REVIEW
Maternal obesity and the developmental programming of
hypertension: a role for leptin
P. D. Taylor, A.-M. Samuelsson and L. Poston
Division of Women’s Health, Women’s Health Academic Centre, King’s College London and King’s Health Partners, London, UK
Received 23 July 2013,
revision requested 6 September
2013,
revision received 12 December
2013,
accepted 13 December 2013
Correspondence: P. D. Taylor,
Division of Women’s Health,
King’s College London, Women’s
Health Academic Centre KHP, St
Thomas’ Hospital, 10th Floor,
North Wing, 1 Westminster
Bridge, London SE1 7EH, UK.
E-mail: [email protected]
Abstract
Mother–child cohort studies have established that both pre-pregnancy
body mass index (BMI) and gestational weight gain are independently
associated with cardio-metabolic risk factors in young adult offspring,
including systolic and diastolic blood pressure. Animal models in sheep
and non-human primates provide further evidence for the influence of
maternal obesity on offspring cardiovascular function, whilst recent studies
in rodents suggest that perinatal exposure to the metabolic milieu of
maternal obesity may permanently change the central regulatory pathways
involved in blood pressure regulation. Leptin plays an important role in
the central control of appetite, is also involved in activation of efferent
sympathetic pathways to both thermogenic and non-thermogenic tissues,
such as the kidney, and is therefore implicated in obesity-related hyperten-
sion. Leptin is also thought to have a neurotrophic role in the development
of the hypothalamus, and altered neonatal leptin profiles secondary to
maternal obesity are associated with permanently altered hypothalamic
structure and function. In rodent studies, maternal obesity confers persis-
tent sympathoexcitatory hyper-responsiveness and hypertension acquired
in the early stages of development. Experimental neonatal hyperleptina-
emia in naive rat pups provides further evidence of heightened sympathetic
tone and proof of principle that hyperleptinaemia during a critical window
of hypothalamic development may directly lead to adulthood hyperten-
sion. Insight from these animal models raises the possibility that early-life
exposure to leptin in humans may lead to early onset essential hyperten-
sion. Ongoing mother–child cohort and intervention studies in obese preg-
nant women provide a unique opportunity to address associations between
maternal obesity and offspring cardiovascular function. The goal of the
review is to highlight the potential importance of leptin in the develop-
mental programming of hypertension in obese pregnancy.
Keywords developmental programming, hypertension, leptin, obesity,
pregnancy.
The WHO Global Burden of Disease database cur-
rently identifies 26% of women of reproductive age in
the United Kingdom as being obese, whilst the preva-
lence of maternal obesity has risen in line with the
general population and more than doubled in the past
two decades, with approximately one in five UK preg-
nant women now obese (Heslehurst et al. 2008,
2010). A recent landmark paper reported maternal
© 2014 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd, doi: 10.1111/apha.12223508
Acta Physiol 2014, 210, 508–523
obesity in pregnancy was associated with an increase
in all-cause mortality in adult offspring and specifi-
cally increased mortality from cardiovascular events
(Reynolds et al. 2013). It is therefore now more
important than ever before that we understand the
consequences of the obesity epidemic for pregnant
women, not only just in terms of pregnancy outcome,
but also in terms of the potential impact on the car-
diovascular health of the next generation. This review
will discuss the evidence from human epidemiological
data suggesting that maternal obesity predisposes off-
spring to cardiovascular dysfunction in later life, and
then with reference to experimental studies in animals,
illustrate the potential mechanisms involved in the
developmental programming of hypertension in partic-
ular, and the putative role for early-life hyperleptina-
emia in hardwiring the developing CNS and
cardiovascular system for increased sympathetic drive,
cardiovascular reactivity and hypertension.
Epidemiological evidence supporting the
developmental programming of obesity and
hypertension secondary to maternal obesity
Maternal obesity and offspring cardiovascular risk
Maternal obesity and excessive gestational weight gain
(GWG) constitute the most common obstetric risk fac-
tors and have direct implications not only just in
terms of perinatal and maternal morbidity and mortal-
ity outcomes (Heslehurst et al. 2008, Nelson et al.
2010, Poston et al. 2011), and healthcare costs
(Heslehurst et al. 2008, Denison et al. 2009) but also
from a longer-term public health perspective through
increased risk of obesity in the next generation
(Mingrone et al. 2008, Oken et al. 2008, Norman &
Reynolds 2011). Numerous reports suggest a ‘trans-
generational acceleration’ of obesity; an independent
relationship between maternal body mass index (BMI)
and body fat mass in older children. There is now
widespread concern that exposure to obesity in utero
and in the perinatal period may beget obesity and
related disorders in childhood (Drake & Reynolds
2010, Poston 2012, O’Reilly & Reynolds 2013).
Obesity in pregnancy is strongly associated with
gestational diabetes mellitus (GDM), and independent
associations between maternal diabetes and offspring
cardiovascular risk have been reported including child-
hood blood pressure and elevated plasma cardiovascu-
lar biomarkers (Wright et al. 2009, Krishnaveni et al.
2010, West et al. 2011, 2013). An alteration in the
ECG QRS complex suggests left axis deviation in
infants of diabetic mothers (Bacharova et al. 2012),
and foetal ST suppression during labour is described
(Yli et al. 2008). Macrosomic infants born to diabetic
mothers have increased aortic intermedia thickness at
delivery, with an additive effect of maternal obesity
(Akcakus et al. 2007), and there is a report of
increased arterial stiffness in 12-year-old children of
diabetic mothers (Tam et al. 2012). Hypertrophic car-
diomyopathy in neonates born to diabetic women
seems to resolve by 1 year of life, although there is
minimal information on its longer-term influences
(Marco et al. 2012). As the relationship between
maternal obesity and GDM is underpinned by
increased maternal insulin resistance associated with
obesity, it is reasonable to suggest that maternal obes-
ity per se may similarly influence cardiovascular func-
tion in the child and there is also evidence from
animal studies for a direct effect of leptin on cardiac
development (Samuelsson et al. 2013b), discussed in
more detail later. However, no detailed assessment
of cardiovascular function has been undertaken in
children of obese mothers, with or without GDM
diagnosis.
Boney and colleagues, in their studies of Pima Indi-
ans, demonstrated how maternal obesity, especially
when it resulted in gestational diabetes, increased the
risk of metabolic syndrome and type 2 diabetes devel-
oping in the offspring (Boney et al. 2005, Vohr & Bo-
ney 2008). Whilst these associations between maternal
obesity and childhood health may be due to shared
genetic obesogenic traits, which influence body weight
and blood pressure, converging lines of evidence sug-
gest that susceptibility to obesity and cardiovascular
disease is partly programmed in the developing foetus
or neonate through exposure to adverse metabolic fac-
tors during critical periods of development in early
life.
Maternal pre-pregnancy obesity vs. GWG and
cardiovascular risk of offspring
Compared with childhood adiposity/BMI, the relation-
ship between maternal BMI and childhood cardiovas-
cular function has infrequently been addressed and is
almost exclusively confined to measurement of blood
pressure; however, several mother–child cohort studies
now report independent relationships between mater-
nal BMI and blood pressure in older children and ado-
lescents (Laura et al. 2010, Filler et al. 2011, Wen
et al. 2011, Hochner et al. 2012). A recent study has
also observed that maternal pre-pregnancy obesity/
overweight is associated with increased systolic blood
pressure (SBP) in 7-year-old children (Wen et al.
2011). The Amsterdam Born Children and their
Development (ABCD) study recently reported that
pre-pregnancy BMI, in 3074 women, was positively
linearly associated with offspring diastolic blood pres-
sure (DBP) and SBP at 5–6 years of age (Gademan
© 2014 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd, doi: 10.1111/apha.12223 509
Acta Physiol 2014, 210, 508–523 P D Taylor et al. ·Neonatal hyperleptinaemia and hypertension
et al. 2013). Birth weight did not mediate the effect
and was negatively and independently associated with
blood pressure.
Childhood blood pressure is also reported to be
higher in children of mothers with excessive GWG
(Mamun et al. 2009, Fraser et al. 2011). Mamun
et al. (2009) reported an independent relationship
between GWG and offspring BMI and blood pressure
at 21 years of age. Most recently, the Jerusalem
cohort study reported that both pre-pregnancy BMI
and GWG were independently associated with cardio-
metabolic risk factors in adult offspring, at 32 years
of age, including SBP and DBP (Hochner et al. 2012).
However, causation is difficult to establish in
human cohort studies, and all the aforementioned
studies are essentially observational in nature and
therefore subject to residual confounding. It should
also be noted that not all mother–child observational
cohort studies have supported an association between
maternal overweight or obesity and increased
cardiovascular risk (Lawlor et al. 2012, O’Reilly &
Reynolds 2013). However, many of the earlier
mother–child cohorts included relatively few obese
women, which may have obscured any association,
and the results of ongoing randomized controlled trials
(RCT) in obese pregnant women are eagerly awaited.
The converging lines of evidence from human
cohort studies are supported by compelling evidence
from animal models in rodents, sheep and non-human
primates, which clearly demonstrate a persistent influ-
ence of prenatal exposure to maternal obesity on off-
spring CV function. We have recently demonstrated in
rodents that offspring of obese dams are hypertensive
as juvenile animals, prior to the development of obes-
ity, suggesting that maternal obesity and related meta-
bolic sequelae directly influence the developing foetal/
neonatal cardiovascular system leading to the develop-
ment of hypertension independent of offspring adipos-
ity (Samuelsson et al. 2010). This demonstrates the
usefulness of animal models in giving insight into
early-life origins of metabolic and cardiovascular dis-
ease and providing hypotheses for direct translation
(Taylor & Poston 2007).
Animal models of the developmental origins
of cardiovascular disease
Various animal models have been developed to manip-
ulate the nutritional and hormonal environment in
pregnancy ostensibly in an attempt to mimic the con-
ditions described in the early epidemiological studies
that gave rise to the developmental programming of
adult disease hypothesis (Hales & Barker 2001, Rose-
boom et al. 2001). This section will discuss the evi-
dence from animal models of maternal obesity and
overnutrition in pregnancy highlighting some of the
potential developmental programming mechanisms
implicated.
Animal studies have several advantages over the
human observational studies, which, as discussed
above, are by their nature largely associative and there-
fore cannot establish cause and effect. Modelling gesta-
tional environments in animals, especially rodents, can
avoid many of the underlying residual confounding
that can ‘plague’ epidemiological studies, in that
genetic and social influences can be removed, experi-
mental conditions can be tightly controlled, and the
underlying physiological, cellular and molecular mech-
anisms can be fully explored at the various ‘critical
windows’ of development. Moreover, the relatively
short life cycles, especially in rodents, that means the
long-term effects of early-life environmental ‘insults’
can be studied in a meaningful time frame. Most of
the research in this area has been concerned with
maternal undernutrion and the developmental
programming of hypertension (for reviews see Ojeda
et al. 2008, Langley-Evans 2013).
Developmental programming of blood pressure in
animal models of overnutrition
Relatively few studies have examined the effects of
overnutrition on blood pressure, and the majority of
work in this field has been performed in rodents. In
general, maternal overnutrition has been found to
result in increased SBP in the offspring (for reviews
see Armitage et al. 2005b, Nathanielsz et al. 2007a,
Poston 2011). Maternal pre-pregnancy obesity has
been induced by preconditioning rodents prior to
pregnancy through the introduction of semi-synthetic,
high-fat diets in which carbohydrates are replaced by
dietary fat sources such as lard. In some instances,
simple sugars have been added to the high-fat diet to
further increase palatability and food intake or a ‘caf-
eteria-style’ diet is employed, in which highly palat-
able ‘junk foods’ typical of a Western diet provide
high-fat and high-sugar intake in rodents (Bayol et al.
2005, Akyol et al. 2009). The addition of highly pal-
atable sugars to a high-fat diet or introduction of a
cafeteria-style diet appears to overcome the tight ho-
moeostatic control of caloric intake seen in rodents to
affect a more rapid shift towards a positive energy
balance. Diet-induced obesity (DIO) in rodent dams,
similar to obese human pregnancy, appears to be asso-
ciated with a degree of gestational diabetes in that
maternal overnutrition models are associated with
maternal hyperinsulinaemia and glucose intolerance in
pregnancy and/or lactation (Taylor et al. 2003, Hole-
mans et al. 2004, Srinivasan et al. 2006, Chen et al.
2008, Samuelsson et al. 2008, Nivoit et al. 2009).
© 2014 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd, doi: 10.1111/apha.12223510
Neonatal hyperleptinaemia and hypertension · P D Taylor et al. Acta Physiol 2014, 210, 508–523
Rodent models developed in our laboratory (Khan
et al. 2003, 2005, Taylor et al. 2004, 2005, Armitage
et al. 2005a, 2007, Samuelsson et al. 2008, Kirk et al.
2009, Nivoit et al. 2009) show deleterious conse-
quences for cardiovascular and metabolic function in
the progeny of obese animals, observations confirmed
worldwide (Nathanielsz et al. 2007a, Taylor & Poston
2007, Morris & Chen 2009, Poston 2011). Adult off-
spring of diet-induced obese mice develop systolic and
mean arterial hypertension by 3 months of age associ-
ated with resistance artery endothelial dysfunction
(Samuelsson et al. 2008). Hypertension was also asso-
ciated with increased visceral adiposity and hyperlepti-
naemia, which suggests obesity-related hypertension in
this model, that is, leptin-mediated hypertension acting
through central sympathetic pathways (for review see
Rahmouni et al. 2005). However, in the rat, a larger
species in which it is technically possible to measure
blood pressure in younger animals, blood pressure was
already elevated in juvenile offspring of obese dams
prior to the development of offspring obesity and con-
tinued to increase into adulthood (Samuelsson et al.
2010). Juvenile offspring of the obese dams also
showed an enhanced pressor response to restraint
stress, and spectral analysis of the heart rate variability
derived from the blood pressure telemetry record
revealed increased ratio of low-frequency to high-fre-
quency oscillations at 30 and 90 days of age, indica-
tive of an increased sympathetic component in the
autonomic regulation of blood pressure. There was
also evidence of altered baroreceptor sensitivity, and
taken together, these observations suggest the develop-
mental programming of a primary hypertension of
sympathetic origin in the offspring of obese dams.
Maternal obesity and neuronal development of the
neonatal brain
Maternal obesity was associated with a marked hyper-
leptinaemia in the neonate during a critical period
in brain development when leptin is thought to play
a permissive neurotrophic role in establishing the
neural circuitry of the hypothalamus, involved in both
appetite and blood pressure control (Bouret et al.
2004a,b). The elevation in blood pressure in early life
in offspring of obese rodents may arise from perturba-
tion of central leptin sensitivity and dysregulation of
the normal neurotrophic action of leptin. Young off-
spring of obese rats show behavioural and cell signal-
ling deficits in leptin sensitivity with evidence of
altered neuronal development in the hypothalamus
(Kirk et al. 2009).
Data from animal studies add to the increasing evi-
dence for developmental plasticity in the central effer-
ent pathways of the hypothalamus and nucleus of the
solitary tract involved in the autonomic nervous sys-
tem (ANS). In rats and mice, there is a surge in the
plasma leptin concentration during the early post-
natal period (Devaskar et al. 1997, Rayner et al.
1997, Ahima et al. 1998, Morash et al. 2001, Yura
et al. 2005, Cottrell et al. 2009), during which ani-
mals maintain a high level of food intake favouring
rapid growth. Pups therefore demonstrate resistance
to the anorectic effects of leptin, suggesting that the
leptin signalling pathways are incomplete at this stage
of development and that leptin is acting primarily as a
modulator of hypothalamic neuronal outgrowth dur-
ing this critical developmental window (Cottrell et al.
2009, Bouret 2010).
Bouret and colleagues found reduced neural projec-
tions from the arcuate nucleus (ARC) of the hypothal-
amus to the paraventricular hypothalamic nucleus
(PVH) in leptin-deficient (ob/ob) mice (Bouret et al.
2004b). Administering exogenous leptin to leptin-defi-
cient (ob/ob) neonates reinstated normal hypothalamic
development and provided the first demonstration of
the neurotrophic effects of leptin in early post-natal
life; no such effects of leptin were observed in adult
ob/ob mice, again highlighting the neonatal period as
being critical to hypothalamic development. Attenua-
tion of these ARC projections has also been reported
in rats genetically predisposed to develop DIO (Bouret
et al. 2008). These two genetically determined models
(Bouret et al. 2004b, 2008) also show reduced
immunoreactivity for agouti-related peptide (AgRP) in
projections from the ARC to the PVH (Bouret et al.
2004b, 2008). Suboptimal development of ARC
projections including AgRP-containing neurones may
permanently influence the formation and function of
neural circuits involved in the regulation of not
only energy balance via leptin signalling but also
cardiovascular regulation via the ANS (Fig. 1). More-
over, AgRP is the endogenous antagonist of the mela-
nocortin-4 receptor (MC4R); therefore, a reduced
antagonism may increase MC4R signalling at sites rel-
evant to blood pressure regulation and hypertension
(Ye & Li 2011).
Using a model of diet-induced obesity, we have
recently reported attenuated AgRP immunoreactivity
in the PVH of OffOb at post-natal day 30 (PD30),
which was associated with an exaggerated and pro-
longed neonatal leptin surge (Kirk et al. 2009). We
suggest that this similarity between our model and ob/
ob mice (Bouret et al. 2004b) is associated with leptin
resistance in the former and leptin deficiency in the
latter and highlights the exquisite balance of leptin
levels and signalling required for the normal develop-
ment of the neonatal brain.
The neonatal plasma leptin profile was paralleled
by increased leptin gene expression in pup adipocytes,
© 2014 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd, doi: 10.1111/apha.12223 511
Acta Physiol 2014, 210, 508–523 P D Taylor et al. ·Neonatal hyperleptinaemia and hypertension
suggesting that neonatal adipocytes are the source of
the leptin surge. A similar relationship between adipo-
cyte leptin gene expression and plasma leptin has been
described by others (Devaskar et al. 1997, Ahima
et al. 1998, Yura et al. 2005), and the maternal nutri-
tional status is known to influence the neonatal leptin
profile (Yura et al. 2005, Vickers et al. 2008). In
rodents, this will be reflected, through milk ingestion,
in the composition of the neonatal plasma, and we
have shown that the neonatal plasma insulin profile
peaks several days before leptin in OffOb rats (Fig. 2).
As insulin is known to accelerate maturation and dif-
ferentiation of pre-adipocytes into mature adipocytes
(Kim et al. 2008), which alone express leptin, this
hormone may thereby indirectly contribute to the
development of neonatal hyperleptinaemia (Lee &
Fried 2009a; see below determinants of the leptin
surge).
Nutritional manipulation of the leptin surge
There has been much focus on the role of leptin,
prompted by the neuroendocrine and structural neuro-
nal abnormalities observed in leptin-deficient (ob/ob)
mice, and extensive evidence for early nutrition
impacting on the development of neuronal systems of
the foetal/neonatal hypothalamus now exists (Elmquist
& Flier 2004, Cripps et al. 2005, Grove et al. 2005,
McMillen & Robinson 2005, Muhlhausler et al.
2005, Ferezou-Viala et al. 2007, Bautista et al. 2008,
Bouret et al. 2008, Chang et al. 2008, Chen et al.
2008, Delahaye et al. 2008, Morris & Chen 2009,
Glavas et al. 2010).
Both maternal undernutrition and maternal overnu-
trition have now been shown to impact on the timing
and magnitude of the neonatal leptin surge to influ-
ence the adult phenotype. Altered neonatal leptin pro-
files have been reported in several models of
developmental programming of metabolic dysfunction
(Yura et al. 2005, Delahaye et al. 2008). Further evi-
dence for a persistent effect of leptin in the neonatal
Figure 1 Leptin signalling, blood pressure and MC4-R pathway. The precise intracellular signalling pathways and brain sites
by which leptin regulates blood pressure are not fully understood, and there is good evidence that leptin requires activation of
the brain melanocortin system to exert its effects on renal SNA. Leptin and insulin act synergistically to activate shared central
sympathoexcitatory pathways which are mediated by the melanocortin-4 receptor (MC4R) and the PI3 kinase pathway. Region-
ally distinct neuronal pathways contribute to different elements of the sympathetic response to leptin and insulin.
(a)
(b)
Figure 2 Neonatal serum leptin and insulin concentrations
in offspring of control and obese dams. Serum leptin (a) and
insulin (b) were measured in offspring of control dams (open
bars) and obese dams (closed bars) over the suckling period.
*P < 0.05, **P < 0.01 and ***P < 0.01 vs. offspring of con-
trol dams for the same period (n = 3–6). For longitudinal
comparisons, a significant difference (P < 0.05) from the pre-
ceding period is indicated by # for offspring of control dams
and by † for offspring of obese dams.
© 2014 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd, doi: 10.1111/apha.12223512
Neonatal hyperleptinaemia and hypertension · P D Taylor et al. Acta Physiol 2014, 210, 508–523
period is suggested by the observation that exogenous
manipulation of the neonatal leptin profile can modu-
late offspring phenotype (Vickers et al. 2005, 2008,
Yura et al. 2005, Attig et al. 2008, Stocker & Caw-
thorne 2008, Samuelsson et al. 2013b).
Determinants of the neonatal leptin surge in rodents
An understanding of the factors mediating the effects
of nutritional status on neonatal leptin could inform
interventions to reduce the risk of obesity and hyper-
tension. Little is known about the origins of the neo-
natal leptin surge. The milk supply is an obvious
source as maternal leptin can pass unaltered through
the immature neonatal gut in rodents (Casabiell et al.
1997). However, we (Kirk et al. 2009) and others
(Ahima et al. 1998, Bautista et al. 2008) have found
no evidence for an association between milk leptin
and pup serum leptin in neonatal rodents. The stom-
ach has also been identified as a potential source of
leptin in adult animals; however, levels in neonatal
stomach tissue are extremely low, and leptin is consid-
ered not to be produced by the neonatal stomach epi-
thelium until after post-natal day 15 (Oliver et al.
2002). However, in offspring of obese rats, we have
reported that serum leptin levels are paralleled by
increases in the leptin mRNA expression in adipose
tissue over the period of the leptin surge suggesting
that leptin is neonatal rather than maternal in origin
(Kirk et al. 2009). This relationship between increased
adipocyte leptin gene expression and the plasma leptin
surge has also been described by others (Devaskar
et al. 1997, Ahima et al. 1998, Yura et al. 2005).
The plasma leptin concentration in the neonatal
rodent, unlike the adult, is independent of fat mass as
indicated by the observation that fat mass continues
to increase despite the fall in leptin (Ahima et al.
1998, Bautista et al. 2008); however, the determinants
are not known, and several candidates as modulators
of adipocyte leptin gene expression show poor associ-
ation (Ahima et al. 1998). The transient nature of the
leptin surge that returns to normal levels by the end
of suckling could reflect the changing nutritional pro-
files in the milk, or alternatively, it might be indicative
of humoral suppression of leptin production.
Whilst many humoral factors are recognized as
determinants of adult adipocyte leptin gene expression
and leptin secretion, those factors in plasma or milk
that determine neonatal leptin gene expression and
secretion, as part of the normal physiological leptin
surge in the rodent, are yet to be defined. In the adult
rodent, nutrients and hormones associated with a
positive energy balance such as glucose and insulin are
associated with an increase in adipose tissue leptin
mRNA expression, whereas sympathetic activity
appears to decrease expression via catecholamine
activity (Lee et al. 2007, Lee & Fried 2009b). Again
in adults, there is also evidence that certain fatty acids
antagonize insulin stimulation of leptin production
and thereby suppress basal leptin expression. Insulin is
adipogenic and acutely increases the production of
leptin by adipose tissue (Lee & Fried 2009b). Preli-
minary data from OffOb neonates indicate that insu-
lin profiles peak several days before the leptin surge,
in parallel with glucose profiles in the milk, and
highlight a candidate role for insulin and glucose in
the altered leptin surge (Fig. 2). Studies are warranted
to determine the effect of neonatal glucose exposure
on both the insulin and leptin surge.
As only mature adipocytes express the leptin gene,
disturbance of the normal maturation processes of adi-
pocyte proliferation and differentiation in the neonatal
rat will affect the leptin surge. Hormones such as insu-
lin and leptin that may influence pathways regulating
adipocyte proliferation and differentiation are, there-
fore, candidates for nutritional programming. Alterna-
tively, Ailhaud et al. (2006, 2008) have proposed that
adipocyte exposure to a high n-6/n-3 fatty acid ratio in
early life causes precocious development resulting in a
greater pool of mature adipocytes persisting to adult-
hood. We have previously reported an increase in the
ratio of arachidonic acid (n-6) to eicosapentaenoic and
docosahexaenoic acids (n-3) in obese offspring (Kirk
et al. 2009) which could contribute to accelerated
maturation of the pre-adipocytes and the exaggerated
leptin surge. The transgenic fat-1 mouse is capable of
endogenously converting n-6 PUFA to n-3 PUFA via
ubiquitous expression of a Caenorhabditis elegans-
derived n-3 desaturase. Transgenic fat-1 mice with an
increase in n-3/n-6 fatty acid ratio demonstrate
reduced maternal obesity-associated inflammation with
a marked reduction in pro-inflammatory cytokines,
and wild-type offspring of hemizygous fat-1 dams are
protected from placental and foetal liver triglyceride
deposition and were protected from diet-induced obes-
ity and fatty liver disease as adults (Heerwagen et al.
2013). Hence, reducing the n-6/n-3 fatty acid ratio in
pregnancies complicated by maternal obesity may be a
promising therapy for improving inflammation and
lipid dysmetabolism, preventing adverse foetal meta-
bolic outcomes, whilst also modulating foetal/neonatal
leptin exposure.
Pathophysiological role for leptin and insulin in
developmental programming of an overactive SNS
Leptin is critical to the regulation of energy balance,
acting at the ARC of the hypothalamus to inhibit food
intake and increase energy expenditure via sympa-
thetic stimulation to metabolically active tissues
© 2014 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd, doi: 10.1111/apha.12223 513
Acta Physiol 2014, 210, 508–523 P D Taylor et al. ·Neonatal hyperleptinaemia and hypertension
(Haynes et al. 1997). Leptin also plays a cardiovascu-
lar modulatory role in the CNS (Haynes et al. 1997).
Infusion of leptin or leptin over-expression in mice
increases renal sympathetic nerve activity (RSNA) and
blood pressure (Shek et al. 1998, Dunbar & Lu 1999,
Carlyle et al. 2002, Rahmouni et al. 2005), whereas
leptin deficiency, in both humans and animals, causes
obesity in the absence of hypertension (Mark et al.
1999, Ozata et al. 1999). Acquired selective leptin
resistance, whereby chronic hyperleptinaemia leads to
loss of its anorexic action, whilst its pressor effects
remain intact, is hypothesized to account for obesity-
related hypertension (Rahmouni et al. 2005, Harlan
et al. 2011). We have reported selective leptin resis-
tance in juvenile OffOb rats, which demonstrate an
enhanced pressor response to leptin compared with
controls, whilst the anorexic effects of leptin are lost
(Kirk et al. 2009, Rahmouni 2010, Samuelsson et al.
2010). Consistent with this, phosphorylated STAT3, a
marker of leptin signalling, was selectively reduced in
the ARC of 30-day-old-OffOb rats, but no change
was seen in the ventromedial hypothalamic nucleus
(VMN; Kirk et al. 2009), a site through which leptin
may exert its pressor effects. Importantly, this
occurred prior to the development of obesity and hy-
perleptinaemia suggesting that this selective leptin
resistance was not obesity related, but a direct conse-
quence of early-life ‘exposure’ to maternal obesity.
We conclude that selective leptin resistance and the
exaggerated pressor response to leptin may contribute
to the developmental origins of ANS-mediated hyper-
tension secondary to maternal obesity (Fig. 3). The
apparent paradox of ‘selective leptin resistance’, in
which offspring were less responsive to leptin-induced
appetite suppression, is similar to that observed in
adult obese rodents and explicable on the basis that
the cardiovascular and appetite regulatory actions of
leptin may occur in regionally distinct hypothalamic
neurones with differing ontogeny (Fig. 1).
The ANS has not been extensively studied in the
children of obese women, although a correlation has
been observed between foetal cardiac sympatho-vagal
activation during labour and maternal BMI (Ojala
et al. 2009). The ABCD study of 3074 women
recently reported that pre-pregnancy BMI was posi-
tively linearly associated with offspring DBP and SBP,
but not with sympathetic or parasympathetic drive;
however, only a small proportion (5%) of the women
studied were clinically obese (Gademan et al. 2013).
Ongoing studies will characterize ANS as part of a
follow-up study of neonates and 3-year-old children
born to obese pregnant women participating in the
UPBEAT RCT (UK pregnancy and better eating trial)
compared with offspring born to lean control moth-
ers. In the UPBEAT cohort, obese pregnant women
were randomized to either a complex lifestyle (diet
and exercise) intervention in pregnancy, or routine
care, thus providing the opportunity to also investi-
gate the effect of intervention on offspring cardiovas-
cular function.
To investigate the direct role of neonatal hyperlepti-
naemia in offspring cardiovascular dysfunction, we
treated naive rat pups with exogenous leptin to mimic
the exaggerated leptin surge observed in neonate off-
spring of obese dams (Samuelsson et al. 2013b). Pups
from lean Sprague–Dawley rats were treated either
with leptin (L-Tx; 3 mg kg�1 i.p.) or saline (S-Tx;
i.p.) twice daily from post-natal day (PD) 9 until
PD15. Cardiovascular function was assessed by radio-
telemetry at 30 days, and 2 and 12 months. In juve-
nile (30 day) L-Tx, night-time (active period) SBP was
raised by 13 mmHg compared with S-Tx. The pressor
response to a restraint stress and leptin challenge was
also enhanced, and spectral analysis of heart rate vari-
ability revealed an increased low/high frequency ratio,
indicative of heightened sympathetic efferent tone in
30-day L-Tx rats. Basal renal tissue noradrenaline
content was increased twofold in L-Tx vs. S-Tx,
whilst sympathetic inhibition by combined administra-
tion of the a1-adrenergic receptor antagonist,
terazosin and the b1/b2-adrenergic receptor antago-
nist, propranolol normalized MAP and led to a
Figure 3 Schematic: mechanisms in foe-
tal programming of obesity and hyper-
tension. The proposed developmental
origin of ‘selective leptin resistance’ in
which the anorexic effects of leptin are
lost, whilst the pressor effect of leptin is
enhanced.
© 2014 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd, doi: 10.1111/apha.12223514
Neonatal hyperleptinaemia and hypertension · P D Taylor et al. Acta Physiol 2014, 210, 508–523
greater fall in basal MAP in L-Tx rats compared with
S-Tx. This heightened sympathetic tone was observed
in L-Tx, despite these rats showing no increase in fat
mass or hyperleptinaemia at this age. Trevenzoli et al.
(2007) have previously described increased SBP (tail-
cuff method), in adult 150-day-old rats treated with
leptin in the neonatal period (post-natal days 1–10),
but this could have arisen secondary to the associated
increase in body weight in adulthood. Data from L-Tx
rats suggest a direct influence of early leptin exposure
on the developing pathways of blood pressure control
(Samuelsson et al. 2013b).
Leptin treatment from post-natal days 9–14 also
caused leptin resistance at 30 and 90 days of age, as
indicated by feeding behaviour following a leptin chal-
lenge. L-Tx rats showed impaired anorectic responses
to the leptin challenge compared with S-Tx, as dem-
onstrated by an absence of a reduction in food intake
or body weight over a 24-h period. Others have
reported hypothalamic leptin resistance in rats follow-
ing administration of leptin in neonatal life (Toste
et al. 2006, Vickers et al. 2008). Similarly, leptin
administration to neonatal mice results in resistance to
the weight-reducing effect of peripheral leptin in
adulthood (Yura et al. 2005). However, this is the
first evidence to suggest that hyperleptinaemia during
a critical window of hypothalamic development may
directly lead to adulthood sympathetic hypertension
and confirms a role for leptin in the acquired ‘selective
leptin resistance’ observed in juvenile offspring of
obese rats (Fig. 3). Leptin is likely to play a key mech-
anistic role in the relationship between maternal obes-
ity and cardiovascular and metabolic dysfunction of
the offspring. However, compared with L-Tx, the Of-
fOb rats have a more deleterious MAP profile (Samu-
elsson et al. 2010), indicating that neonatal leptin
exposure alone may not account for the entire OffOb
phenotype (Samuelsson et al. 2013b). Foetal hyperin-
sulinaemia secondary to maternal obesity and glucose
intolerance (Samuelsson et al. 2008, Nivoit et al.
2009) is also likely to play a role in hypothalamic
neurodevelopment (Plagemann 2006) and may contrib-
ute to the programming of hypertension in this model.
Mechanisms underlying leptin-induced sympatho-
excitation
Leptin and insulin act synergistically to activate shared
central sympathoexcitatory pathways which are medi-
ated by the melanocortin-4 receptor (MC4R) and the
PI3 kinase pathway (Morgan et al. 2008). Humans
with inactivating mutations of MC4R are obese, but
not hypertensive (Greenfield et al. 2009). Moreover,
the sympathoexcitatory responses to acute leptin and
insulin administration are abolished by i.c.v. adminis-
tration of the MC4R antagonist SHU9119 (Greenfield
et al. 2009) and in melanocortin deficient mice
(Rahmouni et al. 2003). Regionally distinct neuronal
pathways contribute to different elements of the sym-
pathetic response to leptin and insulin. Microinjection
of leptin into the dorsomedial hypothalamic nucleus
of rats increases arterial pressure and heart rate, but
not RSNA, whereas microinjection of leptin into the
VMN increases the arterial pressure and RSNA, but
not heart rate (Marsh et al. 2003). Peripheral leptin
also exerts indirect effects on the SNS by activating
melanocortin receptors in the PVN leading to
increased neuronal activity in the rostral ventrolateral
medulla (RVLM) and increased RSNA. In contrast,
MC4R signalling indirectly induced by insulin acti-
vates neurones upstream of the PVN and increases
glutamatergic drive from the PVN to the RVLM, acti-
vating the lumbar sympathetic nerve, but not the renal
sympathetic nerve (Ward et al. 2011). We have found
that intracerebroventricular administration of the
MC3/4R antagonist SHU9119 decreases MAP to a
greater degree in OffObs compared with controls
(Samuelsson et al. 2013a). Quantitative real-time PCR
revealed increased hypothalamic MC4 mRNA expres-
sion in 3-month-old OffOb rats (Fig. 4). These data
suggest that maternal obesity results in increased
hypothalamic melanocortin signalling in the adult
Figure 4 PCR showing MC4R mRNA expression in whole hypothalamus in male and female offspring of Control (OffC) and
Obese (OffOb) dams weaned onto either control or obesogenic diet (OffC-C, OffC-Ob, OffOb-C, OffOb-Ob). Genes are nor-
malized to the geometric mean of the three housekeeping genes, B-actin, gapdh, B3, using geNormTM software’ and expressed
relative to this normalization factor geNorm analysis software (PrimerDesign, Southampton, UK). *P < 0.05, **P < 0.01 vs.
OffCon-C, t-test, n = 4–6 per group.
© 2014 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd, doi: 10.1111/apha.12223 515
Acta Physiol 2014, 210, 508–523 P D Taylor et al. ·Neonatal hyperleptinaemia and hypertension
offspring which contributes to hypertension in this
model. It is tempting to speculate, therefore, that
increased signalling via MC4R in the PVN, VMN and
RVLM mediates the primary sympathetic hypertension
in offspring of obese pregnant rats; however, there is
also evidence for the involvement of MC4R in the
brainstem. Re-expression of MC4Rs specifically in
cholinergic neurones (including sympathetic pregangli-
onic neurones) restores obesity-associated hypertension
in MC4R null mice (Sohn et al. 2013). Studies to elu-
cidate the regionally distinct neuronal pathways
affected specifically by maternal obesity are currently
underway in our laboratory. We can hypothesize that
this neuronal ‘rewiring’ will be prevented by maternal
interventions which reverse the post-natal hyperlepti-
naemia and/or hyperinsulinaemia. Rodent studies are
warranted to investigate the effect of exercise and
dietary interventions in obese pregnancy on offspring
cardiovascular function.
Developmental programming of cardiac function
Several animal studies have implied that perturbations
of the nutritional or metabolic environment can influ-
ence myocardial development and function in later life
(Roigas et al. 1996, Bae et al. 2003, Davis et al.
2003, Li et al. 2003, Han et al. 2004, Almeida &
Mandarim-de-Lacerda 2005, Battista et al. 2005, Che-
ema et al. 2005, Catta-Preta et al. 2006, Fernandez-
Twinn et al. 2006, Xu et al. 2006, Elmes et al. 2007,
2008, Chan et al. 2009, Porrello et al. 2009, Tappia
et al. 2009, Xue & Zhang 2009). Experimental pla-
cental mass reduction, foetal hypertension and cortisol
exposure all affect proliferation and terminal matura-
tion of the neonatal cardiac myocytes (Giraud et al.
2006, Jonker et al. 2007, Louey et al. 2007). As the
number of myocytes in all species is determined in
utero and in early post-natal life (Anatskaya et al.
2009), perinatal ‘programming’ has been proposed to
be a determinant of cardiac dysfunction in adult life
(Thornburg & Louey 2005, Porrello et al. 2009).
Most of the relevant literature focuses on undernutri-
tion and associated foetal growth restriction, but a
recent study in obese pregnant sheep has reported
markedly altered structure and function in foetal hearts
in late gestation. Phosphorylation of AMP-activated
protein kinase (AMPK), a cardio-protective signalling
pathway, was reduced, whilst the stress signalling path-
way, p38 MAPK, was up-regulated (Wang et al. 2010).
In addition, foetal hearts from obese dams showed
impaired cardiac insulin signalling which if persistent
into adult life would predispose offspring to insulin
resistance and cardiac dysfunction (Wang et al. 2010).
The neurotrophic neonatal leptin surge, discussed
above (Ahima et al. 1998), also coincides with the
critical period for cardiac plasticity (Anatskaya et al.
2009). Micro-echocardiography showed altered left
ventricular structure and systolic function in 30-day
female L-Tx vs. S-Tx (Samuelsson et al. 2013b).
Thirty-day-old juvenile female L-Tx showed increased
left ventricle internal diameter at systole (LVIDs),
increased left ventricle volume at systole (LVVols) and
decreased intraventricular septal thickness at diastole
vs. S-Tx, associated with a reduced ejection fraction
(EF) and fractional shortening (FS) in female L-Tx vs.
S-Tx. These disorders persisted to adulthood. At
12 months, both male and female L-Tx showed mark-
edly increased LV mass, increased LVVols increased left
ventricle internal diameter (LVIDs), associated with
decreased EF and FS, indicating that exogenously
imposed hyperleptinaemia in neonatal rats permanently
influences blood pressure and cardiac structure and
function. In contrast to the OffOb cardiac phenotype
reported above (Fernandez-Twinn et al. 2012), the car-
diac hypertrophy indicated by the increased heart
weight in L-Tx rats was explained by an increase in
myocyte number, indicating possible divergent roles for
leptin and insulin in cardiac development. Although the
potential mechanism remains unclear, previous reports
have shown that leptin added to rat neonatal myocyte
culture can lead to hypertrophy (Rajapurohitam et al.
2003) or hyperplasia (Tajmir et al. 2004).
The alterations in cardiac function in juvenile L-Tx
rats as assessed by echocardiography were similar to
those we have observed in a preliminary study in
adult OffOb mice (Rajani et al. 2009). The cardiac
dilatation observed together with impaired contractil-
ity may reflect a second, ‘decompensatory’ phase of
myocardial failure (Hein et al. 2003).
Most recently, employing the same model, Ozanne
et al. have demonstrated in offspring of obese mice
the developmental programming of cardiac hypertro-
phy, associated with hyperinsulinaemia, AKT, ERK
and mTOR activation, prior to the onset of adult
obesity in this model (Fernandez-Twinn et al. 2012).
Consistent with structural changes in the heart, the
expression of molecular markers of cardiac hypertro-
phy was also increased including Nppb(BNP),
Myh7-Myh6(betaMHC-alphaMHC) and mir-133a.
Notably, p38MAPK phosphorylation was also
increased, suggesting pathological remodelling.
Increased Ncf2(p67(phox)) expression and impaired
manganese superoxide dismutase levels suggested
oxidative stress, together with an increase in lipid
peroxidation (4-hydroxy-2-trans-nonenal). Maternal
diet-induced obesity therefore appears to promote off-
spring cardiac hypertrophy, independent of offspring
obesity, associated with hyperinsulinaemia-induced
activation of AKT, mammalian target of rapamycin,
ERK and oxidative stress.
© 2014 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd, doi: 10.1111/apha.12223516
Neonatal hyperleptinaemia and hypertension · P D Taylor et al. Acta Physiol 2014, 210, 508–523
It will prove difficult, however, to determine whether
the cardiac abnormalities occur simply as a result of an
increase in blood pressure and haemodynamic load or
though altered neurohumoral signalling. Further stud-
ies will be required, preferably across species, with
translation to ongoing mother–child cohort studies to
establish the significance, aetiology and underlying
mechanism of these observed alterations in cardiac
structure and function secondary to maternal obesity.
Relevance of animal models to human
obesity in pregnancy
Obese pregnant women are insulin resistant, and
maternal hyperglycaemia leads to foetal hyperinsulina-
emia (Catalano et al. 2009). They also demonstrate
hyperleptinaemia, and cord blood leptin is also raised
in babies born to obese women (Catalano et al.
2009). Thus, the foetus of an obese woman is, in com-
mon with the neonatal rodent, exposed to both hyper-
insulinaemia and hyperleptinaemia (Nelson et al.
2010). It is important, however, in extrapolation from
the rodent models to appreciate that rodents are altri-
cial species, that is, they are born at a more immature
stage of development than the human newborn. The
period of developmental plasticity in the human hypo-
thalamus is likely to be most relevant to the third tri-
mester but may well extend into post-natal life, as
evidenced in non-human primates (Grove et al. 2005).
Studies in non-human primates and sheep suggest sim-
ilar metabolic profiles in the adult offspring of obese
mothers supporting the translation to precocial species
(Nathanielsz et al. 2007b). The relative maturity
between the human brain and that of the rodent post-
partum requires consideration. In rodents, hypotha-
lamic neurones expressing appetite and cardiovascular
regulatory peptides develop in the last week of gesta-
tion, and development is not complete until 2 weeks
after delivery (Grove & Smith 2003). Studies of the
human brain are understandably few, but NPY is
present at 21 weeks of gestation when projections to
associated nuclei are already present (Koutcherov
et al. 2002). However, based on observations in non-
human primates, in which the density of the neurite
projections continues to increase post-partum (Gray-
son et al. 2006), ongoing hypothalamic development
is likely in the post-partum human infant; thus, sus-
ceptibility to the neurotrophic influences of leptin
could also occur in both antenatal and post-partum
periods. A role for leptin in developmental processes
could be inferred from the inexplicably high cord
blood neonatal leptin concentration in infants, which
falls rapidly post-partum (Schubring et al. 1999), and
is related to birthweight (Matsuda et al. 1997, Cetin
et al. 2000).
Intervention strategies to improve maternal
metabolic profiles in obese pregnancy
Interventions that reduce maternal GWG or improve
glucose homoeostasis, in obese pregnant women, are
hypothesized to improve pregnancy outcome. How-
ever, to date, few relevant studies have been reported
in obese pregnancy, which can inform policy for effec-
tive intervention strategies (Dodd et al. 2010, Gardner
et al. 2011).
Two elegant studies of siblings born to mothers
before and after bariatric surgery for extreme obesity
have provided some support for an association
between maternal and offspring cardio-metabolic risk
factors (Kral et al. 2006, Smith et al. 2009). In both,
the prevalence of overweight and obesity was higher
in the children born before, compared with those born
after surgery. Although sibling studies such as these
help to minimize residual confounding, through
shared genetic background environment, these were
not randomized controlled trials, which are likely to
confer greater insight into causality.
At present, two large RCTs are underway to evaluate
the efficacy of dietary and lifestyle interventions on
pregnancy outcome in obese pregnancies; the UPBEAT
study in the United Kingdom (Poston PI, NIHR pro-
gramme; ISRCTN89971375) and the LIMIT trial in A-
delaide, Australia (Dodd J PI; ACTRN1260700
0161426). Both studies will follow up the children to
investigate cardiovascular and metabolic phenotype
and offer a unique opportunity to investigate the effect
of diet and lifestyle intervention on the relationship
between maternal metabolic profile and the cardiovas-
cular health of the child. Studies of neonatal cardiovas-
cular parameters are currently ongoing as part of
UPBEAT Tempo; however, the influence on childhood
outcomes will not be known for several years.
These studies will address the primary hypothesis
that maternal obesity is an independent determinant of
cardiovascular risk in young children and will directly
test the relevance of rodent models of maternal obesity
to the human condition in regard to developmental
origins of cardiovascular disease, particularly in regard
to autonomic control of blood pressure, that we and
others have extensively characterized in these models.
RCT intervention studies have the potential to
contribute to our understanding of the physiological
mechanisms controlling autonomic development and
function and will also identify novel pathways in the
early-life origins of essential hypertension.
The programming of offspring BMI and blood pressure
One of the challenges in ascribing cause and effect
between maternal obesity and offspring cardiovascular
© 2014 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd, doi: 10.1111/apha.12223 517
Acta Physiol 2014, 210, 508–523 P D Taylor et al. ·Neonatal hyperleptinaemia and hypertension
risk is illustrated by the fact that the cardiovascular risk
factors described in epidemiological studies often
appear to coexist with risk of obesity in the offspring.
Many reports particularly in older children are
complicated by associations between current BMI and
blood pressure, with few being attempted in younger
children. The indirect programming of obesity-related
hypertension, secondary to maternal obesity, through
greater adiposity in offspring and enhanced leptin-medi-
ated renal sympathetic activity could is therefore an
important contributor to the association between off-
spring blood pressure and maternal obesity. This is illus-
trated in the recent report from the ABCD study, which
showed a positive linear relationship between maternal
pre-pregnancy BMI and offspring SBP and DBP at 5–6
years of age. When childhood BMI was put into the
regression model, the effect size was halved although a
significant association between maternal obesity and
childhood blood pressure remained (ABCD study).
Conclusions
Obesity in pregnancy, perhaps compounded by addi-
tive effects of GDM, demonstrates independent associ-
ations with offspring cardio-metabolic risk including
childhood blood pressure and elevated plasma cardio-
vascular risk biomarkers. The extent to which elevated
blood pressure and other cardiovascular risk factors
are dependent on the development of childhood obesity
requires further studies in younger children and neo-
nates born to obese women. Animal studies strongly
support an influence of the maternal obesogenic envi-
ronment in pregnancy on determinants of cardiovascu-
lar control, independent of, but also coexistent with
the programming of hyperphagia and obesity. Rodent
models in particular suggest that early-life exposure to
hyperleptinaemia may directly predispose to early
onset hypertension, hyperphagia and cardiac dysfunc-
tion. Mechanistically, sympathetic hypertension
secondary to maternal obesity or experimental hyper-
leptinaemia appears to originate in the hypothalamus,
where neural pathways are exquisitely sensitive to the
neurotrophic actions of leptin in development.
Impaired development of the melanocortin pathway in
the hypothalamus is apparent in juvenile offspring of
obese rats (Kirk et al. 2009). AgRP is the endogenous
antagonist of the melanocortin-4 receptor (MC4R);
therefore, a reduced antagonism through a reduction in
AgRP-containing neurones may increase MC4R signal-
ling at sites relevant to blood pressure regulation,
inducing hypertension (Ye & Li 2011). Indeed, preli-
minary pharmacological studies indicate that maternal
obesity results in increased hypothalamic melanocortin
signalling contributing to hypertension in rodents.
Ongoing RCT cohort studies in obese pregnant women
provide the opportunity to address associations
between maternal obesity and offspring cardiovascular
function in neonates and through to adulthood.
Conflict of interest
The authors declare no conflict of interest.
PT is funded by the British Heart Foundation and BBSRC.
AMS is supported by the British Heart Foundation (FS/10/
003/28163). LP is funded by Tommy’s Charity (1060508).
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Acta Physiol 2014, 210, 508–523 P D Taylor et al. ·Neonatal hyperleptinaemia and hypertension