens and
cortex by birth (Hu et al., 2004). Therefore, investigations into the in
utero programming of the reward system may more readily translate
from mouse to man than for some other systems.
Programming learning and memory: leptin and the hippocampus
Offspring exposed to maternal obesity are slower to acquire an executive
function task, in which they demonstrate greater impulsivity but
no difference in attention (Grissom et al., 2014b). The hippocampus
mediates learning and develops perinatally in both humans and rodents
(Semple et al., 2013). In rodents, an important period of synaptogenesis
and dendritic spine formation in the developing hippocampus coincides
with the peak of the postnatal leptin surge in rodents, which is significant
as leptin induces excitatory synaptogenesis and promotes dendritic
spine formation in the adult hippocampus (Dhar et al., 2014a,b). Leptin
also potentiates GABAergic transmission in postsynaptic CA3 pyramidal
cells from the hippocampi of newborn rats (Guimond et al., 2014). The
basal activity of these cells is reduced in leptin-deficient mice, as is a
marker of presynaptic GABA synthesis, indicating that leptin signalling
is critical for GABAergic transmission in the developing hippocampus
(Guimond et al., 2014). In addition, chronic leptin treatment during
the first two postnatal weeks alters the expression of genes involved
in NMDA signalling and synaptic machinery and reduces long-term
potentiation in pre-weaning rats (Walker et al., 2007). A similar phenotype
is observed in hyperleptinaemic neonates exposed to maternal
HFD from late gestation through lactation (Walker et al., 2008). As
such, altered leptin signalling in early life may impair the formation of
synapses and dendritic spines and thus the maturation of the hippocampus,
which may underpin the reported impaired cognition, learning
and memory in later life and predisposition for psychopathologies and
obesity (Valleau and Sullivan, 2014).
In addition, the programming of obesity and psychiatric disorders by
maternal obesity has been attributed to increased maternal-foetal inflammatory
signalling (Bolton and Bilbo, 2014; Marques et al., 2014a). It has
recently been shown that the impairment in Arc-PVH neuropeptide Y
(NPY) projections seen in mice exposed to maternal DIO may be due to
increased foetal exposure to the inflammatory cytokine interleukin-6
(IL-6) (Sanders et al., 2014). Maternal IL-6 is also increased midgestation
in mothers with GDM and inversely correlates with birth
weight and glucose tolerance (Hassiakos et al., 2015). In fact, the correlation
between GDM and IL-6 levels is so strong that circulating IL-6 alone
can predict GDM status. In addition, maternal obesity is associated with
increased levels of inflammatory cytokines (Challier et al., 2008;
Kepczynska et al., 2013; Kim et al., 2014), of which IL-6 is associated
with increased risk of obesity in the offspring (Dahlgren et al., 2001;
Smith et al., 2007). Therefore, inflammatory cytokines are also candidate
programming mediators in the early life programming of central dysfunction
by maternal obesity.
146 N.C. Penfold, S.E. Ozanne / Hormones and Behavior 76 (2015) 143–152
Candidate programming mechanisms and factors in maternal obesity
Potential molecular mediators of the programming of cardiometabolic
disease and central neuroendocrine pathways by maternal obesity
have been highlighted by recent mechanistic studies. Identification of
the key programming factors is vital for the development of rational
intervention strategies. It is also important to understand the key
windows for intervention: do we aim to intervene before or during
pregnancy and/or during early postnatal life? Should interventions
target maternal diet, maternal obesity or both?
In utero exposure to maternal obesity is an important target for
intervention. It is important to note here the differences in placental
biology and developmental timings between rodents, the key model for
mechanistic studies, and humans. Rodent placentae structure and blood
flow differ from human placentae, however mice have been used successfully
to model intra-uterine growth restriction (Gonzalez-Bulnes and
Astiz, 2015). Sheep and pig models are more common in investigations
into placental biology and intrauterine development, due to their closer
resemblance to human placental morphology but also the ability to insert
catheters into the maternal and foetal circulation in order to monitor placental
transfer over time in vivo (Barry and Anthony, 2008).
Maternal obesity during pregnancy may impair foetal nutrition via
placental adaptations (Tarrade et al., 2015). Indeed placentae from
obese women transport less maternal taurine, a critical beta-amino
acid involved in placental development and foetal growth (Ditchfield
et al., 2014) and have higher levels of oxidative stress and impaired
mitochondrial respiration (Hastie and Lappas, 2014; Mele et al., 2014).
In addition, maternal DIO in mice is associated with decreased placental
mTOR signalling, which may contribute to the decreased foetal:placental
weight ratio in late gestation via altered amino acid transport (Lager et al.,
2014). Conversely maternal high-fat feeding, whether accompanied by
obesity or not, is associated with foetal overgrowth and up-regulation of
glucose and amino acid transport across the placenta (Jones et al., 2009;
Sferruzzi-Perri et al., 2013). Thus, foetal growth may be altered in maternal
obesity due to alterations in placental function.
In addition, altered maternal intake of vital micronutrients in maternal
obesity may contribute to offspring epigenetic programming. Dietary intake
of key methyl donors varies seasonally in certain populations such
Fig. 1. Maternal obesity programs obesity, cardiometabolic disease and neuropsychiatric disorders in the offspring. Maternal factors involved include hyperinsulinaemia, hyperglycaemia,
hyperleptinaemia, hyperlipidaemia, and impaired placental function. Common programming mechanisms in offspring tissues include oxidative stress, epigenetics, and inflammation.
Inflammation, insulin, leptin and ghrelin have all been implicated in brain development. The early life programming of brain circuits [HIP — hippocampus, HYP — hypothalamus,
ML — mesolimbic pathway] may contribute to altered energy balance, motivated and other behaviours. Altered central control of the autonomic nervous system (ANS) may underlie
cardiac and pancreatic phenotypes in the offspring. Programmed changes in adipose tissue, the liver, pancreas, and skeletal muscle function contribute to impaired glucose homeostasis.
Overall, alterations in individual tissue function contribute to the increased risk of obesity, cardiometabolic disease, and neuropsychiatric disorder in the offspring. Current strategies aim
to ameliorate metabolic status of the obese mother via lifestyle or pharmacological interventions before conception or during pregnancy in order to normalise offspring phenotype.
147N.C. Penfold, S.E. Ozanne / Hormones and Behavior 76 (2015) 143–152
as those in the Gambia where the timing of pregnancy in relation to the
seasons is associated with permanent alterations in DNA methylation at
key loci in the offspring (Dominguez-Salas et al., 2014). This provides
some of the earliest evidence for the impact of human maternal methyl
donor dietary intake during pregnancy on life-long epigenetic programming
in the offspring. In rodents, maternal dietary supplementation
with methyl donors ameliorates the increased body weight gain in offspring
of obese dams (Carlin et al., 2013; Cordero et al., 2014) and restores
fat preference to control levels in association with normalisation of the
methylation status at promoter regions of key genes involved in the central
reward system (Carlin et al., 2013).
The early postnatal life and the lactation period is another target for intervention.
Rodents experience fluctuations in hormonal levels during the
first three weeks of life that have been implicated in the development and
maturation of key hypothalamic circuitry (Bouret, 2013). Whilst this is
different to human development, early postnatal life in humans is also
considered to be a vital time for the maturation of the brain and adipose
tissue. As such, exposure to maternal obesity during lactation is a factor
in offspring health, with one potential mediator being alterations in breast
milk lipid content. In both humans and rodents, over-nutrition and accelerated
growth during the neonatal period is associated with increased adiposity
in later life (Plagemann et al., 2012). The combination of maternal
obesity and HFD consumption reduces breast milk lipids, whilst HFD consumption
during lactation alone increases them (Rolls et al., 1986). Breast
milk lipid content is decreased in HFD-fed obese dams during lactation
compared to HFD-fed control dams, due to impaired mammary fatty
acid synthesis (Saben et al., 2014). In a maternal DIO rat model, breast
milk levels of triglycerides are elevated but free fatty acids are decreased
early in lactation and increased in the latter stages (Kirk et al., 2009).
As discussed above, maternal obesity during pregnancy and lactation
is associated with elevated maternal circulating leptin, insulin, glucose
and inflammatory cytokines, all of which have been linked to cardiometabolic
dysfunction in the offspring (Fig. 1). Exposure to these maternal
factors both in utero and during early postnatal life can alter offspring development.
As such, interventions should aim to target women planning
to conceive or soon after pregnancy is confirmed. Ensuring appropriate
maternal dietary nutrition, improving the metabolic status of obese
women in order to normalise hormonal levels, ameliorate inflammation
and improve placental sufficiency, and optimizing infant growth and
nutrition in the neonatal period are key aims of intervention.
Interventions to improve outcomes of offspring exposed to
maternal obesity
Improving women's metabolic health at the time when they are trying
to reproduce is an attractive target, since it would benefit the health of
both mother and child and only a temporary improvement in maternal
health could improve public health for generations. Notably, dietary and
lifestyle advice has been shown to be effective in overweight and obese
pregnant women (Dodd et al., 2014).
Rodent models of maternal obesity have been used to study the
effectiveness of dietary and exercise interventions in the mother on offspring
metabolic and behavioural phenotype, due to the ability to
enforce exercise and easily control diets in these species. Dietary intervention
from before pregnancy or during lactation normalises the
increased adiposity and circulating leptin, insulin and triglycerides in
weanling offspring, rescues the altered motivation and hyperphagia
and partially normalises glucose homeostasis and adipocyte morphology
in adulthood (Bayol et al., 2007; Rodriguez et al., 2012; Zambrano et al.,
2010). In addition, maternal dietary intervention rescues the increased
anxiety and altered social behaviours in female offspring of maternal
DIO mice in association with amelioration of central inflammation in
these offspring (Kang et al., 2014). However, the same reversal is not
seen in male offspring. Voluntary exercise before and during pregnancy
in lean dams improves glucose homeostasis in the offspring (Carter
et al., 2012, 2013) and prevents hyperleptinaemia (Laker et al., 2014;
Vega et al., 2013). This may be due to the reduction in levels of maternal
circulating triglycerides, glucose, insulin, cholesterol, oxidative stress and
corticosterone (Vega et al., 2013).
Randomised controlled trials (RCTs) are now being used to investigate
whether the same improvements can be seen in obese human pregnancies.
A low glycaemic index (GI) diet during pregnancy has been
shown to increase weight loss from pre-pregnancy to three months
after birth in overweight women and thus may minimise gestational
weight gain (Horan et al., 2014). Current RCTs are addressing the effect
of exercise alone (Sagedal et al., 2013; Seneviratne et al., 2014) or in combination
with dietary intervention (Briley et al., 2014) to improve health
outcomes in overweight and obese mothers and their children.
In addition, pharmacological studies are addressing the possibility of
normalising the maternal metabolic and hormonal state with a view to
improving offspring health. Metformin, an insulin sensitiser, has been
trialled as an alternative to insulin treatment for gestational diabetes,
with initial results indicating no effect on offspring blood pressure at
2 years of age in comparison to insulin treatment nor in maternal postpartum
weight loss when compared to placebo (Battin et al., 2015;
Refuerzo et al., 2015). There is currently a trial underway to test whether
metformin administration during pregnancy in obese women will
prevent macrosomia and this study will include investigation of maternal
factors, including insulin resistance, inflammation and adiposity, as
well as foetal adiposity (Chiswick et al., 2015). However, concerns
have been raised as to the lack of long-term safety data in offspring
exposed to metformin during gestation (Fantus, 2015). Animal models
are invaluable to help address this issue. An initial study into the effects
of metformin administration during pregnancy in a maternal obesity
mouse model found that offspring from metformin-treated dams were
protected from glucose intolerance and key gene expression changes
in skeletal muscle (Tong et al., 2011). A more recently published study
suggests that offspring from high-fat fed dams treated with metformin
during pregnancy are protected against the exacerbated body weight
gain upon exposure to a high fat diet in adulthood (Salomaki et al.,
2014). However, this was not a model of maternal obesity and the number
of litters studied was low. Additional investigations in rodent
models are needed to understand the long-term effects of gestational
exposure to metformin and to complement the human trials on shortterm
outcomes in obese pregnancies.
Further study in animal models is therefore required to inform the
most effective timing and intensity of specific dietary and pharmacological
interventions, including in altricial species to model intervention
periods in line with human developmental timings (Nathanielsz et al.,
2013).
Conclusion
In summary, recent animal studies of developmental programming by
maternal obesity have advanced our understanding of the underlying
mechanisms as well as further elucidated aspects of offspring physiology
that contribute to their increased risk of obesity, cardiometabolic disease
and mental health disorders. As the focus shifts towards designing interventions
to curtail the developmental programming by maternal obesity,
studies in both animals and humans are necessary to ensure safety, effectiveness,
and specificity.
Acknowledgments
NCP holds a Wellcome Trust PhD studentship; SEO is a member of the
MRC Metabolic Diseases Unit and is funded by MRC grant MC_UU_12012/
4. We thank Laura Dearden for her helpful discussions.
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