maternal obesity and the developmental programming of hypertension: a role for leptin

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).


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,



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.



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



(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.



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.



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.



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



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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maternal obesity and the developmental programming of hypertension: a role for leptin

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