Nutrients 2015, 7, 8090-8111; doi:10.3390/nu7095384
OPEN ACCESS
nutrients
ISSN 2072-6643
www.mdpi.com/journal/nutrients
Review
Early Life Nutrition and Energy Balance Disorders in Offspring
in Later Life
Clare M. Reynolds, Clint Gray, Minglan Li, Stephanie A. Segovia and Mark H. Vickers *
Liggins Institute and Gravida: National Centre for Growth and Development, University of Auckland,
Auckland 1142, New Zealand; E-Mails: c.reynolds@auckland.ac.nz (C.M.R.);
c.gray@auckland.ac.nz (C.G.); m.li@auckland.ac.nz (M.L.); s.segovia@auckland.ac.nz (S.A.S.)
* Author to whom correspondence should be addressed; E-Mail: m.vickers@auckland.ac.nz;
Tel.: +64-9-9236687; Fax: +64-9-3737039.
Received: 10 June 2015 / Accepted: 11 September 2015 / Published: 21 September 2015
Abstract: The global pandemic of obesity and type 2 diabetes is often causally linked
to changes in diet and lifestyle; namely increased intake of calorically dense foods and
concomitant reductions in physical activity. Epidemiological studies in humans and
controlled animal intervention studies have now shown that nutritional programming in
early periods of life is a phenomenon that affects metabolic and physiological functions
throughout life. This link is conceptualised as the developmental programming hypothesis
whereby environmental influences during critical periods of developmental plasticity can
elicit lifelong effects on the health and well-being of the offspring. The mechanisms by
which early environmental insults can have long-term effects on offspring remain poorly
defined. However there is evidence from intervention studies which indicate altered wiring
of the hypothalamic circuits that regulate energy balance and epigenetic effects including
altered DNA methylation of key adipokines including leptin. Studies that elucidate the
mechanisms behind these associations will have a positive impact on the health of future
populations and adopting a life course perspective will allow identification of phenotype and
markers of risk earlier, with the possibility of nutritional and other lifestyle interventions that
have obvious implications for prevention of non-communicable diseases.
Keywords: developmental programming; maternal nutrition; energy balance;
metabolic syndrome
Nutrients 2015, 7 8091
1. Background
The prevalence of overweight and obesity has risen markedly in Western societies over the past few
decades and the trend is mirrored in developing nations that are transitioning to first-world economies.
Obesity results from a chronic imbalance between energy intake and energy expenditure [1]. As such,
disorders of systems regulating energy balance can lead to obesity and related metabolic complications.
In this context, it is now well established that alterations in the early life nutritional environment can
lead to perturbations in the regulation of energy balance and energy sensing pathways in later life. The
Developmental Origins of Health and Disease (DOHaD) hypothesis has highlighted the link between
the periconceptual, fetal, and early infant phases of life and the subsequent development of metabolic
disorders in later life [2–4]. Under the DOHaD model, the fetus or neonate makes predictive adaptations
in response to cues from the early life environment, resulting in adjustments in homeostatic systems to aid
immediate survival and improve success in an expected postnatal environment of adversity. However,
inappropriate interpretations of these cues or changes to the environment may result in a mismatch
between prenatal predictions and postnatal reality. As a result, these adaptations, or predictive adaptive
responses (PARs) [5], may be disadvantageous in postnatal life, leading to an increased risk of chronic
diseases in adulthood that may be transmitted into future generations [6]. In particular, the hypothalamic
neuronal circuits located in the arcuate nucleus controlling appetite and energy expenditure are set early
in life and have been shown in a number of models to be perturbed by a range of early life nutritional
insults [7]. These include epigenetic modifications which regulate hypothalamic gene expression and
therefore represent potential molecular mechanisms linking maternal diet during pregnancy to the
later risk of disorders in energy balance and obesity in offspring. Disorders of energy balance as a
consequence of developmental programming remain poorly defined on a mechanistic basis. Human
evidence is limited and based largely on semi-quantitative approaches or limited metabolic physiological
endpoints. Animal models have provided some mechanistic insight but this has primarily focused around
hypothalamic re-programming and integration with behavioral/food preferences and direct measures of
energy expenditure still remain largely unexplored.
2. Developmental Programming and Disorders of Energy Balance: Human Evidence
Evidence from both epidemiological studies and intervention studies in animal models has shown that
the metabolic programming of energy balance begins with and can be modified by nutrition in the very
early stages of development. Therefore, pregnancy and lactation are revealed as critical periods where
food restriction may lead to permanent adaptations with lasting effects on metabolic mechanisms in the
offspring; thereby changing the predisposition to obesity in adult life. Evidence to date has shown that
the different outcomes of these adaptations on later health depend on the type, duration, period, and
severity of the restriction and that they are, at least in part, sex specific.
The Dutch Famine (1944–1945) cohort is one of the most cited human cohorts used to examine the
effects of poor early life nutrition on later metabolic and cardiovascular outcomes. Individuals exposed to
the famine have increased adiposity, which may arise due to changes in energy intake, physical activity,
and/or metabolic efficiency and are also dependent upon the timing of famine exposure [8,9]. Many
of these data are collated via food frequency and physical activity data questionnaires and associations
Nutrients 2015, 7 8092
appear to differ according to the reference population used [10]. However, persistent small changes
in energy balance could explain the increased weight of famine-exposed individuals. Further, work by
Lussana et al. reported that famine exposure was associated with a preference for fatty foods and a
tendency to be less physically active when studied in men and women at 58 years of age [11]. Data from
adults born between 1954 and 1964 from the 2002 China National Nutrition and Health Survey show
that exposure to the Chinese famine during fetal life or infancy was associated with an increased risk of
metabolic syndrome in adulthood but little is known about altered regulation of energy balance in this
cohort [12]. In the Helsinki Birth Cohort Study, with participants aged 56–70, whose birth weight and
length were recorded, it was concluded that prenatal growth may modify food and macronutrient intake
later in life, and altered dietary habits could potentially explain the increased risk of chronic disease in
individuals born with small body size [13]. There are also reports on the effects of seasonality on fetal
growth and postnatal outcomes in offspring related to alterations in energy balance. For example, in
rural Gambian women, pronounced naturally occurring seasonal differences in diet can lead to persistent
and systemic changes in epigenetic profiles in offspring including altered methylation at imprinted
loci [14,15].
Recent work by Neymotin and Nemzer has also detailed a concept around “locus of control” as
relates to obesity [16]. Health locus of control has been associated with a variety of health outcomes and
designed to predict behaviors and cognitive processes relevant to both mental and physical health [17,18].
In the context of energy balance, this concept suggests that, in humans, overlaid on the complex system
for modulating energy intake, there exists a wide variation in “perceived locus of control”. Locus of
control is an important characteristic in relation to obesity as, by definition, it indicates whether an
individual believes that his or her environment and choices are under his or her control. An example of
this is the treatment of obese individuals with dexamphetamine (for a psychotropic effect on motivation)
coupled with a basic behavioural intervention which was shown to be effective for weight loss with no
significant complications reported [19]. Further work by Levy et al. has used stimulant medication
(mainly amphetamine) in a female cohort of obese individuals with attention deficit hyperactivity
disorders; significant weight lost was observed and suggested to be a result of positive effects of treatment
on self-directedness, persistence and behavioural change as regards diet compliance [20]. Thus, in
addition to actual physical cues of hunger or satiation, the ability to interpret those cues appropriately
in a given social setting may help determine how obesity develops and persists and therefore may be a
component underlying developmental programming of altered energy balance that has yet to be explored.
3. Developmental Programming and Disorders of Energy Balance: Evidence from
Experimental Models
Human evidence is limited due to long generation times for prospective studies and the quality of
data records for retrospective studies. Data are primarily derived from rodent models due to the short
timeframe required to generate offspring and there are now a number of examples showing lasting
effects of the perinatal environment on neurodevelopment and regulation of energy balance [21–23].
Circulating hormones influence multiple aspects of hypothalamic development and play a role in
directing formation of neural circuits. Thus, a deficiency in any of these essential factors during a
critical period of development may have permanent structural consequences. Hypothalamic development
Nutrients 2015, 7 8093
in large mammals is in contrast to the situation in rodents that are either altricial at birth or born
immature [24]. Consequently, hypothalamic maturation in the rodent is initiated prenatally but does not
finalise until the second week of postnatal life [25]. Nutrient supply is therefore determined by maternal
lactational capacity rather than being dependent on placental nutrient transfer capacity. Changes in
milk composition therefore have the potential to have a pronounced effect on extent of hypothalamic
maturation mediated through changes in hormone concentration of the milk. For example, rat pups born
to obese dams show a precocious surge in circulating insulin together with an abnormal and pronged
neonatal leptin surge [26]. These effects are likely to be driven by changes in milk composition. As
an example, a maternal high fat diet in the rat is associated with increased fat [27,28] and protein
concentrations in milk which appears to induce early overnutrition and has been shown to be paralleled
by obesity and adrenal and thyroid dysfunction in male offspring at the time of weaning [29]. However,
despite the different developmental time windows across the range of models used, both altricial and
precocial species share several common offspring programming mechanisms, particularly as regards
hypothalamic re-wiring.
A particular focus has been on the adipokine leptin, an important neurotropic factor during
postnatal development [30,31]. Leptin deficiency during critical periods of development may have later
consequences in body weight regulation and control of appetite and energy expenditure [32,33]. In
the rat, pre- and postnatal calorie restriction perturbs hypothalamic neuropeptide regulation of energy
balance, altered by the timing and magnitude of the leptin surge and therefore setting the stage for
hyperphagia and reduced energy expenditure, hallmarks of obesity. Leptin in turn reverses this phenotype
by increasing hypothalamic ObRb signaling (sensitivity) and affecting only the orexigenic arm of the
neuropeptide balance [34]. Importantly, leptin replacement in the neonatal period has been shown in
some experimental animal models to rescue the effects associated with adverse early life developmental
programming [34–37]. However, the effects of leptin can differ based on the experimental model used.
For example leptin intervention appears directionally (and sex) dependent upon the level of maternal
nutrition [38]—it can be protective in offspring of mothers undernourished during pregnancy [35,37]
but may induce an adverse phenotype when treatment is provided to offspring of normally nourished
mothers [36,39].
The brain is not the only tissue that is sensitive to perinatal conditions and responsible for the perinatal
programming of body weight control. Recent data indicate that the development of other structures, such
as peripheral innervations of the sympathetic nervous system, may also be altered during development
and have an important impact on future adiposity and metabolism of the offspring [40]. In addition, an
altered early life environment may modify food and taste preferences in offspring [41]. As an example,
prenatal to a maternal low protein (LP) diet programmes a preference for high fat foods in young adult
offspring [42]. Such changes may be driven by alterations in taste receptor expression. Recent studies
have demonstrated that taste receptors in tongue, gut, and pancreas are associated with local hormone
secretion including that of TNF-α and leptin [43]. In these studies, in addition to the regulation of food
intake, taste perception appeared to be tightly linked to circulating metabolic hormone levels. Further
understanding of the link between taste perception and peripheral metabolic control could therefore
potentially lead to the development of intervention therapies for obesity or type 2 diabetes (T2DM).
Nutrients 2015, 7 8094
Studies in the rodent have primarily utilised maternal undernutrition (primarily either global or LP)
or uterine artery ligation to induce intrauterine growth restricted (IUGR) offspring. In addition, it
is also proposed that intrauterine stress exposure may interact with the nutritional milieu, and that
stress biology may represent an underlying mechanism mediating the effects of diverse intrauterine
perturbations and later programming effects on brain and peripheral targets of programming of body
composition, energy balance homeostasis and metabolic function [44]. Several studies utilising maternal
perinatal undernutrition have produced consistent evidence that the programmed offspring present with
low birth weight, hyperphagia in postnatal life and develop obesity, insulin resistance and sedentary
behaviours in adulthood [31,45–47]. The hyperphagia is exacerbated in the presence of a postnatal
high fat diet (HFD) [45]. In addition to structural changes in the hypothalamus, the rodent models
have also shown modifications in key neuropeptides in the arcuate nucleus including the anorexigenic
proopiomelanocortin (POMC), and the orexogenic peptides agouti gene-related protein (AgRP) and
neuropeptide Y (NPY). Although the timing and severity of undernutrition differs across models,
the data appear consistent with increased hypothalamic NPY and AgRP and decreased POMC gene
expression in postnatal offspring [7,48,49]. In addition to changes in AgRP, offspring from malnourished
dams also present with dysregulation in the hypothalamic melanocortin (melanocortin receptor 4) and
α-melanin-stimulating hormone (α-MSH) system with a series of alterations: impaired neurogenesis and
neuronal functionality, disorganization of feeding pathways, impaired glucose control, and leptin/insulin
resistance. Overall, these alterations may account for the long-lasting dysregulation of energy balance
and obesity [50]. In addition to leptin, the impact of maternal UN on other factors such as serotonin
(5-HT) and dopamine and later disorders of energy balance have also been investigated [51]. In
the rodent, maternal undernutrition is associated with changes in hypothalamic 5-HT and dopamine
expression concomitant with hyperphagia and obesity.
Although the rodent has a number of advantages over other models species (including short gestation
length and relative ease of genetic manipulation), the critical periods for the setting of pathways
regulating energy balance differ significantly between rodents and humans [52]. The setting down of
neural pathways develops in the early postnatal period in the rodent while in the human and other model
species (e.g., sheep, primate, pig) these pathways develop prenatally [53]. Despite these developmental
differences in key periods of plasticity, the rodent outcome data appears similar to a number of studies
that also report programming of altered energy balance following early life nutritional perturbations in
large animal models including sheep, swine and non-human primate (NHP). In the sheep, both twinning
and periconceptional undernutrition are associated with epigenetic changes in fetal hypothalamic POMC
and glucocorticoid receptor genes, potentially resulting in altered energy balance regulation in the
offspring [54]. A recent study in sheep reported no effect of IUGR on early postnatal hypothalamic
energy balance gene expression; this was associated with major sex differences in adiposity and
leptinemia [55]. These IUGR offspring were suckled by overnourished mothers that may explain the
lack of hypothalamic phenotype in this model. As with the rodent studies, programming effects related
to undernutrition can be sexually dimorphic. As an example, male offspring from undernourished ewes
develop increased adiposity which is not observed in females [56]. It is possible that these effects
are a consequence of decreased central insulin action resulting in lower POMC expression thereby
reducing food intake [48] or estrogen-mediated regulation of leptin and insulin resulting in compensatory
Nutrients 2015, 7 8095
mechanisms in females to curtail the effects of undernutrition. In a swine model of maternal energy
restriction, differences in hypothalamic gene expression at birth and higher growth and adiposity in
adulthood suggested a programming effect in offspring towards a positive energy balance, possibly due
to overexposure to endogenous stress-induced glucocorticoids [57]. Moreover these effects were sex
specific with only females affected.
In addition to the extensive work on the central pathways involved in energy balance and
thermogenesis, there are now also reports related to altered maternal nutrition and skeletal muscle
response to changes in energy balance. There is evidence that a maternal LP diet and postnatal
HF nutrition may increase the risk for T2DM by decreasing skeletal muscle oxidative respiration
via increased Sirtuin (Sirt)-3 and possibly by decreased amounts of the active form of succinate
dehydrogenase enzyme. Undernutrition during pregnancy can also lead to dysfunctional cardiac
muscle respiration in adult offspring [58]. Maternal obesity can also have adverse effects on muscle
development [59] with a maternal HFD significantly decreasing muscle myogenic differentiation 1
(MYOD1) and glucose transporter type 4 (GLUT4) mRNA expression in male rat offspring which
is normalized by maternal exercise [60]. Maternal obesity can also lead to alterations in regulators
of mitochondrial function in skeletal muscle of offspring (including peroxisome proliferator-activated
receptor gamma coactivator (PGC1)α, PGC1β) which is paralleled by reduced energy expenditure and
impaired fat utilisation as assessed by indirect calorimetry [61].
Much of the early work in the developmental programming field focused on models of maternal
undernutrition to induce varying degrees of fetal growth restriction. However, there are now a large
number of models detailing the effects of a maternal/neonatal obesogenic environment on altered energy
balance in offspring. These approaches are detailed in a recent review by Williams et al. [62]. A
number of studies have now shown that a maternal obesogenic environment plays a critical role in
programming of hypothalamic pathways that regulate feeding and energy balance [53]. In the rodent,
overfeeding in the early postnatal period increases the orexigenic peptide NPY and AgRP in the arcuate
nucleus of the hypothalamus [53] and offspring of mothers fed a HFD have reduced sensitivity to
the anorectic effects of leptin [63,64]. A HFD during pregnancy can stimulate the proliferation of
neuroepithelial and neuronal precursor cells of the embryonic hypothalamic third ventricle and stimulates
the proliferation and differentiation of neurons and their migration toward hypothalamic areas where
ultimately a greater proportion of the new neurons expressed orexigenic peptides. This increase in
neurogenesis, closely associated with increased blood lipids, may play a role in producing the long-term
behavioural and physiological changes observed in offspring after weaning, including an increase in
food intake, preference for fat, hyperlipidemia, and higher body weight [65]. Rats fed a highly palatable
cafeteria diet for 2 weeks show impaired sensory-specific satiety following consumption of a high calorie
solution and these deficits remain even following the withdrawal of the cafeteria foods [66]. Further, a
cafeteria diet can lead to neuroadaptive responses in brain circuits underlying reward with unrestrained
consumption of palatable food shown to increase the reinforcing value of food and weaken inhibitory
control [66,67]. In the context of developmental programming, it has been shown that perinatal exposure
to high-fat, high-sugar diets results in altered development of the central reward system, resulting in
increased fat intake and altered response of the reward system to excessive junk-food intake in offspring
in postnatal life [68]. Maternal gestational diabetes (GDM) has also been shown to program changes
Nutrients 2015, 7 8096
in the hypothalamic neural network controlling appetite in offspring. Experimentally induced diabetes
leads to offspring with increased glucose and insulin concentrations, hyperphagia and increased body
weight. Offspring of GDM mothers also exhibit structural alterations that affect the density of AgRP
and MSH fibers in the paraventricular nucleus with impaired leptin sensitivity [69]. Plagemann et al.
have reported that offspring of GDM mothers have increased numbers of NPY and galanin containing
neurons thus further highlighting that maternal diabetes leads to “malprogramming” of hypothalamic
neuropeptidergic neurons in offspring [70]. Importantly, restoration of these neural circuits can be
achieved by normalising gestational hyperglycemia [71].
As with the undernutrition models, rodent models are the most widely used in the investigation of
programming effects arising from a maternal obesogenic environment. However, a range of large animal
models have also been utilised in this area. Maternal obesity in the sheep increases fatty acid synthesis,
upregulates nutrient transporters, and increases adiposity in adult male offspring after a feeding
challenge [72]. Lambs born to obese sheep have elevated cortisol concentrations and this may play a
role in disrupting the normal peak of leptin thereby predisposing them to increased appetite and weight
gain in later life [73]. Further, maternal obesity in this model appears to lead to altered programming of
the leptin surge that is transmitted to the F2 generation [74] with similar effects reported in a piglet model
of maternal obesity [75–77]. In the NHP, chronic consumption of a HFD during pregnancy, independent
of maternal obesity and diabetes, leads to widespread activation of proinflammatory cytokines that may
alter the development of the melanocortin system. The abnormalities observed in the fetal POMC system,
if maintained into the postnatal period, may therefore impact several systems, including body weight
homeostasis, stress responses, and cardiovascular function.
4. Epigenetic Mechanisms
An alternative mechanism by which environmental factors at critical periods of development
could have long-term phenotypic consequences may involve epigenetic modifications (including DNA
methylation, histone modifications and microRNA (miRNA)). Epigenetic processes are now widely
viewed as a leading mechanism to explain the lifelong persistence of such developmental programming
of energy balance [78,79]. As epigenetic regulation during development undergoes dynamic changes,
the epigenome displays a labile nature, which allows it to respond and adapt to environmental stressors,
including suboptimal nutrition [80]. A number of studies have therefore focussed on the epigenetic
contributions to disease manifestation arising as a consequence of adverse early life events [81–83].
In the setting of altered early life nutrition, organisms can fine tune gene expression to achieve
environmental adaptation via epigenetic alterations of histone markers of gene accessibility [84].
Experimental models of programming have now shown that a range of challenges during pregnancy
or early neonatal life result in changes in promoter methylation which directly or indirectly affect
gene expression in pathways associated with a range of processes related to energy balance [85–89].
Mechanisms underlying epigenetic modification of tissue function resulting in a predisposition to altered
programming of leptin and insulin signalling are discussed by Holness et al. [90]. Leptin has a 3-kb
promoter region embedded within a CpG island and contains many putative binding sites for known
transcription factors including a glucocorticoid response element. It has been shown that leptin’s
promoter is subject to epigenetic programming, and leptin’s expression can be modulated by DNA
Nutrients 2015, 7 8097
methylation [91–93]. Methylation of a CpG island in the leptin promoter plays an important role in
leptin expression during pre-adipocyte differentiation [92,93]. Protective effects of leptin during the
suckling period against later obesity may be associated with changes in promoter methylation of the
hypothalamic POMC gene [32]. In addition, activation of the leptin receptor also induces expression
of suppressor of cytokine signaling-3 (SOCS-3). This protein inhibits further leptin signal transduction
and also inhibits signalling by the insulin receptor. Altered SOCS-3 methylation may therefore have
effects on the leptin-insulin feedback loop (the adipoinsular axis) and adversely impact developmental
programming [90]. Methylation of a proximal region of the leptin promoter constitutes a significant
determinant of leptin expression in human adult tissues [94] and variation in DNA methylation of
the leptin promoter in animals models varies with the degree of obesity [95,96] and the epigenetic
regulation of leptin signalling pathways can be manipulated by nutrients and food compounds as
detailed recently [97]. In addition, leptin treatment during the neonatal period in the setting of maternal
undernutrition can reverse the adverse programming effects in offspring [34,35,37]. Further, leptin
treatment during the neonatal period has been shown to promote epigenetic modifications in the POMC
promoter, which may confer protection from an obesogenic environment in adulthood [32].
In addition to leptin, a further candidate re epigenetic regulation is that of the fat mass
and obesity-associated (FTO) gene [98–100]. The potential programming effects of FTO in the
developmental of obesity has recently been reviewed by Sebert and colleagues [98]. Both sheep and
rat models (utilising both under- and overnutrition) have shown that the FTO gene may be a key
target for nutritional programming. As an example, altered FTO methylation and gene regulation
may provide a link between obesity-associated leptin resistance following IUGR and rapid postnatal
weight gain [101]. However, as with many methylation data, although strong associations between
FTO and BMI are consistently replicated in humans, the precise biological mechanisms by which
FTO regulates weight gain remains unclear (e.g., does RNA demethylation impact on the control of
energy balance). In addition, different nutritional perturbation lead to differential effects on FTO
regulation e.g., placental expression of the obesity-associated gene FTO is reduced by fetal growth
restriction but not by macrosomia in rats and humans [102]. Interestingly, it has been shown that
the beneficial effects of early short-term exercise in offspring of obese mothers are accompanied by
alterations in the hypothalamic expression of appetite regulators and FTO gene [103]. There are also
data related to specific vulnerability genes—owing to single nucleotide polymorphisms (SNPs)—which
place the individual at risk for obesity when the affected genes are expressed or silenced [104]. As one
example, several longitudinal cohorts of children assessed genetic contributions to childhood obesity and
confirmed a strong association with a polymorphism in the FTO gene. Expression of the SNP-related
allele has been correlated with increased BMI, adiposity, circulating leptin, and energy intake; impaired
control of energy balance; and satiety [105–107].
One of the molecular phenotypes associated with IUGR in the rat is decreased expression
of pancreatic and duodenal homeobox factor-1 (PDX1), a key transcription factor regulating
pancreatic development. Recently, reduced PDX1 activity was associated with alterations in histone
modifications [108]. It addition to leptin, it has been shown that the glucagon-like peptide-1 analog
Exendin-4 increases histone acetylase activity and reverses epigenetic modifications that silence PDX1
in the IUGR rat [109]. Further, in line with lifestyle modifications preventing mitochondrial alterations
Nutrients 2015, 7 8098
and metabolic disorders, exercise has also been shown to change DNA methylation of the promoter of
PGC1α to favour gene expression responsible for mitochondrial biogenesis and function [110].
In addition to maternal dietary restriction models, a number of reports now suggest that maternal
obesity and early life overnutrition can elicit epigenetic changes in offspring. For example, overnutrition
during the suckling period can lead to epigenetic modifications in key genes involved in the insulin
signaling pathway in skeletal muscle and lead to later development of insulin resistance [111]. Marco
et al. showed that a maternal HFD induced hypermethylation of the hypothalamic POMC promoter and
obesity in post-weaning rats [112]. A maternal HFD can also alter methylation and gene expression of
dopamine and opioid-related genes thus is a further potential mechanism for programming of appetite
and preference for energy dense foods in postnatal life [113].
In addition to programming effects on DNA methylation, there is also evidence, albeit limited, for a
role of the early life nutritional environment in alterations in miRNA profiles and histone modifications.
miRNAs are able to control gene expression at a post-transcriptional level, thus representing an important
class of regulatory molecules, and are also directly connected to the epigenetic machinery through a
regulatory loop [114]. miRNAs play an essential role in the maintenance of insulin signaling and glucose
homeostasis and dysregulation of miRNAs (e.g., miR-103, miR-107, miR-802 and the let-7 family)
is associated with features of the metabolic syndrome, obesity, and type 2 diabetes in a number of
experimental models [115–118]. An essential role for miRNAs has also recently been described for
the maintenance and differentiation of brown adipocytes [119]. Experimentally, maternal undernutrition
around the time of conception can induce changes in the expression of miRNAs in offspring which
appears to play a role in the development of insulin resistance in later life [120]. Periconceptional or
preimplantation undernutrition in the sheep leads to alterations in a number of miRNAs that relate to
insulin signalling and gluconeogenesis [121]. Similar effects have been reported in a sheep model of
maternal obesity with altered regulation of miRNAs involved in insulin signalling in offspring—these
effects being ablated with a period of dietary restriction in the periconceptional period [122].
A number of histone-modifying enzymes have also been identified, including histone lysine, arginine
methyltransferases and different classes of histone deacetylases (HDACs) with altered expression linked
to a range of metabolic disorders. Several reports have now described the direct effects of dietary methyl
group inadequacy on the modification of histone proteins [123]. Pogribny et al. demonstrated that
feeding rats a methyl donor-deficient diet resulted in loss of histone H3K9 and H4K20 methylation
and a role for folate in enzymatic degradation of histones [124]. However, most work to date on
histones has examined effects related to carcinogenesis with little known in the context of alterations in
systems regulating energy balance in the setting of developmental programming. At a mechanistic level,
studies in humans linking epigenetic change to metabolic disease risk remain limited although there is
evidence for inheritance of tissue specific DNA methylation patterns [125]. Aims currently pursued
are the early identification of epigenetic biomarkers concerned in individual’s disease susceptibility and
the description of protocols for tailored dietary treatments/advice to counterbalance adverse epigenomic
events. These approaches will allow diagnosis and prognosis implementation and facilitate therapeutic
strategies in a personalised “epigenomically modelled” manner to combat obesity related disorders of
energy balance [126]. However, it needs to be noted that most work to date is associative in nature and
the extent to which epigenetic modifications may mediate the effects of developmental programming
Nutrients 2015, 7 8099
of altered energy balance remain unclear. For example, measuring DNA methylation in blood may
provide little linkage with phenotype and therefore cannot be easily justified on a functional basis [24].
Furthermore, a recent review by Waterland raised a number of questions including: in what cells/tissues
is epigenetic regulation most important for energy balance? Does developmental programming of human
body weight regulation occur via epigenetic mechanisms? Do epigenetic mechanisms have a greater
impact on food intake or energy expenditure [78]? So far, these mechanisms include permanent structural
changes in organs arising from suboptimal levels of important factors during a critical developmental
period, changes in gene expression caused by epigenetic modifications and permanent changes in
cellular ageing.
5. Brown Adipose Tissue (BAT)
In experimental models, alterations in maternal nutrition leads to altered adipogenesis in offspring
including promoting an increased number of adipocyte precursor cells and an increase in expression
of genes involved in both white and brown adipogenesis [24,127]. In particular, recent attention
has turned to the role of BAT. Until recently, BAT was primarily viewed as the thermogenic organ
for maintenance of core body temperature in small mammals with the role in humans restricted to
the newborn period. Recent reports of BAT in adult humans have resulted in a renewed interest in
BAT and it is now postulated to play a vital role in the regulation of energy balance and obesity in
humans [24,128]. Uncoupling protein 1 (UCP1) drives non-shivering thermogenesis within BAT and, in
the context of developmental programming, fetal and neonatal expression of UCP1 in BAT is regulated
by maternal nutrition during gestation [129]. In the sheep, BAT genes in pericardial adipose tissue of
newborns are downregulated by maternal nutrient restriction in late gestation [130], thus potentially
placing these offspring at increased risk of hypothermia after birth. As with most other outcomes related
to developmental programming, the magnitude and direction of the offspring response is dependent
upon the timing and duration of the nutritional perturbation [24]. As an example, suboptimal maternal
nutrition during early- to mid-gestation in the sheep can increase UCP1 expression, while a similar
nutritional challenge in late gestation can reduce UCP1 expression in a fat depot specific manner [131].
In the rat, excess weight gain during the early postnatal period (via litter size reduction) is associated
with permanent reprogramming of BAT adaptive thermogenesis (including persistent changes in UCP1)
and sympathetic outflow (decreased beta 3-adrenergic receptor expression and diminished response to
the sympathetic receptor agonist isoproterenol) [132]. However, the physiological roles of human BAT
remain highly complex, and may exert potential health impacts beyond thermogenesis and body weight
regulation with interactions with core physiological processes including glucose homeostasis, cachexia,
physical activity, bone structure, sleep, and circadian rhythms [128].
6. Conclusions
The exquisite system for regulation of energy balance is established once in each individual’s life.
In addition to genetics, environmental influences during critical periods of developmental plasticity
determine the outcome of this process, with lasting consequences for body weight regulation [78]. A
number of epidemiological and clinical observations and a wide range of animal models across a range
of species have clearly highlighted the importance of the early life environment in programming of
Nutrients 2015, 7 8100
many aspects of physiology and behaviour including metabolism, body weight set point and energy
balance regulation. Further, more recent studies have illustrated how the finely tuned long-term
control of energy intake and of energy expenditure are both developmentally plastic and susceptible
to environmentally-induced change that may persist with that individual throughout their adult life,
invariably rendering them more susceptible to greater adipose tissue deposition [133]. A wide range of
nutritional interventions in pregnancy and lactation, including both undernutrition and maternal obesity,
can lead to range of metabolic disorders in offspring, which are mediated in part by epigenetic processes
encompassing the chromatin information encrypted by DNA methylation patterns, histone covalent
modifications and miRNA [126].
Offspring from both undernourished dams and those dams fed an obesogenic diet present with
hypothalamic reprogramming with a number of alterations that appear similar across the range of
experimental animal models: altered neurogenesis and neuronal functionality, disorganization of feeding
pathways, modified glucose sensing, and leptin/insulin resistance [50]. Overall, these alterations may
account for the long-lasting dysregulation of energy balance and obesity following adverse early life
events. An increasing focus has been on epigenetic readouts but to date these remain largely associative
and functional roles of observed changes are not yet established. However, perinatal epigenetic analysis
may have utility in identifying individual vulnerability to later obesity and metabolic disease e.g.,
epigenetic gene promoter methylation at birth and later childhood adiposity [134]. However, there are
still many key questions to be answered: How responsive is the system re interventions and what are the
critical windows of development at which strategies should be targeted; how many generations does it
take to reverse epigenetic imprinting and can reliable markers be developed for disease prediction? [135].
Evidence to date suggests that a “one size fits all” approach is problematic with some evidence that leptin
or methyl donor treatment, for example, in the setting of normal pregnancies may indeed elicit adverse
outcomes in offspring [36,136].
Given their importance in orchestrating and stabilizing cellular differentiation, epigenetic mechanisms
must play a central role in maintaining the various physiological set points that act to promote obesity
in our current obesogenic environment [78]. Dietary components may reshape the genome in utero
and epigenetic changes induced during early life may permanently alter the phenotype in the adult
organism [79]. As such, a better understanding of the epigenetic basis of developmental programming
and how these effects may be transmitted across generations is essential for the implementation of
initiatives aimed at curbing the current obesity and diabetes crisis. Further, many studies to date have
failed to recognise the importance of sex-specific effects in programming and these differences need to
be accounted for in future studies as they aid in the mechanistic understanding of how phenotypes evolve.
Adopting a life course perspective allows identification of phenotype and markers of risk earlier [137],
with the possibility of nutritional and other lifestyle interventions that have obvious implications for
prevention of non-communicable diseases, particularly in populations undergoing nutritional transition.
Acknowledgments
The author acknowledges funding support from the Health Research Council of New Zealand,
the Marsden Fund of the Royal Society of New Zealand and Gravida: National Centre for Growth
and Development.
Nutrients 2015, 7 8101
Conflicts of Interest
The authors declare no conflicts of interest.
References
1. Jequier, E. Leptin signaling, adiposity, and energy balance. Ann. N. Y. Acad. Sci. 2002, 967,
379–388. [CrossRef] [PubMed]
2. Fernandez-Twinn, D.S.; Ozanne, S.E. Early life nutrition and metabolic programming. Ann. N. Y.
Acad. Sci. 2010, 1212, 78–96. [CrossRef] [PubMed]
3. Ross, M.G.; Desai, M. Developmental programming of offspring obesity, adipogenesis, and
appetite. Clin. Obstet. Gynecol. 2013, 56, 529–536. [CrossRef] [PubMed]
4. Vickers, M.H. Early life nutrition, epigenetics and programming of later life disease. Nutrients
2014, 6, 2165–2178. [CrossRef] [PubMed]
5. Gluckman, P.D.; Hanson, M.A.; Beedle, A.S.; Spencer, H.G. Predictive adaptive responses in
perspective. Trends Endocrinol. Metab. 2008, 19, 109–110. [CrossRef] [PubMed]
6. Aiken, C.E.; Ozanne, S.E. Transgenerational developmental programming. Hum. Reprod. Update
2014, 20, 63–75. [CrossRef] [PubMed]
7. Ramamoorthy, T.G.; Begum, G.; Harno, E.; White, A. Developmental programming of
hypothalamic neuronal circuits: Impact on energy balance control. Front. Neurosci. 2015, 9.
[CrossRef] [PubMed]
8. Roseboom, T.J.; Painter, R.C.; van Abeelen, A.F.; Veenendaal, M.V.; de Rooij, S.R. Hungry in
the womb: What are the consequences? Lessons from the Dutch famine. Maturitas 2011, 70,
141–145. [CrossRef] [PubMed]
9. Roseboom, T.J.; van der Meulen, J.H.; Ravelli, A.C.; Osmond, C.; Barker, D.J.; Bleker, O.P.
Effects of prenatal exposure to the Dutch famine on adult disease in later life: An overview. Mol.
Cell Endocrinol. 2001, 185, 93–98. [CrossRef]
10. Stein, A.D.; Rundle, A.; Wada, N.; Goldbohm, R.A.; Lumey, L.H. Associations of gestational
exposure to famine with energy balance and macronutrient density of the diet at age 58 years
differ according to the reference population used. J. Nutr. 2009, 139, 1555–1561. [CrossRef]
[PubMed]
11. Lussana, F.; Painter, R.C.; Ocke, M.C.; Buller, H.R.; Bossuyt, P.M.; Roseboom, T.J. Prenatal
exposure to the Dutch famine is associated with a preference for fatty foods and a more
atherogenic lipid profile. Am. J. Clin. Nutr. 2008, 88, 1648–1652. [CrossRef] [PubMed]
12. Li, Y.; He, Y.; Qi, L.; Jaddoe, V.W.; Feskens, E.J.; Yang, X.; Ma, G.; Hu, F.B. Exposure to
the Chinese famine in early life and the risk of hyperglycemia and type 2 diabetes in adulthood.
Diabetes 2010, 59, 2400–2406. [CrossRef] [PubMed]
13. Perala, M.M.; Mannisto, S.; Kaartinen, N.E.; Kajantie, E.; Osmond, C.; Barker, D.J.; Valsta, L.M.;
Eriksson, J.G. Body size at birth is associated with food and nutrient intake in adulthood.
PLoS ONE 2012, 7, e46139. [CrossRef] [PubMed]
Nutrients 2015, 7 8102
14. Dominguez-Salas, P.; Moore, S.E.; Baker, M.S.; Bergen, A.W.; Cox, S.E.; Dyer, R.A.;
Fulford, A.J.; Guan, Y.; Laritsky, E.; Silver, M.J.; et al. Maternal nutrition at conception modulates
DNA methylation of human metastable epialleles. Nat. Commun. 2014, 5. [CrossRef] [PubMed]
15. Cooper, W.N.; Khulan, B.; Owens, S.; Elks, C.E.; Seidel, V.; Prentice, A.M.; Belteki, G.;
Ong, K.K.; Affara, N.A.; Constancia, M.; Dunger, D.B. DNA methylation profiling at imprinted
loci after periconceptional micronutrient supplementation in humans: Results of a pilot
randomized controlled trial. FASEB J. 2012, 26, 1782–1790. [CrossRef] [PubMed]
16. Neymotin, F.; Nemzer, L.R. Locus of control and obesity. Front. Endocrinol. (Lausanne) 2014,
5. [CrossRef] [PubMed]
17. Moshki, M.; Ashtarian, H. Perceived health locus of control, self-esteem, and its relations to
psychological well-being status in Iranian students. Iran J. Public Health 2010, 39, 70–77.
[PubMed]
18. Ozcan, S.; Duyan, V. Fetal health locus of control in a sample of pregnant Turkish women. Turk.
J. Med. Sci. 2015, 45, 714–722. [CrossRef] [PubMed]
19. Poulton, A.S.; Hibbert, E.J.; Champion, B.L.; Cook, T.L.; Alais, D.; Coulshed, D.S. Piloting a
new approach to the treatment of obesity using dexamphetamine. Front. Endocrinol. (Lausanne)
2015, 6. [CrossRef] [PubMed]
20. Levy, L.D.; Fleming, J.P.; Klar, D. Treatment of refractory obesity in severely obese adults
following management of newly diagnosed attention deficit hyperactivity disorder. Int. J. Obes.
(Lond.) 2009, 33, 326–334. [CrossRef] [PubMed]
21. Plagemann, A.; Harder, T.; Rake, A.; Janert, U.; Melchior, K.; Rohde, W.; Dorner, G.
Morphological alterations of hypothalamic nuclei due to intrahypothalamic hyperinsulinism in
newborn rats. Int. J. Dev. Neurosci. 1999, 17, 37–44. [CrossRef]
22. Garcia, A.P.; Palou, M.; Priego, T.; Sanchez, J.; Palou, A.; Pico, C. Moderate caloric
restriction during gestation results in lower arcuate nucleus NPY- and αMSH-neurons and impairs
hypothalamic response to fed/fasting conditions in weaned rats. Diabetes Obes. Metab. 2010, 12,
403–413. [CrossRef] [PubMed]
23. Horvath, T.L.; Bruning, J.C. Developmental programming of the hypothalamus: A matter of fat.
Nat. Med. 2006, 12, 52–53. [CrossRef] [PubMed]
24. Ojha, S.; Fainberg, H.P.; Sebert, S.; Budge, H.; Symonds, M.E. Maternal health and eating habits:
Metabolic consequences and impact on child health. Trends Mol. Med. 2015, 21, 126–133.
[CrossRef] [PubMed]
25. Bouret, S.G.; Simerly, R.B. Developmental programming of hypothalamic feeding circuits.
Clin. Genet. 2006, 70, 295–301. [CrossRef] [PubMed]
26. Taylor, P.D.; Samuelsson, A.M.; Poston, L. Maternal obesity and the developmental programming
of hypertension: A role for leptin. Acta Physiol. (Oxf.) 2014, 210, 508–523. [CrossRef]
[PubMed]
27. Purcell, R.H.; Sun, B.; Pass, L.L.; Power, M.L.; Moran, T.H.; Tamashiro, K.L. Maternal stress
and high-fat diet effect on maternal behavior, milk composition, and pup ingestive behavior.
Physiol. Behav. 2011, 104, 474–479. [CrossRef] [PubMed]
Nutrients 2015, 7 8103
28. Loh, T.C.; Foo, H.L.; Abdul Wahab, Z.; Tan, B.K. Effects of feeding fat during pregnancy and
lactation on growth performance, milk composition and very low density lipoprotein composition
in ratstc “density lipoprotein composition in rats”. Malays. J. Nutr. 2002, 8, 125–135. [PubMed]
29. Franco, J.G.; Fernandes, T.P.; Rocha, C.P.; Calvino, C.; Pazos-Moura, C.C.; Lisboa, P.C.;
Moura, E.G.; Trevenzoli, I.H. Maternal high-fat diet induces obesity and adrenal and thyroid
dysfunction in male rat offspring at weaning. J. Physiol. 2012, 590, 5503–5518. [CrossRef]
[PubMed]
30. Bouret, S.G.; Draper, S.J.; Simerly, R.B. Trophic action of leptin on hypothalamic neurons that
regulate feeding. Science 2004, 304, 108–110. [CrossRef] [PubMed]
31. Yura, S.; Itoh, H.; Sagawa, N.; Yamamoto, H.; Masuzaki, H.; Nakao, K.; Kawamura, M.;
Takemura, M.; Kakui, K.; Ogawa, Y.; et al. Role of premature leptin surge in obesity resulting
from intrauterine undernutrition. Cell Metab. 2005, 1, 371–378. [CrossRef] [PubMed]
32. Palou, M.; Pico, C.; McKay, J.A.; Sanchez, J.; Priego, T.; Mathers, J.C.; Palou, A. Protective
effects of leptin during the suckling period against later obesity may be associated with changes
in promoter methylation of the hypothalamic pro-opiomelanocortin gene. Br. J. Nutr. 2011, 106,
769–778. [CrossRef] [PubMed]
33. Vickers, M.H.; Sloboda, D.M. Leptin as mediator of the effects of developmental programming.
Best Pract. Res. Clin. Endocrinol. Metab. 2012, 26, 677–687. [CrossRef] [PubMed]
34. Gibson, L.C.; Shin, B.C.; Dai, Y.; Freije, W.; Kositamongkol, S.; Cho, J.; Devaskar, S.U. Early
leptin intervention reverses perturbed energy balance regulating hypothalamic neuropeptides in
the pre- and postnatal calorie-restricted female rat offspring. J. Neurosci. Res. 2015, 93, 902–912.
[CrossRef] [PubMed]
35. Vickers, M.H.; Gluckman, P.D.; Coveny, A.H.; Hofman, P.L.; Cutfield, W.S.; Gertler, A.;
Breier, B.H.; Harris, M. Neonatal leptin treatment reverses developmental programming.
Endocrinology 2005, 146, 4211–4216. [CrossRef] [PubMed]
36. Vickers, M.H.; Gluckman, P.D.; Coveny, A.H.; Hofman, P.L.; Cutfield, W.S.; Gertler, A.;
Breier, B.H.; Harris, M. The effect of neonatal leptin treatment on postnatal weight gain in male
rats is dependent on maternal nutritional status during pregnancy. Endocrinology 2008, 149,
1906–1913. [CrossRef] [PubMed]
37. Attig, L.; Djiane, J.; Gertler, A.; Rampin, O.; Larcher, T.; Boukthir, S.; Anton, P.M.;
Madec, J.Y.; Gourdou, I.; Abdennebi-Najar, L. Study of hypothalamic leptin receptor expression
in low-birth-weight piglets and effects of leptin supplementation on neonatal growth and
development. Am. J. Physiol. Endocrinol. Metab. 2008, 295, E1117–E1125. [CrossRef]
[PubMed]
38. Gluckman, P.D.; Lillycrop, K.A.; Vickers, M.H.; Pleasants, A.B.; Phillips, E.S.; Beedle, A.S.;
Burdge, G.C.; Hanson, M.A. Metabolic plasticity during mammalian development is directionally
dependent on early nutritional status. Proc. Natl. Acad. Sci. USA 2007, 104, 12796–12800.
[CrossRef] [PubMed]
39. Trevenzoli, I.H.; Rodrigues, A.L.; Oliveira, E.; Thole, A.A.; Carvalho, L.; Figueiredo, M.S.;
Toste, F.P.; Neto, J.F.; Passos, M.C.; Lisboa, P.C.; Moura, E.G. Leptin treatment during lactation
Nutrients 2015, 7 8104
programs leptin synthesis, intermediate metabolism, and liver microsteatosis in adult rats. Horm.
Metab. Res. 2010, 42, 483–490. [CrossRef] [PubMed]
40. Garcia, A.P.; Palou, M.; Sanchez, J.; Priego, T.; Palou, A.; Pico, C. Moderate caloric restriction
during gestation in rats alters adipose tissue sympathetic innervation and later adiposity in
offspring. PLoS ONE 2011, 6, e17313. [CrossRef] [PubMed]
41. Trabulsi, J.C.; Mennella, J.A. Diet, sensitive periods in flavour learning, and growth. Int. Rev.
Psychiatry 2012, 24, 219–230. [CrossRef] [PubMed]
42. Bellinger, L.; Lilley, C.; Langley-Evans, S.C. Prenatal exposure to a maternal low-protein diet
programmes a preference for high-fat foods in the young adult rat. Br. J. Nutr. 2004, 92, 513–520.
[CrossRef] [PubMed]
43. Wang, R.; van Keeken, N.M.; Siddiqui, S.; Dijksman, L.M.; Maudsley, S.; Derval, D.; van
Dam, P.S.; Martin, B. Higher TNF-α, IGF-1, and Leptin Levels are Found in Tasters than
Non-Tasters. Front. Endocrinol. (Lausanne) 2014, 5, 125. [CrossRef] [PubMed]
44. Entringer, S.; Wadhwa, P.D. Developmental programming of obesity and metabolic dysfunction:
Role of prenatal stress and stress biology. Nestle Nutr. Inst. Workshop. Ser. 2013, 74, 107–120.
[PubMed]
45. Vickers, M.H.; Breier, B.H.; Cutfield, W.S.; Hofman, P.L.; Gluckman, P.D. Fetal origins of
hyperphagia, obesity, and hypertension and postnatal amplification by hypercaloric nutrition. Am
J. Physiol. Endocrinol. Metab. 2000, 279, E83–E87. [PubMed]
46. Vickers, M.H.; Breier, B.H.; McCarthy, D.; Gluckman, P.D. Sedentary behavior during postnatal
life is determined by the prenatal environment and exacerbated by postnatal hypercaloric nutrition.
Am. J. Physiol. Regul. Integr. Comp. Physiol. 2003, 285, R271–R273. [CrossRef] [PubMed]
47. Ozanne, S.E. Metabolic programming in animals. Br. Med. Bull. 2001, 60, 143–152. [CrossRef]
[PubMed]
48. Delahaye, F.; Breton, C.; Risold, P.Y.; Enache, M.; Dutriez-Casteloot, I.; Laborie, C.; Lesage, J.;
Vieau, D. Maternal perinatal undernutrition drastically reduces postnatal leptin surge and affects
the development of arcuate nucleus POMC neurons in neonatal male rat pups. Endocrinology
2008, 149, 470–475. [CrossRef] [PubMed]
49. Breton, C.; Lukaszewski, M.A.; Risold, P.Y.; Enache, M.; Guillemot, J.; Riviere, G.; Delahaye, F.;
Lesage, J.; Dutriez-Casteloot, I.; Laborie, C.; et al. Maternal prenatal undernutrition alters the
response of POMC neurons to energy status variation in adult male rat offspring. Am. J. Physiol.
Endocrinol. Metab. 2009, 296, E462–E472. [CrossRef] [PubMed]
50. Wattez, J.S.; Delahaye, F.; Lukaszewski, M.A.; Risold, P.Y.; Eberle, D.; Vieau, D.; Breton, C.
Perinatal nutrition programs the hypothalamic melanocortin system in offspring. Horm. Metab.
Res. 2013, 45, 980–990. [CrossRef] [PubMed]
51. Manuel-Apolinar, L.; Rocha, L.; Damasio, L.; Tesoro-Cruz, E.; Zarate, A. Role of prenatal
undernutrition in the expression of serotonin, dopamine and leptin receptors in adult mice:
Implications of food intake. Mol. Med. Rep. 2014, 9, 407–412. [CrossRef] [PubMed]
52. Sullivan, E.L.; Smith, M.S.; Grove, K.L. Perinatal exposure to high-fat diet programs energy
balance, metabolism and behavior in adulthood. Neuroendocrinology 2011, 93, 1–8. [CrossRef]
[PubMed]
Nutrients 2015, 7 8105
53. Grove, K.L.; Grayson, B.E.; Glavas, M.M.; Xiao, X.Q.; Smith, M.S. Development of metabolic
systems. Physiol. Behav. 2005, 86, 646–660. [CrossRef] [PubMed]
54. Begum, G.; Stevens, A.; Smith, E.B.; Connor, K.; Challis, J.R.; Bloomfield, F.; White, A.
Epigenetic changes in fetal hypothalamic energy regulating pathways are associated with maternal
undernutrition and twinning. FASEB J. 2012, 26, 1694–1703. [CrossRef] [PubMed]
55. Adam, C.L.; Bake, T.; Findlay, P.A.; Milne, J.S.; Aitken, R.P.; Wallace, J.M. Impact of birth
weight and gender on early postnatal hypothalamic energy balance regulatory gene expression in
the young lamb. Int. J. Dev. Neurosci. 2013, 31, 608–615. [CrossRef] [PubMed]
56. Begum, G.; Davies, A.; Stevens, A.; Oliver, M.; Jaquiery, A.; Challis, J.; Harding, J.;
Bloomfield, F.; White, A. Maternal undernutrition programs tissue-specific epigenetic changes in
the glucocorticoid receptor in adult offspring. Endocrinology 2013, 154, 4560–4569. [CrossRef]
[PubMed]
57. Ovilo, C.; Gonzalez-Bulnes, A.; Benitez, R.; Ayuso, M.; Barbero, A.; Perez-Solana, M.L.;
Barragan, C.; Astiz, S.; Fernandez, A.; Lopez-Bote, C. Prenatal programming in an obese
swine model: Sex-related effects of maternal energy restriction on morphology, metabolism and
hypothalamic gene expression. Br. J. Nutr. 2014, 111, 735–746. [CrossRef] [PubMed]
58. Beauchamp, B.; Thrush, A.B.; Quizi, J.; Antoun, G.; McIntosh, N.; al-Dirbashi, O.Y.; Patti, M.E.;
Harper, M.E. Undernutrition during pregnancy in mice leads to dysfunctional cardiac muscle
respiration in adult offspring. Biosci. Rep. 2015, 35. [CrossRef] [PubMed]
59. MacPherson, R.E.; Castelli, L.M.; Miotto, P.M.; Frendo-Cumbo, S.; Milburn, A.; Roy, B.D.;
LeBlanc, P.J.; Ward, W.E.; Peters, S.J. A maternal high fat diet has long-lasting effects on skeletal
muscle lipid and PLIN protein content in rat offspring at young adulthood. Lipids 2015, 50,
205–217. [CrossRef] [PubMed]
60. Raipuria, M.; Bahari, H.; Morris, M.J. Effects of maternal diet and exercise during pregnancy on
glucose metabolism in skeletal muscle and fat of weanling rats. PLoS ONE 2015, 10, e0120980.
[CrossRef] [PubMed]
61. Borengasser, S.J.; Faske, J.; Kang, P.; Blackburn, M.L.; Badger, T.M.; Shankar, K. In utero
exposure to prepregnancy maternal obesity and postweaning high-fat diet impair regulators of
mitochondrial dynamics in rat placenta and offspring. Physiol. Genomics 2014, 46, 841–850.
[CrossRef] [PubMed]
62. Williams, L.; Seki, Y.; Vuguin, P.M.; Charron, M.J. Animal models of in utero exposure to a high
fat diet: A review. Biochim. Biophys. Acta 2014, 1842, 507–519. [CrossRef] [PubMed]
63. Walker, C.D.; Naef, L.; d’Asti, E.; Long, H.; Xu, Z.; Moreau, A.; Azeddine, B. Perinatal maternal
fat intake affects metabolism and hippocampal function in the offspring: A potential role for
leptin. Ann. N. Y. Acad. Sci. 2008, 1144, 189–202. [CrossRef] [PubMed]
64. Gorski, J.N.; Dunn-Meynell, A.A.; Hartman, T.G.; Levin, B.E. Postnatal environment overrides
genetic and prenatal factors influencing offspring obesity and insulin resistance. Am. J. Physiol.
Regul. Integr. Comp. Physiol. 2006, 291, R768–R778. [CrossRef] [PubMed]
65. Chang, G.Q.; Gaysinskaya, V.; Karatayev, O.; Leibowitz, S.F. Maternal high-fat diet and fetal
programming: Increased proliferation of hypothalamic peptide-producing neurons that increase
risk for overeating and obesity. J. Neurosci. 2008, 28, 12107–12119. [CrossRef] [PubMed]
Nutrients 2015, 7 8106
66. Reichelt, A.C.; Morris, M.J.; Westbrook, R.F. Cafeteria diet impairs expression of sensory-specific
satiety and stimulus-outcome learning. Front. Psychol. 2014, 5. [CrossRef] [PubMed]
67. Gugusheff, J.R.; Ong, Z.Y.; Muhlhausler, B.S. Naloxone treatment alters gene expression in the
mesolimbic reward system in “junk food” exposed offspring in a sex-specific manner but does not
affect food preferences in adulthood. Physiol. Behav. 2014, 133, 14–21. [CrossRef] [PubMed]
68. Ong, Z.Y.; Muhlhausler, B.S. Maternal “junk-food” feeding of rat dams alters food choices and
development of the mesolimbic reward pathway in the offspring. FASEB J. 2011, 25, 2167–2179.
[CrossRef] [PubMed]
69. Steculorum, S.M.; Bouret, S.G. Maternal diabetes compromises the organization of hypothalamic
feeding circuits and impairs leptin sensitivity in offspring. Endocrinology 2011, 152, 4171–4179.
[CrossRef] [PubMed]
70. Plagemann, A.; Harder, T.; Melchior, K.; Rake, A.; Rohde, W.; Dorner, G. Elevation of
hypothalamic neuropeptide Y-neurons in adult offspring of diabetic mother rats. Neuroreport
1999, 10, 3211–3216. [CrossRef] [PubMed]
71. Franke, K.; Harder, T.; Aerts, L.; Melchior, K.; Fahrenkrog, S.; Rodekamp, E.; Ziska, T.;
van Assche, F.A.; Dudenhausen, J.W.; Plagemann, A. “Programming” of orexigenic and
anorexigenic hypothalamic neurons in offspring of treated and untreated diabetic mother rats.
Brain Res. 2005, 1031, 276–283. [CrossRef] [PubMed]
72. Long, N.M.; Rule, D.C.; Tuersunjiang, N.; Nathanielsz, P.W.; Ford, S.P. Maternal obesity in sheep
increases fatty acid synthesis, upregulates nutrient transporters, and increases adiposity in adult
male offspring after a feeding challenge. PLoS ONE 2015, 10, e0122152. [CrossRef] [PubMed]
73. Long, N.M.; Ford, S.P.; Nathanielsz, P.W. Maternal obesity eliminates the neonatal lamb plasma
leptin peak. J. Physiol. 2011, 589, 1455–1462. [CrossRef] [PubMed]
74. Shasa, D.R.; Odhiambo, J.F.; Long, N.M.; Tuersunjiang, N.; Nathanielsz, P.W.; Ford, S.P.
Multigenerational impact of maternal overnutrition/obesity in the sheep on the neonatal leptin
surge in granddaughters. Int. J. Obes. (Lond.) 2015, 39, 695–701. [CrossRef] [PubMed]
75. Barbero, A.; Astiz, S.; Ovilo, C.; Lopez-Bote, C.J.; Perez-Solana, M.L.; Ayuso, M.;
Garcia-Real, I.; Gonzalez-Bulnes, A. Prenatal programming of obesity in a swine model of leptin
resistance: Modulatory effects of controlled postnatal nutrition and exercise. J. Dev. Orig. Health
Dis. 2014, 5, 248–258. [CrossRef] [PubMed]
76. Gonzalez-Bulnes, A.; Astiz, S.; Ovilo, C.; Lopez-Bote, C.J.; Sanchez-Sanchez, R.;
Perez-Solana, M.L.; Torres-Rovira, L.; Ayuso, M.; Gonzalez, J. Early-postnatal changes in
adiposity and lipids profile by transgenerational developmental programming in swine with
obesity/leptin resistance. J. Endocrinol. 2014, 223, M17–M29. [CrossRef] [PubMed]
77. Gonzalez-Bulnes, A.; Torres-Rovira, L.; Ovilo, C.; Astiz, S.; Gomez-Izquierdo, E.;
Gonzalez-Anover, P.; Pallares, P.; Perez-Solana, M.L.; Sanchez-Sanchez, R. Reproductive,
endocrine and metabolic feto-maternal features and placental gene expression in a swine breed
with obesity/leptin resistance. Gen. Comp. Endocrinol. 2012, 176, 94–101. [CrossRef]
[PubMed]
78. Waterland, R.A. Epigenetic mechanisms affecting regulation of energy balance: Many questions,
few answers. Annu. Rev. Nutr. 2014, 34, 337–355. [CrossRef] [PubMed]
Nutrients 2015, 7 8107
79. Chango, A.; Pogribny, I.P. Considering maternal dietary modulators for epigenetic regulation and
programming of the fetal epigenome. Nutrients 2015, 7, 2748–2770. [CrossRef] [PubMed]
80. Jang, H.; Serra, C. Nutrition, Epigenetics, and Diseases. Clin. Nutr. Res. 2014, 3, 1–8. [PubMed]
81. Tobi, E.W.; Goeman, J.J.; Monajemi, R.; Gu, H.; Putter, H.; Zhang, Y.; Slieker, R.C.; Stok, A.P.;
Thijssen, P.E.; Muller, F.; et al. DNA methylation signatures link prenatal famine exposure to
growth and metabolism. Nat. Commun. 2014, 5. [CrossRef] [PubMed]
82. Godfrey, K.M.; Lillycrop, K.A.; Burdge, G.C.; Gluckman, P.D.; Hanson, M.A. Epigenetic
mechanisms and the mismatch concept of the developmental origins of health and disease.
Pediatr. Res. 2007, 61, 5R–10R. [CrossRef] [PubMed]
83. Ozanne, S.E. Epigenetics and metabolism in 2014: Metabolic programming—Knowns, unknowns
and possibilities. Nat. Rev. Endocrinol. 2015, 11, 67–68. [CrossRef] [PubMed]
84. Zinkhan, E.K.; Fu, Q.; Wang, Y.; Yu, X.; Callaway, C.W.; Segar, J.L.; Scholz, T.D.;
McKnight, R.A.; Joss-Moore, L.; Lane, R.H. Maternal hyperglycemia disrupts histone 3 lysine
36 trimethylation of the IGF-1 gene. J. Nutr. Metab. 2012, 2012. [CrossRef] [PubMed]
85. Jirtle, R.L.; Skinner, M.K. Environmental epigenomics and disease susceptibility. Nat. Rev.
Genet. 2007, 8, 253–262. [CrossRef] [PubMed]
86. Pham, T.D.; MacLennan, N.K.; Chiu, C.T.; Laksana, G.S.; Hsu, J.L.; Lane, R.H. Uteroplacental
insufficiency increases apoptosis and alters p53 gene methylation in the full-term IUGR rat kidney.
Am. J. Physiol. Regul. Integr. Comp. Physiol. 2003, 285, R962–R970. [CrossRef] [PubMed]
87. Bogdarina, I.; Welham, S.; King, P.J.; Burns, S.P.; Clark, A.J. Epigenetic modification of the
renin-angiotensin system in the fetal programming of hypertension. Circ. Res. 2007, 100,
520–526. [CrossRef] [PubMed]
88. Weaver, I.C.; Cervoni, N.; Champagne, F.A.; D’Alessio, A.C.; Sharma, S.; Seckl, J.R.; Dymov, S.;
Szyf, M.; Meaney, M.J. Epigenetic programming by maternal behavior. Nat. Neurosci. 2004, 7,
847–854. [CrossRef] [PubMed]
89. Dudley, K.J.; Sloboda, D.M.; Connor, K.L.; Beltrand, J.; Vickers, M.H. Offspring of mothers fed
a high fat diet display hepatic cell cycle inhibition and associated changes in gene expression and
DNA methylation. PLoS ONE 2011, 6, e21662. [CrossRef] [PubMed]
90. Holness, M.J.; Sugden, M.C. Epigenetic regulation of metabolism in children born small for
gestational age. Curr. Opin. Clin. Nutr. Metab. Care 2006, 9, 482–488. [CrossRef] [PubMed]
91. Iliopoulos, D.; Malizos, K.N.; Tsezou, A. Epigenetic regulation of leptin affects MMP-13
expression in osteoarthritic chondrocytes: Possible molecular target for osteoarthritis therapeutic
intervention. Ann. Rheum. Dis. 2007, 66, 1616–1621. [CrossRef] [PubMed]
92. Melzner, I.; Scott, V.; Dorsch, K.; Fischer, P.; Wabitsch, M.; Bruderlein, S.; Hasel, C.;
Moller, P. Leptin gene expression in human preadipocytes is switched on by maturation-induced
demethylation of distinct CpGs in its proximal promoter. J. Biol. Chem. 2002, 277, 45420–45427.
[CrossRef] [PubMed]
93. Stoger, R. In vivo methylation patterns of the leptin promoter in human and mouse. Epigenetics
2006, 1, 155–162. [CrossRef] [PubMed]
94. Marchi, M.; Lisi, S.; Curcio, M.; Barbuti, S.; Piaggi, P.; Ceccarini, G.; Nannipieri, M.;
Anselmino, M.; di Salvo, C.; Vitti, P.; et al. Human leptin tissue distribution, but not weight
Nutrients 2015, 7 8108
loss-dependent change in expression, is associated with methylation of its promoter. Epigenetics
2011, 6, 1198–1206. [CrossRef] [PubMed]
95. Shen, W.; Wang, C.; Xia, L.; Fan, C.; Dong, H.; Deckelbaum, R.J.; Qi, K. Epigenetic modification
of the leptin promoter in diet-induced obese mice and the effects of N-3 polyunsaturated fatty
acids. Sci. Rep. 2014, 4. [CrossRef] [PubMed]
96. Crujeiras, A.B.; Carreira, M.C.; Cabia, B.; Andrade, S.; Amil, M.; Casanueva, F.F. Leptin
resistance in obesity: An epigenetic landscape. Life Sci. 2015. [CrossRef] [PubMed]
97. Haggarty, P. Epigenetic consequences of a changing human diet. Proc. Nutr. Soc. 2013, 72,
363–371. [CrossRef] [PubMed]
98. Sebert, S.; Salonurmi, T.; Keinanen-Kiukaanniemi, S.; Savolainen, M.; Herzig, K.H.;
Symonds, M.E.; Jarvelin, M.R. Programming effects of FTO in the development of obesity. Acta
Physiol. (Oxf.) 2014, 210, 58–69. [CrossRef] [PubMed]
99. Sebert, S.P.; Hyatt, M.A.; Chan, L.L.; Yiallourides, M.; Fainberg, H.P.; Patel, N.; Sharkey, D.;
Stephenson, T.; Rhind, S.M.; Bell, R.C.; et al. Influence of prenatal nutrition and obesity on
tissue specific fat mass and obesity-associated (FTO) gene expression. Reproduction 2010, 139,
265–274. [CrossRef] [PubMed]
100. Dina, C.; Meyre, D.; Gallina, S.; Durand, E.; Korner, A.; Jacobson, P.; Carlsson, L.M.; Kiess, W.;
Vatin, V.; Lecoeur, C.; et al. Variation in FTO contributes to childhood obesity and severe adult
obesity. Nat. Genet. 2007, 39, 724–726. [CrossRef] [PubMed]
101. Sebert, S.; Sharkey, D.; Budge, H.; Symonds, M.E. The early programming of metabolic health:
Is epigenetic setting the missing link? Am. J. Clin. Nutr. 2011, 94, 1953S–1958S. [CrossRef]
[PubMed]
102. Mayeur, S.; Cisse, O.; Gabory, A.; Barbaux, S.; Vaiman, D.; Vambergue, A.; Fajardy, I.;
Deloof, S.; Junien, C.; Laborie, C.; et al. Placental expression of the obesity-associated gene
FTO is reduced by fetal growth restriction but not by macrosomia in rats and humans. J. Dev.
Orig. Health Dis. 2013, 4, 134–138. [CrossRef] [PubMed]
103. Caruso, V.; Bahari, H.; Morris, M.J. The beneficial effects of early short-term exercise in the
offspring of obese mothers are accompanied by alterations in the hypothalamic gene expression
of appetite regulators and FTO (fat mass and obesity associated) gene. J. Neuroendocrinol. 2013,
25, 742–752. [CrossRef] [PubMed]
104. Wahlqvist, M.L.; Krawetz, S.A.; Rizzo, N.S.; Dominguez-Bello, M.G.; Szymanski, L.M.;
Barkin, S.; Yatkine, A.; Waterland, R.A.; Mennella, J.A.; Desai, M.; et al. Early-life influences on
obesity: From preconception to adolescence. Ann. N. Y. Acad. Sci. 2015, 1347, 1–28. [CrossRef]
[PubMed]
105. Speakman, J.R. Functional analysis of seven genes linked to body mass index and adiposity by
genome-wide association studies: A review. Hum. Hered. 2013, 75, 57–79. [CrossRef] [PubMed]
106. Warrington, N.M.; Howe, L.D.; Paternoster, L.; Kaakinen, M.; Herrala, S.; Huikari, V.; Wu, Y.Y.;
Kemp, J.P.; Timpson, N.J.; Pourcain, B.S.; et al. A genome-wide association study of body mass
index across early life and childhood. Int. J. Epidemiol. 2015, 44, 700–712. [CrossRef] [PubMed]
107. Elks, C.E.; Loos, R.J.; Sharp, S.J.; Langenberg, C.; Ring, S.M.; Timpson, N.J.; Ness, A.R.;
Smith, G.D.; Dunger, D.B.; Wareham, N.J.; et al. Genetic markers of adult obesity risk are
Nutrients 2015, 7 8109
associated with greater early infancy weight gain and growth. PLoS Med. 2010, 7, e1000284.
[CrossRef] [PubMed]
108. Park, J.H.; Stoffers, D.A.; Nicholls, R.D.; Simmons, R.A. Development of type 2 diabetes
following intrauterine growth retardation in rats is associated with progressive epigenetic silencing
of Pdx1. J. Clin. Investig. 2008, 118, 2316–2324. [CrossRef] [PubMed]
109. Pinney, S.E.; Jaeckle Santos, L.J.; Han, Y.; Stoffers, D.A.; Simmons, R.A. Exendin-4 increases
histone acetylase activity and reverses epigenetic modifications that silence Pdx1 in the
intrauterine growth retarded rat. Diabetologia 2011, 54, 2606–2614. [CrossRef] [PubMed]
110. Cheng, Z.; Almeida, F.A. Mitochondrial alteration in type 2 diabetes and obesity: An epigenetic
link. Cell Cycle 2014, 13, 890–897. [CrossRef] [PubMed]
111. Liu, H.W.; Mahmood, S.; Srinivasan, M.; Smiraglia, D.J.; Patel, M.S. Developmental
programming in skeletal muscle in response to overnourishment in the immediate postnatal life in
rats. J. Nutr. Biochem. 2013, 24, 1859–1869. [CrossRef] [PubMed]
112. Marco, A.; Kisliouk, T.; Weller, A.; Meiri, N. High fat diet induces hypermethylation of the
hypothalamic Pomc promoter and obesity in post-weaning rats. Psychoneuroendocrinology 2013,
38, 2844–2853. [CrossRef] [PubMed]
113. Vucetic, Z.; Kimmel, J.; Totoki, K.; Hollenbeck, E.; Reyes, T.M. Maternal high-fat diet alters
methylation and gene expression of dopamine and opioid-related genes. Endocrinology 2010,
151, 4756–4764. [CrossRef] [PubMed]
114. Iorio, M.V.; Piovan, C.; Croce, C.M. Interplay between microRNAs and the epigenetic machinery:
An intricate network. Biochim. Biophys. Acta 2010, 1799, 694–701. [CrossRef] [PubMed]
115. Frost, R.J.; Olson, E.N. Control of glucose homeostasis and insulin sensitivity by the Let-7 family
of microRNAs. Proc. Natl. Acad. Sci. USA 2011, 108, 21075–21080. [CrossRef] [PubMed]
116. Kornfeld, J.W.; Baitzel, C.; Konner, A.C.; Nicholls, H.T.; Vogt, M.C.; Herrmanns, K.; Scheja, L.;
Haumaitre, C.; Wolf, A.M.; Knippschild, U.; et al. Obesity-induced overexpression of miR-802
impairs glucose metabolism through silencing of Hnf1b. Nature 2013, 494, 111–115. [CrossRef]
[PubMed]
117. Trajkovski, M.; Hausser, J.; Soutschek, J.; Bhat, B.; Akin, A.; Zavolan, M.; Heim, M.H.;
Stoffel, M. MicroRNAs 103 and 107 regulate insulin sensitivity. Nature 2011, 474, 649–653.
[CrossRef] [PubMed]
118. Ferland-McCollough, D.; Ozanne, S.E.; Siddle, K.; Willis, A.E.; Bushell, M. The involvement
of microRNAs in Type 2 diabetes. Biochem. Soc. Trans. 2010, 38, 1565–1570. [CrossRef]
[PubMed]
119. Kim, H.J.; Cho, H.; Alexander, R.; Patterson, H.C.; Gu, M.; Lo, K.A.; Xu, D.; Goh, V.J.;
Nguyen, L.N.; Chai, X.; et al. MicroRNAs are required for the feature maintenance and
differentiation of brown adipocytes. Diabetes 2014, 63, 4045–4056. [CrossRef] [PubMed]
120. Lie, S.; Morrison, J.L.; Williams-Wyss, O.; Suter, C.M.; Humphreys, D.T.; Ozanne, S.E.;
Zhang, S.; Maclaughlin, S.M.; Kleemann, D.O.; Walker, S.K.; et al. Periconceptional
undernutrition programs changes in insulin-signaling molecules and microRNAs in skeletal
muscle in singleton and twin fetal sheep. Biol. Reprod. 2013. [CrossRef] [PubMed]
Nutrients 2015, 7 8110
121. Lie, S.; Morrison, J.L.; Williams-Wyss, O.; Suter, C.M.; Humphreys, D.T.; Ozanne, S.E.;
Zhang, S.; MacLaughlin, S.M.; Kleemann, D.O.; Walker, S.K.; et al. Impact of embryo number
and maternal undernutrition around the time of conception on insulin signaling and gluconeogenic
factors and microRNAs in the liver of fetal sheep. Am. J. Physiol. Endocrinol. Metab. 2014, 306,
E1013–E1024. [CrossRef] [PubMed]
122. Nicholas, L.M.; Rattanatray, L.; MacLaughlin, S.M.; Ozanne, S.E.; Kleemann, D.O.;
Walker, S.K.; Morrison, J.L.; Zhang, S.; Muhlhausler, B.S.; Martin-Gronert, M.S.; et al.
Differential effects of maternal obesity and weight loss in the periconceptional period on the
epigenetic regulation of hepatic insulin-signaling pathways in the offspring. FASEB J. 2013, 27,
3786–3796. [CrossRef] [PubMed]
123. Butler, J.S.; Koutelou, E.; Schibler, A.C.; Dent, S.Y. Histone-modifying enzymes: Regulators
of developmental decisions and drivers of human disease. Epigenomics 2012, 4, 163–177.
[CrossRef] [PubMed]
124. Pogribny, I.P.; Tryndyak, V.P.; Muskhelishvili, L.; Rusyn, I.; Ross, S.A. Methyl deficiency,
alterations in global histone modifications, and carcinogenesis. J. Nutr. 2007, 137, 216S–222S.
[PubMed]
125. Silva, A.J.; White, R. Inheritance of allelic blueprints for methylation patterns. Cell 1988, 54,
145–152. [CrossRef]
126. Martinez, J.A.; Cordero, P.; Campion, J.; Milagro, F.I. Interplay of early-life nutritional
programming on obesity, inflammation and epigenetic outcomes. Proc. Nutr. Soc. 2012, 71,
276–283. [CrossRef] [PubMed]
127. Symonds, M.E.; Sebert, S.P.; Hyatt, M.A.; Budge, H. Nutritional programming of the metabolic
syndrome. Nat. Rev. Endocrinol. 2009, 5, 604–610. [CrossRef] [PubMed]
128. Cypess, A.M.; Haft, C.R.; Laughlin, M.R.; Hu, H.H. Brown fat in humans: Consensus points and
experimental guidelines. Cell Metab. 2014, 20, 408–415. [CrossRef] [PubMed]
129. Symonds, M.E.; Pearce, S.; Bispham, J.; Gardner, D.S.; Stephenson, T. Timing of nutrient
restriction and programming of fetal adipose tissue development. Proc. Nutr. Soc. 2004, 63,
397–403. [CrossRef] [PubMed]
130. Ojha, S.; Robinson, L.; Yazdani, M.; Symonds, M.E.; Budge, H. Brown adipose tissue genes in
pericardial adipose tissue of newborn sheep are downregulated by maternal nutrient restriction in
late gestation. Pediatr. Res. 2013, 74, 246–251. [CrossRef] [PubMed]
131. Ojha, S.; Symonds, M.E.; Budge, H. Suboptimal maternal nutrition during early-to-mid gestation
in the sheep enhances pericardial adiposity in the near-term fetus. Reprod. Fertil. Dev. 2014.
[CrossRef] [PubMed]
132. Xiao, X.Q.; Williams, S.M.; Grayson, B.E.; Glavas, M.M.; Cowley, M.A.; Smith, M.S.;
Grove, K.L. Excess weight gain during the early postnatal period is associated with permanent
reprogramming of brown adipose tissue adaptive thermogenesis. Endocrinology 2007, 148,
4150–4159. [CrossRef] [PubMed]
133. Gardner, D.S.; Rhodes, P. Developmental origins of obesity: Programming of food intake or
physical activity? Adv. Exp. Med. Biol. 2009, 646, 83–93. [PubMed]
Nutrients 2015, 7 8111
134. Godfrey, K.M.; Sheppard, A.; Gluckman, P.D.; Lillycrop, K.A.; Burdge, G.C.; McLean, C.;
Rodford, J.; Slater-Jefferies, J.L.; Garratt, E.; Crozier, S.R.; et al. Epigenetic gene promoter
methylation at birth is associated with child’s later adiposity. Diabetes 2011, 60, 1528–1534.
[CrossRef] [PubMed]
135. Milagro, F.I.; Mansego, M.L.; de Miguel, C.; Martinez, J.A. Dietary factors, epigenetic
modifications and obesity outcomes: Progresses and perspectives. Mol Aspects Med. 2013, 34,
782–812. [CrossRef] [PubMed]
136. Burdge, G.C.; Lillycrop, K.A. Folic acid supplementation in pregnancy: Are there devils in the
detail? Br. J. Nutr. 2012, 108, 1924–1930. [CrossRef] [PubMed]
137. Godfrey, K.M.; Gluckman, P.D.; Hanson, M.A. Developmental origins of metabolic disease:
Life course and intergenerational perspectives. Trends Endocrinol. Metab. 2010, 21, 199–205.
[CrossRef] [PubMed]
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