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

Acta Physiol 2014, 210, 508–523

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 hypertension. 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 persistent sympathoexcitatory hyper-responsiveness and hypertension acquired in the early stages of development. Experimental neonatal hyperleptinaemia 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 hypertension. Insight from these animal models raises the possibility that early-life exposure to leptin in humans may lead to early onset essential hypertension. Ongoing mother–child cohort and intervention studies in obese pregnant 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 developmental programming of hypertension in obese pregnancy. Keywords developmental programming, hypertension, leptin, obesity, pregnancy.

The WHO Global Burden of Disease database currently identifies 26% of women of reproductive age in the United Kingdom as being obese, whilst the prevalence of maternal obesity has risen in line with the 508

general population and more than doubled in the past two decades, with approximately one in five UK pregnant 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.12223

Acta Physiol 2014, 210, 508–523

obesity in pregnancy was associated with an increase in all-cause mortality in adult offspring and specifically 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 cardiovascular health of the next generation. This review will discuss the evidence from human epidemiological data suggesting that maternal obesity predisposes offspring 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 particular, and the putative role for early-life hyperleptinaemia 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 factors and have direct implications not only just in terms of perinatal and maternal morbidity and mortality 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 ‘transgenerational 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 childhood blood pressure and elevated plasma cardiovascular 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

P D Taylor et al.

· Neonatal hyperleptinaemia and hypertension

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 cardiomyopathy 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 obesity per se may similarly influence cardiovascular function 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 Indians, demonstrated how maternal obesity, especially when it resulted in gestational diabetes, increased the risk of metabolic syndrome and type 2 diabetes developing in the offspring (Boney et al. 2005, Vohr & Boney 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 suggest that susceptibility to obesity and cardiovascular disease is partly programmed in the developing foetus or neonate through exposure to adverse metabolic factors 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 relationship between maternal BMI and childhood cardiovascular 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 maternal BMI and blood pressure in older children and adolescents (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 pressure (DBP) and SBP at 5–6 years of age (Gademan


509

Neonatal hyperleptinaemia and hypertension

· P D Taylor et al.

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 cardiometabolic 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 influence of prenatal exposure to maternal obesity on offspring CV function. We have recently demonstrated in rodents that offspring of obese dams are hypertensive as juvenile animals, prior to the development of obesity, suggesting that maternal obesity and related metabolic sequelae directly influence the developing foetal/ neonatal cardiovascular system leading to the development of hypertension independent of offspring adiposity (Samuelsson et al. 2010). This demonstrates the usefulness of animal models in giving insight into early-life origins of metabolic and cardiovascular disease 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 manipulate the nutritional and hormonal environment in pregnancy ostensibly in an attempt to mimic the conditions described in the early epidemiological studies that gave rise to the developmental programming of adult disease hypothesis (Hales & Barker 2001, Roseboom et al. 2001). This section will discuss the evidence from animal models of maternal obesity and 510

Acta Physiol 2014, 210, 508–523

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 therefore cannot establish cause and effect. Modelling gestational 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, experimental conditions can be tightly controlled, and the underlying physiological, cellular and molecular mechanisms 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 ‘cafeteria-style’ diet is employed, in which highly palatable ‘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 palatable sugars to a high-fat diet or introduction of a cafeteria-style diet appears to overcome the tight homoeostatic 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 associated 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, Holemans et al. 2004, Srinivasan et al. 2006, Chen et al. 2008, Samuelsson et al. 2008, Nivoit et al. 2009).


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 consequences 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 offspring of diet-induced obese mice develop systolic and mean arterial hypertension by 3 months of age associated with resistance artery endothelial dysfunction (Samuelsson et al. 2008). Hypertension was also associated with increased visceral adiposity and hyperleptinaemia, 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 continued 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-frequency oscillations at 30 and 90 days of age, indicative 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 developmental 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 hyperleptinaemia 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 perturbation of central leptin sensitivity and dysregulation of the normal neurotrophic action of leptin. Young offspring of obese rats show behavioural and cell signalling 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 evidence for developmental plasticity in the central efferent pathways of the hypothalamus and nucleus of the

P D Taylor et al.


solitary tract involved in the autonomic nervous system (ANS). In rats and mice, there is a surge in the plasma leptin concentration during the early postnatal 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 animals 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 during this critical developmental window (Cottrell et al. 2009, Bouret 2010). Bouret and colleagues found reduced neural projections from the arcuate nucleus (ARC) of the hypothalamus to the paraventricular hypothalamic nucleus (PVH) in leptin-deficient (ob/ob) mice (Bouret et al. 2004b). Administering exogenous leptin to leptin-deficient (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. Attenuation 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). Moreover, AgRP is the endogenous antagonist of the melanocortin-4 receptor (MC4R); therefore, a reduced antagonism may increase MC4R signalling at sites relevant 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 prolonged 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 development of the neonatal brain. The neonatal plasma leptin profile was paralleled by increased leptin gene expression in pup adipocytes,


511



Acta Physiol 2014, 210, 508–523

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. Regionally distinct neuronal pathways contribute to different elements of the sympathetic response to leptin and insulin.

suggesting that neonatal adipocytes are the source of the leptin surge. A similar relationship between adipocyte 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 nutritional status is known to influence the neonatal leptin profile (Yura et al. 2005, Vickers et al. 2008). In (a)

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 differentiation 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

(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 control dams for the same period (n = 3–6). For longitudinal comparisons, a significant difference (P < 0.05) from the preceding period is indicated by # for offspring of control dams and by † for offspring of obese dams.

512

There has been much focus on the role of leptin, prompted by the neuroendocrine and structural neuronal 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 overnutrition have now been shown to impact on the timing and magnitude of the neonatal leptin surge to influence the adult phenotype. Altered neonatal leptin profiles have been reported in several models of developmental programming of metabolic dysfunction (Yura et al. 2005, Delahaye et al. 2008). Further evidence for a persistent effect of leptin in the neonatal


Acta Physiol 2014, 210, 508–523

period is suggested by the observation that exogenous manipulation of the neonatal leptin profile can modulate offspring phenotype (Vickers et al. 2005, 2008, Yura et al. 2005, Attig et al. 2008, Stocker & Cawthorne 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 hypertension. Little is known about the origins of the neonatal 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 stomach 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 considered not to be produced by the neonatal stomach epithelium 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 association (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 profiles 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

P D Taylor et al.


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). Preliminary data from OffOb neonates indicate that insulin 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 adipocyte proliferation and differentiation in the neonatal rat will affect the leptin surge. Hormones such as insulin and leptin that may influence pathways regulating adipocyte proliferation and differentiation are, therefore, candidates for nutritional programming. Alternatively, 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 adulthood. 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 elegansderived 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 obesity 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 metabolic 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 sympathetic stimulation to metabolically active tissues


513



(Haynes et al. 1997). Leptin also plays a cardiovascular 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 obesityrelated hypertension (Rahmouni et al. 2005, Harlan et al. 2011). We have reported selective leptin resistance 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 hyperleptinaemia suggesting that this selective leptin resistance was not obesity related, but a direct consequence 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 hypertension 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

Acta Physiol 2014, 210, 508–523

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 positively 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 mothers. 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 investigate the effect of intervention on offspring cardiovascular function. To investigate the direct role of neonatal hyperleptinaemia in offspring cardiovascular dysfunction, we treated naive rat pups with exogenous leptin to mimic the exaggerated leptin surge observed in neonate offspring 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 radiotelemetry at 30 days, and 2 and 12 months. In juvenile (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 variability 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 administration of the a1-adrenergic receptor antagonist, terazosin and the b1/b2-adrenergic receptor antagonist, propranolol normalized MAP and led to a

Figure 3 Schematic: mechanisms in foetal programming of obesity and hypertension. 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.

514


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 (tailcuff 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 challenge. L-Tx rats showed impaired anorectic responses to the leptin challenge compared with S-Tx, as demonstrated 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 following 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 mechanistic role in the relationship between maternal obesity and cardiovascular and metabolic dysfunction of the offspring. However, compared with L-Tx, the OffOb rats have a more deleterious MAP profile (Samuelsson et al. 2010), indicating that neonatal leptin exposure alone may not account for the entire OffOb phenotype (Samuelsson et al. 2013b). Foetal hyperinsulinaemia secondary to maternal obesity and glucose intolerance (Samuelsson et al. 2008, Nivoit et al. 2009) is also likely to play a role in hypothalamic

P D Taylor et al.


neurodevelopment (Plagemann 2006) and may contribute to the programming of hypertension in this model.

Mechanisms underlying leptin-induced sympathoexcitation 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 (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. administration 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 sympathetic 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 activates neurones upstream of the PVN and increases glutamatergic drive from the PVN to the RVLM, activating 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 expression 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 normalized 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



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 preganglionic neurones) restores obesity-associated hypertension in MC4R null mice (Sohn et al. 2013). Studies to elucidate 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 hyperleptinaemia 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 influence 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, Cheema et al. 2005, Catta-Preta et al. 2006, FernandezTwinn 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 placental mass reduction, foetal hypertension and cortisol exposure all affect proliferation and terminal maturation 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 undernutrition 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 pathway, 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 516

Acta Physiol 2014, 210, 508–523

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 markedly 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 cardiac 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 contractility 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 hypertrophy, 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 hypertrophy 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 offspring cardiac hypertrophy, independent of offspring obesity, associated with hyperinsulinaemia-induced activation of AKT, mammalian target of rapamycin, ERK and oxidative stress.


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 studies 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 hyperinsulinaemia (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 common with the neonatal rodent, exposed to both hyperinsulinaemia and hyperleptinaemia (Nelson et al. 2010). It is important, however, in extrapolation from the rodent models to appreciate that rodents are altricial 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 hypothalamus is likely to be most relevant to the third trimester 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 similar 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 postpartum requires consideration. In rodents, hypothalamic neurones expressing appetite and cardiovascular regulatory peptides develop in the last week of gestation, 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 nonhuman primates, in which the density of the neurite projections continues to increase post-partum (Grayson et al. 2006), ongoing hypothalamic development is likely in the post-partum human infant; thus, susceptibility 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).

P D Taylor et al.


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. However, to date, few relevant studies have been reported in obese pregnancy, which can inform policy for effective 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 programme; ISRCTN89971375) and the LIMIT trial in Adelaide, 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 cardiovascular health of the child. Studies of neonatal cardiovascular 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


517



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-mediated renal sympathetic activity could is therefore an important contributor to the association between offspring blood pressure and maternal obesity. This is illustrated 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 additive effects of GDM, demonstrates independent associations with offspring cardio-metabolic risk including childhood blood pressure and elevated plasma cardiovascular 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 neonates born to obese women. Animal studies strongly support an influence of the maternal obesogenic environment in pregnancy on determinants of cardiovascular 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 dysfunction. Mechanistically, sympathetic hypertension secondary to maternal obesity or experimental hyperleptinaemia 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 signalling at sites relevant to blood pressure regulation, inducing hypertension (Ye & Li 2011). Indeed, preliminary 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 518

Acta Physiol 2014, 210, 508–523

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).

References Ahima, R.S., Prabakaran, D. & Flier, J.S. 1998. Postnatal leptin surge and regulation of circadian rhythm of leptin by feeding. Implications for energy homeostasis and neuroendocrine function. J Clin Invest 101, 1020–1027. Ailhaud, G., Massiera, F., Weill, P., Legrand, P., Alessandri, J.M. & Guesnet, P. 2006. Temporal changes in dietary fats: role of n-6 polyunsaturated fatty acids in excessive adipose tissue development and relationship to obesity. Prog Lipid Res 45, 203–236. Ailhaud, G., Guesnet, P. & Cunnane, S.C. 2008. An emerging risk factor for obesity: does disequilibrium of polyunsaturated fatty acid metabolism contribute to excessive adipose tissue development? Br J Nutr 100, 461–470. Akcakus, M., Koklu, E., Baykan, A., Yikilmaz, A., Coskun, A., Gunes, T., Kurtoglu, S. & Narin, N. 2007. Macrosomic newborns of diabetic mothers are associated with increased aortic intima-media thickness and lipid concentrations. Horm Res 67, 277–283. Akyol, A., Langley-Evans, S.C. & McMullen, S. 2009. Obesity induced by cafeteria feeding and pregnancy outcome in the rat. Br J Nutr 102, 1601–1610. Almeida, J.R. & Mandarim-de-Lacerda, C.A. 2005. Overweight is gender-dependent in prenatal protein–calorie restricted adult rats acting on the blood pressure and the adverse cardiac remodeling. Life Sci 77, 1307–1318. Anatskaya, O.V., Sidorenko, N.V., Beyer, T.V. & Vinogradov, A.E. 2009. Neonatal cardiomyocyte ploidy reveals critical windows of heart development. Int J Cardiol 141, 81–91. Armitage, J.A., Lakasing, L., Taylor, P.D., Balachandran, A.A., Jensen, R.I., Dekou, V., Ashton, N., Nyengaard, J.R. & Poston, L. 2005a. Developmental programming of aortic and renal structure in offspring of rats fed fat-rich diets in pregnancy. J Physiol 565, 171–184. Armitage, J.A., Taylor, P.D. & Poston, L. 2005b. Experimental models of developmental programming; Consequences of exposure to an energy rich diet during development. J Physiol 565, 171–184. Armitage, J.A., Ishibashi, A., Balachandran, A.A., Jensen, R.I., Poston, L. & Taylor, P.D. 2007. Programmed aortic dysfunction and reduced Na+, K+-ATPase activity present in first generation offspring of lard-fed rats does not persist to the second generation. Exp Physiol 92, 583–589. Attig, L., Solomon, G., Ferezou, J., Abdennebi-Najar, L., Taouis, M., Gertler, A. & Djiane, J. 2008. Early postnatal leptin blockage leads to a long-term leptin resistance and


Acta Physiol 2014, 210, 508–523 susceptibility to diet-induced obesity in rats. Int J Obes (Lond) 32, 1153–1160. Bacharova, L., Krivosikova, Z., Wsolova, L. & Gajdos, M. 2012. Alterations in the QRS complex in the offspring of patients with metabolic syndrome and diabetes mellitus: early evidence of cardiovascular pathology. J Electrocardiol 45, 244–251. Bae, S., Xiao, Y., Li, G., Casiano, C.A. & Zhang, L. 2003. Effect of maternal chronic hypoxic exposure during gestation on apoptosis in fetal rat heart. Am J Physiol Heart Circ Physiol 285, H983–H990. Battista, M., Calvo, E., Chorvatova, A., Comte, B., Corbeil, J. & Brochu, M. 2005. Intra-uterine growth restriction and the programming of left ventricular remodelling in female rats. J Physiol 565(Pt 1), 197–205. Bautista, C.J., Boeck, L., Larrea, F., Nathanielsz, P.W. & Zambrano, E. 2008. Effects of a maternal low protein isocaloric diet on milk leptin and progeny serum leptin concentration and appetitive behavior in the first 21 days of neonatal life in the rat. Pediatr Res 63, 358–363. Bayol, S.A., Simbi, B.H. & Stickland, N.C. 2005. A maternal cafeteria diet during gestation and lactation promotes adiposity and impairs skeletal muscle development and metabolism in rat offspring at weaning. J Physiol 567, 951–961. Boney, C.M., Verma, A., Tucker, R. & Vohr, B.R. 2005. Metabolic syndrome in childhood: association with birth weight, maternal obesity, and gestational diabetes mellitus. Pediatrics 115, e290–e296. Bouret, S.G. 2010. Neurodevelopmental actions of leptin. Brain Res 1350, 2–9. Bouret, S.G., Draper, S.J. & Simerly, R.B. 2004a. Formation of projection pathways from the arcuate nucleus of the hypothalamus to hypothalamic regions implicated in the neural control of feeding behavior in mice. J Neurosci 24, 2797–2805. Bouret, S.G., Draper, S.J. & Simerly, R.B. 2004b. Trophic action of leptin on hypothalamic neurons that regulate feeding. Science 304, 108–110. Bouret, S.G., Gorski, J.N., Patterson, C.M., Chen, S., Levin, B.E. & Simerly, R.B. 2008. Hypothalamic neural projections are permanently disrupted in diet-induced obese rats. Cell Metab 7, 179–185. Carlyle, M., Jones, O.B., Kuo, J.J. & Hall, J.E. 2002. Chronic cardiovascular and renal actions of leptin: role of adrenergic activity. Hypertension 39, 496–501. Casabiell, X., Pineiro, V., Tome, M.A., Peino, R., Dieguez, C. & Casanueva, F.F. 1997. Presence of leptin in colostrum and/or breast milk from lactating mothers: a potential role in the regulation of neonatal food intake. J Clin Endocrinol Metab 82, 4270–4273. Catalano, P.M., Presley, L., Minium, J. & Hauguel-de Mouzon, S. 2009. Fetuses of obese mothers develop insulin resistance in utero. Diabetes Care 32, 1076–1080. Catta-Preta, M., Oliveira, D.A., Mandarim-de-Lacerda, C.A. & Aguila, M.B. 2006. Adult cardiorenal benefits from postnatal fish oil supplement in rat offspring of low-protein pregnancies. Life Sci 80, 219–229. Cetin, I., Morpurgo, P.S., Radaelli, T., Taricco, E., Cortelazzi, D., Bellotti, M., Pardi, G. & Beck-Peccoz, P. 2000. Fetal plasma leptin concentrations: relationship with different

P D Taylor et al.


intrauterine growth patterns from 19 weeks to term. Pediatr Res 48, 646–651. Chan, L.L., Sebert, S.P., Hyatt, M.A., Stephenson, T., Budge, H., Symonds, M.E. & Gardner, D.S. 2009. Effect of maternal nutrient restriction from early to midgestation on cardiac function and metabolism after adolescent-onset obesity. Am J Physiol Regul Integr Comp Physiol 296, R1455–R1463. Chang, G.Q., Gaysinskaya, V., Karatayev, O. & Leibowitz, S.F. 2008. Maternal high-fat diet and fetal programming: increased proliferation of hypothalamic peptide-producing neurons that increase risk for overeating and obesity. J Neurosci 28, 12107–12119. Cheema, K.K., Dent, M.R., Saini, H.K., Aroutiounova, N. & Tappia, P.S. 2005. Prenatal exposure to maternal undernutrition induces adult cardiac dysfunction. Br J Nutr 93, 471–477. Chen, H., Simar, D., Lambert, K., Mercier, J. & Morris, M.J. 2008. Maternal and postnatal overnutrition differentially impact appetite regulators and fuel metabolism. Endocrinology 149, 5348–5356. Cottrell, E.C., Cripps, R.L., Duncan, J.S., Barrett, P., Mercer, J.G., Herwig, A. & Ozanne, S.E. 2009. Developmental changes in hypothalamic leptin receptor: relationship with the postnatal leptin surge and energy balance neuropeptides in the postnatal rat. Am J Physiol Regul Integr Comp Physiol 296, R631–R639. Cripps, R.L., Martin-Gronert, M.S. & Ozanne, S.E. 2005. Fetal and perinatal programming of appetite. Clin Sci (Lond) 109, 1–11. Davis, L., Roullet, J.B., Thornburg, K.L., Shokry, M., Hohimer, A.R. & Giraud, G.D. 2003. Augmentation of coronary conductance in adult sheep made anaemic during fetal life. J Physiol 547, 53–59. Delahaye, F., Breton, C., Risold, P.Y., Enache, M., DutriezCasteloot, I., Laborie, C., Lesage, J. & Vieau, D. 2008. Maternal perinatal undernutrition drastically reduces postnatal leptin surge and affects the development of arcuate nucleus proopiomelanocortin neurons in neonatal male rat pups. Endocrinology 149, 470–475. Denison, F.C., Norrie, G., Graham, B., Lynch, J., Harper, N. & Reynolds, R.M. 2009. Increased maternal BMI is associated with an increased risk of minor complications during pregnancy with consequent cost implications. BJOG 116, 1467–1472. Devaskar, S.U., Ollesch, C., Rajakumar, R.A. & Rajakumar, P.A. 1997. Developmental changes in ob gene expression and circulating leptin peptide concentrations. Biochem Biophys Res Commun 238, 44–47. Dodd, J.M., Grivell, R.M., Crowther, C.A. & Robinson, J.S. 2010. Antenatal interventions for overweight or obese pregnant women: a systematic review of randomised trials. BJOG 117, 1316–1326. Drake, A.J. & Reynolds, R.M. 2010. Impact of maternal obesity on offspring obesity and cardiometabolic disease risk. Reproduction 140, 387–398. Dunbar, J.C. & Lu, H. 1999. Leptin-induced increase in sympathetic nervous and cardiovascular tone is mediated by proopiomelanocortin (POMC) products. Brain Res Bull 50, 215–221.


519



Elmes, M.J., Gardner, D.S. & Langley-Evans, S.C. 2007. Fetal exposure to a maternal low-protein diet is associated with altered left ventricular pressure response to ischaemiareperfusion injury. Br J Nutr 98, 93–100. Elmes, M.J., McMullen, S., Gardner, D.S. & Langley-Evans, S.C. 2008. Prenatal diet determines susceptibility to cardiac ischaemia-reperfusion injury following treatment with diethylmaleic acid and N-acetylcysteine. Life Sci 82, 149–155. Elmquist, J.K. & Flier, J.S. 2004. Neuroscience. The fat-brain axis enters a new dimension. Science 304, 63–64. Ferezou-Viala, J., Roy, A.F., Serougne, C., Gripois, D., Parquet, M., Bailleux, V., Gertler, A., Delplanque, B., Djiane, J., Riottot, M. & Taouis, M. 2007. Long-term consequences of maternal high-fat feeding on hypothalamic leptin sensitivity and diet-induced obesity in the offspring. Am J Physiol Regul Integr Comp Physiol 293, R1056–R1062. Fernandez-Twinn, D.S., Ekizoglou, S., Wayman, A., Petry, C.J. & Ozanne, S.E. 2006. Maternal low protein diet programs cardiac beta-adrenergic response and signalling in 3 month old male offspring. Am J Physiol Regul Integr Comp Physiol 291, 429–436. Fernandez-Twinn, D.S., Blackmore, H.L., Siggens, L., Giussani, D.A., Cross, C.M., Foo, R. & Ozanne, S.E. 2012. The programming of cardiac hypertrophy in the offspring by maternal obesity is associated with hyperinsulinemia, AKT, ERK, and mTOR activation. Endocrinology 153, 5961–5971. Filler, G., Yasin, A., Kesarwani, P., Garg, A.X., Lindsay, R. & Sharma, A.P. 2011. Big mother or small baby: which predicts hypertension? J Clin Hypertens (Greenwich) 13, 35–41. Fraser, A., Tilling, K., Macdonald-Wallis, C., Hughes, R., Sattar, N., Nelson, S.M. & Lawlor, D.A. 2011. Associations of gestational weight gain with maternal body mass index, waist circumference, and blood pressure measured 16 y after pregnancy: the Avon Longitudinal Study of Parents and Children (ALSPAC). Am J Clin Nutr 93, 1285–1292. Gademan, M.G., van Eijsden, M., Roseboom, T.J., van der Post, J.A., Stronks, K. & Vrijkotte, T.G. 2013. Maternal prepregnancy body mass index and their children’s blood pressure and resting cardiac autonomic balance at age 5 to 6 years. Hypertension 62, 641–647. Gardner, B., Wardle, J., Poston, L. & Croker, H. 2011. Changing diet and physical activity to reduce gestational weight gain: a meta-analysis. Obes Rev 12, e602–e620. Giraud, G.D., Louey, S., Jonker, S., Schultz, J. & Thornburg, K.L. 2006. Cortisol stimulates cell cycle activity in the cardiomyocyte of the sheep fetus. Endocrinology 147, 3643–3649. Glavas, M.M., Kirigiti, M.A., Xiao, X.Q., Enriori, P.J., Fisher, S.K., Evans, A.E., Grayson, B.E., Cowley, M.A., Smith, M.S. & Grove, K.L. 2010. Early overnutrition results in early-onset arcuate leptin resistance and increased sensitivity to high-fat diet. Endocrinology 151, 1598–1610. Grayson, B.E., Allen, S.E., Billes, S.K., Williams, S.M., Smith, M.S. & Grove, K.L. 2006. Prenatal development of hypothalamic neuropeptide systems in the nonhuman primate. Neuroscience 143, 975–986. Greenfield, J.R., Miller, J.W., Keogh, J.M., Henning, E., Satterwhite, J.H., Cameron, G.S., Astruc, B., Mayer, J.P., Brage, S., See, T.C., Lomas, D.J., O’Rahilly, S. & Farooqi,

520

Acta Physiol 2014, 210, 508–523 I.S. 2009. Modulation of blood pressure by central melanocortinergic pathways. N Engl J Med 360, 44–52. Grove, K.L. & Smith, M.S. 2003. Ontogeny of the hypothalamic neuropeptide Y system. Physiol Behav 79, 47–63. Grove, K.L., Grayson, B.E., Glavas, M.M., Xiao, X.Q. & Smith, M.S. 2005. Development of metabolic systems. Physiol Behav 86, 646–660. Hales, C.N. & Barker, D.J. 2001. The thrifty phenotype hypothesis. Br Med Bull 60, 5–20. Han, H.C., Austin, K.J., Nathanielsz, P.W., Ford, S.P., Nijland, M.J. & Hansen, T.R. 2004. Maternal nutrient restriction alters gene expression in the ovine fetal heart. J Physiol 558, 111–121. Harlan, S.M., Morgan, D.A., Agassandian, K., Guo, D.F., Cassell, M.D., Sigmund, C.D., Mark, A.L. & Rahmouni, K. 2011. Ablation of the leptin receptor in the hypothalamic arcuate nucleus abrogates leptin-induced sympathetic activation. Circ Res 108, 808–812. Haynes, W.G., Morgan, D.A., Walsh, S.A., Mark, A.L. & Sivitz, W.I. 1997. Receptor-mediated regional sympathetic nerve activation by leptin. J Clin Invest 100, 270–278. Heerwagen, M.J., Stewart, M.S., de la Houssaye, B.A., Janssen, R.C. & Friedman, J.E. 2013. Transgenic increase in N-3/n-6 fatty acid ratio reduces maternal obesity-associated inflammation and limits adverse developmental programming in mice. PLoS ONE 8, e67791. Hein, S., Arnon, E., Kostin, S., Schonburg, M., Elsasser, A., Polyakova, V., Bauer, E.P., Klovekorn, W.P. & Schaper, J. 2003. Progression from compensated hypertrophy to failure in the pressure-overloaded human heart: structural deterioration and compensatory mechanisms. Circulation 107, 984–991. Heslehurst, N., Simpson, H., Ells, L.J., Rankin, J., Wilkinson, J., Lang, R., Brown, T.J. & Summerbell, C.D. 2008. The impact of maternal BMI status on pregnancy outcomes with immediate short-term obstetric resource implications: a meta-analysis. Obes Rev 9, 635–683. Heslehurst, N., Rankin, J., Wilkinson, J.R. & Summerbell, C.D. 2010. A nationally representative study of maternal obesity in England, UK: trends in incidence and demographic inequalities in 619 323 births, 1989–2007. Int J Obes (Lond) 34, 420–428. Hochner, H., Friedlander, Y., Calderon-Margalit, R., Meiner, V., Sagy, Y., Avgil-Tsadok, M., Burger, A., Savitsky, B., Siscovick, D.S. & Manor, O. 2012. Associations of maternal prepregnancy body mass index and gestational weight gain with adult offspring cardiometabolic risk factors: the Jerusalem Perinatal Family Follow-up Study. Circulation 125, 1381–1389. Holemans, K., Caluwaerts, S., Poston, L. & Van Assche, F.A. 2004. Diet-induced obesity in the rat: a model for gestational diabetes mellitus. Am J Obstet Gynecol 190, 858–865. Jonker, S.S., Faber, J.J., Anderson, D.F., Thornburg, K.L., Louey, S. & Giraud, G.D. 2007. Sequential growth of fetal sheep cardiac myocytes in response to simultaneous arterial and venous hypertension. Am J Physiol Regul Integr Comp Physiol 292, R913–R919. Khan, I.Y., Taylor, P.D., Dekou, V., Seed, P.T., Lakasing, L., Graham, D., Dominiczak, A.F., Hanson, M.A. & Poston, L. 2003. Gender-linked hypertension in offspring of lardfed pregnant rats. Hypertension 41, 168–175.


Acta Physiol 2014, 210, 508–523 Khan, I.Y., Dekou, V., Douglas, G., Jensen, R., Hanson, M.A., Poston, L. & Taylor, P.D. 2005. A high-fat diet during rat pregnancy or suckling induces cardiovascular dysfunction in adult offspring. Am J Physiol Regul Integr Comp Physiol 288, R127–R133. Kim, W.K., Lee, C.Y., Kang, M.S., Kim, M.H., Ryu, Y.H., Bae, K.H., Shin, S.J., Lee, S.C. & Ko, Y. 2008. Effects of leptin on lipid metabolism and gene expression of differentiation-associated growth factors and transcription factors during differentiation and maturation of 3T3-L1 preadipocytes. Endocr J 55, 827–837. Kirk, S.L., Samuelsson, A.M., Argenton, M., Dhonye, H., Kalamatianos, T., Poston, L., Taylor, P.D. & Coen, C.W. 2009. Maternal obesity induced by diet in rats permanently influences central processes regulating food intake in offspring. PLoS ONE 4, e5870. Koutcherov, Y., Mai, J.K., Ashwell, K.W. & Paxinos, G. 2002. Organization of human hypothalamus in fetal development. J Comp Neurol 446, 301–324. Kral, J.G., Biron, S., Simard, S., Hould, F.S., Lebel, S., Marceau, S. & Marceau, P. 2006. Large maternal weight loss from obesity surgery prevents transmission of obesity to children who were followed for 2 to 18 years. Pediatrics 118, e1644–e1649. Krishnaveni, G.V., Veena, S.R., Hill, J.C., Kehoe, S., Karat, S.C. & Fall, C.H. 2010. Intrauterine exposure to maternal diabetes is associated with higher adiposity and insulin resistance and clustering of cardiovascular risk markers in Indian children. Diabetes Care 33, 402–404. Langley-Evans, S.C. 2013. Fetal programming of CVD and renal disease: animal models and mechanistic considerations. Proc Nutr Soc 72, 317–325. Laura, H.C., Menezes, A.B., Noal, R.B., Hallal, P.C. & Araujo, C.L. 2010. Maternal anthropometric characteristics in pregnancy and blood pressure among adolescents: 1993 live birth cohort, Pelotas, southern Brazil. BMC Public Health 10, 434. Lawlor, D.A., Relton, C., Sattar, N. & Nelson, S.M. 2012. Maternal adiposity–a determinant of perinatal and offspring outcomes? Nat Rev Endocrinol 8, 679–688. Lee, M.J. & Fried, S.K. 2009a. Integration of hormonal and nutrient signals that regulate leptin synthesis and secretion. Am J Physiol Endocrinol Metab 296, E1230–E1238. Lee, M.J. & Fried, S.K. 2009b. Integration of hormonal and nutrient signals that regulate leptin synthesis and secretion. Am J Physiol Endocrinol Metab 292, E858–E864. Lee, M.J., Wang, Y., Ricci, M.R., Sullivan, S., Russell, C.D. & Fried, S.K. 2007. Acute and chronic regulation of leptin synthesis, storage, and secretion by insulin and dexamethasone in human adipose tissue. Am J Physiol Endocrinol Metab 292, E858–E864. Li, L., Fink, G.D., Watts, S.W., Northcott, C.A., Galligan, J.J., Pagano, P.J. & Chen, A.F. 2003. Endothelin-1 increases vascular superoxide via endothelin(A)-NADPH oxidase pathway in low-renin hypertension. Circulation 107, 1053–1058. Louey, S., Jonker, S.S., Giraud, G.D. & Thornburg, K.L. 2007. Placental insufficiency decreases cell cycle activity and terminal maturation in fetal sheep cardiomyocytes. J Physiol 580, 639–648.

P D Taylor et al.


Mamun, A.A., O’Callaghan, M., Callaway, L., Williams, G., Najman, J. & Lawlor, D.A. 2009. Associations of gestational weight gain with offspring body mass index and blood pressure at 21 years of age: evidence from a birth cohort study. Circulation 119, 1720–1727. Marco, L.J., McCloskey, K., Vuillermin, P.J., Burgner, D., Said, J. & Ponsonby, A.L. 2012. Cardiovascular disease risk in the offspring of diabetic women: the impact of the intrauterine environment. Exp Diabetes Res 2012, 565160. Mark, A.L., Correia, M., Morgan, D.A., Shaffer, R.A. & Haynes, W.G. 1999. State-of-the-art-lecture: obesityinduced hypertension: new concepts from the emerging biology of obesity. Hypertension 33, 537–541. Marsh, A.J., Fontes, M.A., Killinger, S., Pawlak, D.B., Polson, J.W. & Dampney, R.A. 2003. Cardiovascular responses evoked by leptin acting on neurons in the ventromedial and dorsomedial hypothalamus. Hypertension 42, 488–493. Matsuda, J., Yokota, I., Iida, M., Murakami, T., Naito, E., Ito, M., Shima, K. & Kuroda, Y. 1997. Serum leptin concentration in cord blood: relationship to birth weight and gender. J Clin Endocrinol Metab 82, 1642–1644. McMillen, I.C. & Robinson, J.S. 2005. Developmental origins of the metabolic syndrome: prediction, plasticity, and programming. Physiol Rev 85, 571–633. Mingrone, G., Manco, M., Mora, M.E., Guidone, C., Iaconelli, A., Gniuli, D., Leccesi, L., Chiellini, C. & Ghirlanda, G. 2008. Influence of maternal obesity on insulin sensitivity and secretion in offspring. Diabetes Care 31, 1872–1876. Morash, B., Wilkinson, D., Murphy, P., Ur, E. & Wilkinson, M. 2001. Developmental regulation of leptin gene expression in rat brain and pituitary. Mol Cell Endocrinol 185, 151–159. Morgan, D.A., Thedens, D.R., Weiss, R. & Rahmouni, K. 2008. Mechanisms mediating renal sympathetic activation to leptin in obesity. Am J Physiol Regul Integr Comp Physiol 295, R1730–R1736. Morris, M.J. & Chen, H. 2009. Established maternal obesity in the rat reprograms hypothalamic appetite regulators and leptin signaling at birth. Int J Obes (Lond) 33, 115–122. Muhlhausler, B.S., Adam, C.L., Marrocco, E.M., Findlay, P.A., Roberts, C.T., McFarlane, J.R., Kauter, K.G. & McMillen, I.C. 2005. Impact of glucose infusion on the structural and functional characteristics of adipose tissue and on hypothalamic gene expression for appetite regulatory neuropeptides in the sheep fetus during late gestation. J Physiol 565, 185–195. Nathanielsz, P.W., Poston, L. & Taylor, P.D. 2007a. In utero exposure to maternal obesity and diabetes: animal models that identify and characterize implications for future health. Obstet Gynecol Clin North Am 34, 201–212, vii–viii. Nathanielsz, P.W., Poston, L. & Taylor, P.D. 2007b. In utero exposure to maternal obesity and diabetes: animal models that identify and characterize implications for future health. Clin Perinatol 34, 515–526, v. Nelson, S.M., Matthews, P. & Poston, L. 2010. Maternal metabolism and obesity: modifiable determinants of pregnancy outcome. Hum Reprod Update 16, 255–275.


521



Nivoit, P., Morens, C., Van Assche, F.A., Jansen, E., Poston, L., Remacle, C. & Reusens, B. 2009. Established diet-induced obesity in female rats leads to offspring hyperphagia, adiposity and insulin resistance. Diabetologia 52, 1133–1142. Norman, J.E. & Reynolds, R. 2011. The consequences of obesity and excess weight gain in pregnancy. Proc Nutr Soc 70, 450–456. Ojala, T., Aaltonen, J., Siira, S., Jalonen, J., Ekholm, E., Ekblad, U. & Laitinen, K. 2009. Fetal cardiac sympathetic activation is linked with maternal body mass index. Early Hum Dev 85, 557–560. Ojeda, N.B., Grigore, D. & Alexander, B.T. 2008. Developmental programming of hypertension. insight from animal models of nutritional manipulation. Hypertension 52, 44–50. Oken, E., Rifas-Shiman, S.L., Field, A.E., Frazier, A.L. & Gillman, M.W. 2008. Maternal gestational weight gain and offspring weight in adolescence. Obstet Gynecol 112, 999–1006. Oliver, P., Pico, C., De Matteis, R., Cinti, S. & Palou, A. 2002. Perinatal expression of leptin in rat stomach. Dev Dyn 223, 148–154. O’Reilly, J.R. & Reynolds, R.M. 2013. The risk of maternal obesity to the long-term health of the offspring. Clin Endocrinol (Oxf) 78, 9–16. Ozata, M., Ozdemir, I.C. & Licinio, J. 1999. Human leptin deficiency caused by a missense mutation: multiple endocrine defects, decreased sympathetic tone, and immune system dysfunction indicate new targets for leptin action, greater central than peripheral resistance to the effects of leptin, and spontaneous correction of leptin-mediated defects. J Clin Endocrinol Metab 84, 3686–3695. Plagemann, A. 2006. Perinatal nutrition and hormone-dependent programming of food intake. Horm Res 65(Suppl 3), 83–89. Porrello, E.R., Bell, J.R., Schertzer, J.D., Curl, C.L., McMullen, J.R., Mellor, K.M., Ritchie, R.H., Lynch, G.S., Harrap, S.B., Thomas, W.G. & Delbridge, L.M. 2009. Heritable pathologic cardiac hypertrophy in adulthood is preceded by neonatal cardiac growth restriction. Am J Physiol Regul Integr Comp Physiol 296, R672–R680. Poston, L. 2011. Influence of maternal nutritional status on vascular function in the offspring. Microcirculation 18, 256–262. Poston, L. 2012. Maternal obesity, gestational weight gain and diet as determinants of offspring long term health. Best Pract Res Clin Endocrinol Metab 26, 627–639. Poston, L., Harthoorn, L.F. & Van Der Beek, E.M. 2011. Obesity in pregnancy: implications for the mother and lifelong health of the child. A consensus statement. Pediatr Res 69, 175–180. Rahmouni, K. 2010. Sympathetic tone in the young: the mother weighs in. Hypertension 55, 21–22. Rahmouni, K., Haynes, W.G., Morgan, D.A. & Mark, A.L. 2003. Role of melanocortin-4 receptors in mediating renal sympathoactivation to leptin and insulin. J Neurosci 23, 5998–6004. Rahmouni, K., Correia, M.L., Haynes, W.G. & Mark, A.L. 2005. Obesity-associated hypertension: new insights into mechanisms. Hypertension 45, 9–14.

522

Acta Physiol 2014, 210, 508–523 Rajani, C.K., Samuelsson, A.M., Clark, J., Shattock, M., Poston, L. & Taylor, P.D. 2009. Developmental programming of myocardial dysfunction arising from maternal obesity in a murine model. J Dev Orig Health Dis 1, S247. Rajapurohitam, V., Gan, X.T., Kirshenbaum, L.A. & Karmazyn, M. 2003. The obesity-associated peptide leptin induces hypertrophy in neonatal rat ventricular myocytes. Circ Res 93, 277–279. Rayner, D.V., Dalgliesh, G.D., Duncan, J.S., Hardie, L.J., Hoggard, N. & Trayhurn, P. 1997. Postnatal development of the ob gene system: elevated leptin levels in suckling fa/fa rats. Am J Physiol 273, R446–R450. Reynolds, R.M., Allan, K.M., Raja, E.A., Bhattacharya, S., McNeill, G., Hannaford, P.C., Sarwar, N., Lee, A.J. & Norman, J.E. 2013. Maternal obesity during pregnancy and premature mortality from cardiovascular event in adult offspring: follow-up of 1 323 275 person years. BMJ 347, f4539. Roigas, J., Roigas, C., Heydeck, D. & Papies, B. 1996. Prenatal hypoxia alters the postnatal development of beta-adrenoceptors in the rat myocardium. Biol Neonate 69, 383–388. Roseboom, T.J., van der Meulen, J.H., Ravelli, A.C., Osmond, C., Barker, D.J. & Bleker, O.P. 2001. Effects of prenatal exposure to the Dutch famine on adult disease in later life: an overview. Mol Cell Endocrinol 185, 93–98. Samuelsson, A.M., Matthews, P.A., Argenton, M., Christie, M.R., McConnell, J.M., Jansen, E.H., Piersma, A.H., Ozanne, S.E., Twinn, D.F., Remacle, C., Rowlerson, A., Poston, L. & Taylor, P.D. 2008. Diet-induced obesity in female mice leads to offspring hyperphagia, adiposity, hypertension, and insulin resistance: a novel murine model of developmental programming. Hypertension 51, 383–392. Samuelsson, A.M., Morris, A., Igosheva, N., Kirk, S.L., Pombo, J.M., Coen, C.W., Poston, L. & Taylor, P.D. 2010. Evidence for sympathetic origins of hypertension in juvenile offspring of obese rats. Hypertension 55, 76–82. Samuelsson, A.M., Mullier, A., Stepien, A., Patel, K., Pombo, J., Coen, C.W., Poston, L. & Taylor, P.D. 2013a. Central role for melanocortin system in energy balance and blood pressure regulation in offspring of obese dams. IUPS, Abstract. Samuelsson, A.M., Clark, J., Rudyk, O., Shattock, M.J., Baea, S.E., South, T., Pombo, J., Redington, K., Uppal, E., Coen, C.W., Poston, L. & Taylor, P.D. 2013b. Experimental Hyperleptinemia in neonatal rats leads to selective leptin responsiveness, hypertension and altered myocardial function. Hypertension 62, 627–633. Schubring, C., Siebler, T., Kratzsch, J., Englaro, P., Blum, W.F., Triep, K. & Kiess, W. 1999. Leptin serum concentrations in healthy neonates within the first week of life: relation to insulin and growth hormone levels, skinfold thickness, body mass index and weight. Clin Endocrinol (Oxf) 51, 199–204. Shek, E.W., Brands, M.W. & Hall, J.E. 1998. Chronic leptin infusion increases arterial pressure. Hypertension 31, 409–414. Smith, J., Cianflone, K., Biron, S., Hould, F.S., Lebel, S., Marceau, S., Lescelleur, O., Biertho, L., Simard, S., Kral, J.G. & Marceau, P. 2009. Effects of maternal surgical


Acta Physiol 2014, 210, 508–523 weight loss in mothers on intergenerational transmission of obesity. J Clin Endocrinol Metab 94, 4275–4283. Sohn, J.W., Harris, L.E., Berglund, E.D., Liu, T., Vong, L., Lowell, B.B., Balthasar, N., Williams, K.W. & Elmquist, J.K. 2013. Melanocortin 4 receptors reciprocally regulate sympathetic and parasympathetic preganglionic neurons. Cell 152, 612–619. Srinivasan, M., Katewa, S.D., Palaniyappan, A., Pandya, J.D. & Patel, M.S. 2006. Maternal high-fat diet consumption results in fetal malprogramming predisposing to the onset of metabolic syndrome-like phenotype in adulthood. Am J Physiol Endocrinol Metab 291, E792–E799. Stocker, C.J. & Cawthorne, M.A. 2008. The influence of leptin on early life programming of obesity. Trends Biotechnol 26, 545–551. Tajmir, P., Ceddia, R.B., Li, R.K., Coe, I.R. & Sweeney, G. 2004. Leptin increases cardiomyocyte hyperplasia via extracellular signal-regulated kinase- and phosphatidylinositol 3-kinase-dependent signaling pathways. Endocrinology 145, 1550–1555. Tam, W.H., Ma, R.C., Yip, G.W., Yang, X., Li, A.M., Ko, G.T., Lao, T.T. & Chan, J.C. 2012. The association between in utero hyperinsulinemia and adolescent arterial stiffness. Diabetes Res Clin Pract 95, 169–175. Tappia, P.S., Sandhu, H., Abbi, T. & Aroutiounova, N. 2009. Alterations in the expression of myocardial calcium cycling genes in rats fed a low protein diet in utero. Mol Cell Biochem 324, 93–99. Taylor, P.D. & Poston, L. 2007. Developmental programming of obesity in mammals. Exp Physiol 92, 287–298. Taylor, P.D., Khan, I.Y., Lakasing, L., Dekou, V., O’BrienCoker, I., Mallet, A.I., Hanson, M.A. & Poston, L. 2003. Uterine artery function in pregnant rats fed a diet supplemented with animal lard. Exp Physiol 88, 389–398. Taylor, P.D., Khan, I.Y., Hanson, M.A. & Poston, L. 2004. Impaired EDHF-mediated vasodilatation in adult offspring of rats exposed to a fat-rich diet in pregnancy. J Physiol 558, 943–951. Taylor, P.D., McConnell, J., Khan, I.Y., Holemans, K., Lawrence, K.M., Asare-Anane, H., Persaud, S.J., Jones, P.M., Petrie, L., Hanson, M.A. & Poston, L. 2005. Impaired glucose homeostasis and mitochondrial abnormalities in offspring of rats fed a fat-rich diet in pregnancy. Am J Physiol Regul Integr Comp Physiol 288, R134– R139. Thornburg, K.L. & Louey, S. 2005. Fetal roots of cardiac disease. Heart 91, 867–868. Toste, F.P., de Moura, E.G., Lisboa, P.C., Fagundes, A.T., de Oliveira, E. & Passos, M.C. 2006. Neonatal leptin treatment programmes leptin hypothalamic resistance and intermediary metabolic parameters in adult rats. Br J Nutr 95, 830–837. Trevenzoli, I.H., Valle, M.M., Machado, F.B., Garcia, R.M., Passos, M.C., Lisboa, P.C. & Moura, E.G. 2007. Neonatal hyperleptinaemia programmes adrenal medullary function in adult rats: effects on cardiovascular parameters. J Physiol 580, 629–637.

P D Taylor et al.


Vickers, M.H., Gluckman, P.D., Coveny, A.H., Hofman, P.L., Cutfield, W.S., Gertler, A., Breier, B.H. & Harris, M. 2005. Neonatal leptin treatment reverses developmental programming. Endocrinology 146, 4211–4216. Vickers, M.H., Gluckman, P.D., Coveny, A.H., Hofman, P.L., Cutfield, W.S., Gertler, A., Breier, B.H. & Harris, M. 2008. The effect of neonatal leptin treatment on postnatal weight gain in male rats is dependent on maternal nutritional status during pregnancy. Endocrinology 149, 1906–1913. Vohr, B.R. & Boney, C.M. 2008. Gestational diabetes: the forerunner for the development of maternal and childhood obesity and metabolic syndrome? J Matern Fetal Neonatal Med 21, 149–157. Wang, J., Ma, H., Tong, C., Zhang, H., Lawlis, G.B., Li, Y., Zang, M., Ren, J., Nijland, M.J., Ford, S.P., Nathanielsz, P.W. & Li, J. 2010. Overnutrition and maternal obesity in sheep pregnancy alter the JNK-IRS-1 signaling cascades and cardiac function in the fetal heart. FASEB J 24, 2066–2076. Ward, K.R., Bardgett, J.F., Wolfgang, L. & Stocker, S.D. 2011. Sympathetic response to insulin is mediated by melanocortin 3/4 receptors in the hypothalamic paraventricular nucleus. Hypertension 57, 435–441. Wen, X., Triche, E.W., Hogan, J.W., Shenassa, E.D. & Buka, S.L. 2011. Prenatal factors for childhood blood pressure mediated by intrauterine and/or childhood growth? Pediatrics 127, e713–e721. West, N.A., Crume, T.L., Maligie, M.A. & Dabelea, D. 2011. Cardiovascular risk factors in children exposed to maternal diabetes in utero. Diabetologia 54, 504–507. West, N.A., Kechris, K. & Dabelea, D. 2013. Exposure to maternal diabetes in utero and DNA methylation patterns in the offspring. Immunometabolism 1, 1–9. Wright, C.S., Rifas-Shiman, S.L., Rich-Edwards, J.W., Taveras, E.M., Gillman, M.W. & Oken, E. 2009. Intrauterine exposure to gestational diabetes, child adiposity, and blood pressure. Am J Hypertens 22, 215–220. Xu, Y., Williams, S.J., O’Brien, D. & Davidge, S.T. 2006. Hypoxia or nutrient restriction during pregnancy in rats leads to progressive cardiac remodeling and impairs postischemic recovery in adult male offspring. FASEB J 20, 1251–1253. Xue, Q. & Zhang, L. 2009. Prenatal hypoxia causes a sexdependent increase in heart susceptibility to ischemia and reperfusion injury in adult male offspring: role of PKC {epsilon}. J Pharmacol Exp Ther 330, 624–632. Ye, Z.Y. & Li, D.P. 2011. Activation of the melanocortin-4 receptor causes enhanced excitation in presympathetic paraventricular neurons in obese Zucker rats. Regul Pept 166, 112–120. Yli, B.M., Kallen, K., Stray-Pedersen, B. & Amer-Wahlin, I. 2008. Intrapartum fetal ECG and diabetes. J Matern Fetal Neonatal Med 21, 231–238. Yura, S., Itoh, H., Sagawa, N., Yamamoto, H., Masuzaki, H., Nakao, K., Kawamura, M., Takemura, M., Kakui, K., Ogawa, Y. & Fujii, S. 2005. Role of premature leptin surge in obesity resulting from intrauterine undernutrition. Cell Metab 1, 371–378.


523

Maternal obesity, inflammation, and developmental programming.

Obesity: The many faces of leptin--a novel role for leptin signalling in obesity-induced hypertension.

Developmental programming and transgenerational transmission of obesity.

Developmental Programming of Obesity and Liver Metabolism by Maternal Perinatal Nutrition Involves the Melanocortin System.

Maternal undernutrition and fetal developmental programming of obesity: the glucocorticoid connection.

Thrifty metabolic programming in rats is induced by both maternal undernutrition and postnatal leptin treatment, but masked in the presence of both: implications for models of developmental programming.

Developmental programming by maternal obesity in 2015: Outcomes, mechanisms, and potential interventions.

Developmental programming: the role of growth hormone.

Sex differences in the developmental programming of hypertension.

leptin resistance.

Developmental ORIgins of Healthy and Unhealthy AgeiNg: the role of maternal obesity--introduction to DORIAN.

Impact of maternal obesity on fetal programming of cardiovascular disease.

Role of the Small Intestine in Developmental Programming: Impact of Maternal Nutrition on the Dam and Offspring.

Effects of Maternal Obesity on Fetal Programming: Molecular Approaches.

A Role for the Placenta in Programming Maternal Mood and Childhood Behavioural Disorders.

Central role for melanocortin-4 receptors in offspring hypertension arising from maternal obesity.

Obesity-Related Colorectal Cancer: The Role of Leptin.

A novel role for maternal stress and microbial transmission in early life programming and neurodevelopment.

Non-alcoholic fatty pancreas disease pathogenesis: a role for developmental programming and altered circadian rhythms.

Oxidative stress and altered lipid homeostasis in the programming of offspring fatty liver by maternal obesity.

Maternal obesity (Class I-III), gestational weight gain and maternal leptin levels during and after pregnancy: a prospective cohort study.

Prenatal programming of obesity in a swine model of leptin resistance: modulatory effects of controlled postnatal nutrition and exercise.

Aging, glucocorticoids and developmental programming.

The association of leptin with dyslipidemia, arterial hypertension and obesity in Kyrgyz (Central Asian nation) population.