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Maternal diet-induced obesity and offspring cardiovascular health

Published online by Cambridge University Press:  11 January 2013

H. L. Blackmore  and
S. E. Ozanne
H. L. Blackmore
Affiliation:
Level 4 Metabolic Research Laboratories, Institute of Metabolic Sciences, University of Cambridge, Addenbrookes Hospital, Cambridge, UK
S. E. Ozanne*
Affiliation:
Level 4 Metabolic Research Laboratories, Institute of Metabolic Sciences, University of Cambridge, Addenbrookes Hospital, Cambridge, UK
*
*Address for correspondence: Dr S. E. Ozanne, Level 4 Metabolic Research Laboratories, Institute of Metabolic Sciences, University of Cambridge, Addenbrookes Hospital, Cambridge CB2 0QQ, UK (Email seo10@cam.ac.uk)
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Abstract

It is widely recognized that environmental insults during adulthood including smoking, lack of exercise and a poor diet increases an individual's risk of cardiovascular disease (CVD). However, research initiated over the last two decades has highlighted that our risk of CVD can be programmed following adverse exposures during early development. Such adverse exposures may include, undernutrition, placental insufficiency, hypoxia, overnutrition and obesity. This review aims to address the current Western obesity crisis by addressing the long-term impact of maternal overnutrition and obesity on the offspring's future risk of CVD. Although current human studies have observed the presence of adverse CVD markers in children born to obese mothers, animal models have proved vital in understanding the underlying mechanisms involved. Mechanisms suggested to be involved in the programming of CVD in the offspring include increased oxidative stress, inflammation, lipotoxicity and epigenetics. CVD remains the greatest cause of death worldwide, therefore further understanding of the mechanisms mediating these effects is important in the development of intervention strategies.

Keywords

cardiovascular diseasedevelopmental programmingmaternal obesitymechanismsanimal models

Information

Type
Review
Information
Journal of Developmental Origins of Health and Disease , Volume 4 , Issue 5 , October 2013 , pp. 338 - 347
Copyright
Copyright © Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2013 

Statistics of a global killer

Cardiovascular disease (CVD) encompasses conditions affecting the heart and/or circulatory system and remains the greatest cause of mortality across the globe with the World Health Organization (WHO) estimating it to remain the biggest killer over the next two decades with 23.6 million deaths estimated annually.1 Age is the strongest non-modifiable risk factor for CVD and with significant improvements in medicine and lifestyle within Western populations life expectancy is set to further increase. Obesity is another major risk factor for CVD, also of particular concern as the worldwide prevalence of obesity has doubled over the past 30 years.2 This increase has been attributed to dramatic changes in both personal and working lifestyles over this time period. There has been a shift from active work and personal lives with nutritious simple foods (fruit, meat and vegetables), to a sedentary lifestyle containing fewer active jobs, less time to exercise and a ‘fast food’ culture where diet is rich in sugar and saturated fat.2

Rising levels of maternal obesity

The detrimental effects of obesity on current health, including risk of CVD and type 2 diabetes (T2D) are well established. However, it has only recently been recognized that obesity during pregnancy may not only be detrimental to the mother but also impacts negatively on the long-term health of her child. Data suggest that there is a high proportion of obesity in women of childbearing age (15–44 years old). Geographical areas with the highest proportion of obese women at this age include North America, Cuba, Latin America, the Caribbean and western, eastern and central Europe. The lowest proportions of obese women was observed in Africa and Southeast Asia.Reference Haslam and James3 In the United Kingdom, the National Obesity Observatory provides supporting evidence highlighting an increase in maternal obesity.4 The most common immediate complications associated with maternal obesity include stillbirth, cesarean section and macrosomia. However, strong recent evidence from both human and animal studies highlight how exposure to an obesogenic/nutrient enriched environment in utero and during early life, increases offspring's susceptibility to CVD in adulthood. This has been termed ‘developmental programming’. This review will address the current knowledge regarding this concept in relation to future development of CVD in the offspring.

The history of developmental programming

The concept that an individual's risk of developing CVD could be influenced by the environment in the womb emerged from studies performed by Professor David Barker and colleagues linking birth weight to subsequent risk of CVD. Barker termed this the ‘fetal origins hypothesis’. His initial observations focused on a group of Hertfordshire born men aged 64 years for whom birth weight records were available. These studies used birth weight as a proxy measure of the in utero environment and inverse relationships were observed between birth weight and a number of factors including systolic blood pressure (SBP) and mortality from ischemic heart disease.Reference Barker, Osmond, Golding, Kuh and Wadsworth5, Reference Barker, Winter, Osmond, Margetts and Simmonds6 Since this discovery, a plethora of studies have supported an association between low birth weight (LBW) and a variety of cardiovascular outcomes including atherosclerosis,Reference Martyn, Gale, Jespersen and Sherriff7 early atherosclerotic markers,Reference Skilton, Evans, Griffiths, Harmer and Celermajer8, Reference Forsen, Eriksson, Tuomilehto, Osmond and Barker9 CHDReference Leon, Lithell and Vagero10 and non-fatal myocardial infarction (MI).Reference Rich-Edwards, Stampfer and Manson11 In addition to birth weight, other measures used to assess the quality of the intrauterine environment including ponderal indexReference Barker, Osmond, Simmonds and Wield12 and placental weightReference Barker, Bull, Osmond and Simmonds13 were also associated with adverse cardiovascular outcomes.

Following observations linking birth weight to CVD, subsequent studies showed a similar association between birth weight and a number of metabolic disorders. Studies in the Hertfordshire cohort demonstrated an inverse association between birth weight and risk of impaired glucose tolerance (IGT) and non-insulin dependent diabetes mellitus (NIDDM) or T2D as it is now more commonly referred to.Reference Hales, Barker and Clark14 In fact, when comparing the lowest v. the highest group, risk increased sixfold. These observations led to the proposal of the ‘thrifty phenotype hypothesis’ by Nick Hales and David Barker, which states that during in utero malnutrition resulting from either maternal undernutrition or placental insufficiency, the fetus makes adaptations to ensure both survival up to parturition and preparation for its postnatal environment.Reference Hales, Barker and Clark14 Such changes are designed to ensure adequate nutrient and oxygen supply to vital organs such as the brain, while diverting resources away from non-key organs such as the pancreas, reducing β cell mass and islet function and subsequently predisposing offspring to T2D, especially in conditions of postnatal overnutrition. In addition, metabolic programming was proposed to occur, promoting nutrient storage and thus beneficial to survival in conditions of continued poor postnatal nutrition, but again detrimental in conditions of postnatal overnutrition.

The Predictive Adaptive Response (PAR) hypothesis proposed by Mark Hanson and Peter Gluckman added to the thrifty phenotype hypothesis by stating that adaptations in utero act to equip the offspring in preparation for their postnatal environment (Fig. 1).Reference Gluckman, Hanson and Spencer15 These adaptations result in permanent structural and physiological changes that will only become beneficial to the offspring if the postnatal environment matches what was expected while adapting in utero. These adaptations are termed phenotypic plasticity and create the ability to generate multiple phenotypes from a single genotype in response to varying environmental conditions.Reference Gluckman, Hanson and Spencer15 If the environment postnatally fails to match what was expected, adaptations made by the fetus in utero prove no longer advantageous and are associated with later adulthood disease. Small for gestational age (SGA) offspring who undergo rapid ‘catch up growth’ are proposed to be at increased risk of T2D and CVD as a consequence of such environmental mismatch.Reference Forsen, Eriksson, Tuomilehto, Osmond and Barker9, Reference Barker, Eriksson, Forsen and Osmond16

Fig. 1

Schematic diagram illustrating the theory behind both the predictive adaptive response and the thrifty phenotype. CVD, cardiovascular disease; T2D, type 2 diabetes.

Since the introduction of the fetal origins hypothesis, epidemiological studies have observed that determination of disease susceptibility is not confined to the narrow window of prenatal and early postnatal development. The most recent hypothesis termed ‘Developmental Origins of Health and Disease’ (DOHaD) encompasses the ideology that disease can be influenced throughout a broader developmental window. This suggests that from pre-conception, to the fertilized oocyte, through parturition and throughout childhood, environmental insults, whether nutritionally deprived or enriched, shape our vulnerability to disease. Non-nutritional insults include gestational diabetes, pre-eclampsia and fetal hypoxia. Exposure to gestational diabetes (GDM) increases offspring risk of macrosomia,Reference Ehrenberg, Mercer and Catalano17 obesityReference Gillman, Rifas-Shiman, Berkey, Field and Colditz18 and the metabolic syndrome.Reference Boney, Verma, Tucker and Vohr19, Reference Tam, Ma and Yang20 In addition, exposure to pre-eclampsia elevates offspring blood pressure and risk of stroke.Reference Kajantie, Eriksson, Osmond, Thornburg and Barker21 Fetal hypoxia measured in humans at high altitude results in LBW offspring with increased risk of elevated arterial blood pressure.Reference Giussani22 The indigenous high altitude populations of Tibet resist such effects of hypoxia through adaptations that prevents hypoxic-induced reductions in uterine artery blood flow.Reference Julian, Wilson and Lopez23

Although initially studies focused upon the effect of LBW offspring, there have been subsequent studies that have demonstrated that risk of disease is ‘U’ shaped, with both high and LBW individuals being at increased risk. This has been demonstrated in populations with a large prevalence of maternal obesity such as the Pima Indians.Reference Dabelea, Pettitt and Hanson24

Offspring exposure to maternal obesity programs CVD

Although the long-term impact of maternal undernutrition on the offspring is well characterized, the direct impact of overnutrition is less well established. As a consequence of rising levels of obesity including women of childbearing age,25 the focus of more recent research has been directed toward the long-term impact of overnutrition and obesity on long-term cardiovascular health in the offspring.

Maternal obesity was previously associated most commonly with offspring born large for gestational age (LGA).Reference Surkan, Hsieh, Johansson, Dickman and Cnattingius26 However, research has shown that obese women are just as likely to deliver SGA offspring as they are LGA offspring (18.8% and 13.4%, respectively).Reference Rajasingam, Seed, Briley, Shennan and Poston27 This observation is important for two reasons. First, as the risk of future CVD in the offspring is represented by a ‘U’ shaped risk curve in relation to birth weight, offspring born to obese mothers present an equal risk of future disease if born SGA or LGA. Second, this suggests that maternal overnutrition or obesity per se differs between the mother and fetus, as growth restricted infants can still be born in the presence of maternal overnutrition.

The difficulty in dissecting the mechanisms by which maternal obesity influences future offspring disease is due to the complexities in distinguishing between obesity, overnutrition and additional complications associated with obesity.Reference Drake and Reynolds28 As a consequence, studies have investigated a variety of exposure variables, including the possible consequences of maternal obesity such as GDM upon the offspring risk of future CVD.

Studies have consistently shown a positive association between maternal body mass index (BMI) and early presentation of CVD risk factors in the young.Reference Lawlor, Najman and Sterne29 Gestational weight gain (GWG), partly determined by the mother's lifestyle throughout pregnancy, is positively linked with both SBP and BMI in young adults.Reference Mamun, O'Callaghan and Callaway30 This is supported by a study that showed gaining weight greater than that recommended by the Institute of Medicine (2009) increased offspring SBP, leptin, BMI and fat mass.Reference Fraser, Tilling and Macdonald-Wallis31 In particular, excess weight gain between 14–36 weeks gestation was the most adverse for offspring outcome when observing inflammation and lipid profiles. GDM, a common complication of maternal obesity has been shown to increase childhood presentation of early CVD markers including leptin, waist circumference, BMI and SBP.Reference West, Crume, Maligie and Dabelea32

Similar to maternal obesity, hypercholesterolemia is another example where exposure to excess results in adverse consequences for the offspring. Elevated cholesterol in the maternal serum transmits high levels into the fetal circulation.Reference Zhu, Ma, Long, Du and Ford33 Such exposure to high cholesterol in utero has been associated with increased lesion size, fatty streaks and oxidized LDL in the human fetal aorta.Reference Napoli, D'Armiento and Mancini34 Lesion size was shown to regress in these offspring following birth, however lesion progression in these individuals remained enhanced even in the presence of normal postnatal cholesterol levels.Reference Napoli, Glass and Witztum35 Investigation into long-term effects of maternal obesity is expected in the near future once offspring exposed to this current obesity epidemic grow to the age whereby features of the condition can be easily measured.

Intervention studies involving bariatric surgery have been used in an attempt to address causality in the associations identified between maternal obesity and offspring disease. Some researchers have suggested that the association between maternal obesity and increased cardiovascular risk factors in the exposed offspring is due to inheritance of susceptibility genes to obesity and T2D diabetes from their obese and/or diabetic mothers. Comparing sibling cardiometabolic risk factors and obesity, siblings born prior to bariatric surgery had significantly enhanced metabolic risk factor profiles than those siblings born after maternal weight loss.Reference Kral, Biron and Simard36, Reference Smith, Cianflone and Biron37 These studies support the idea that the intrauterine environment of nutrient excess is a significant risk factor for increasing risk of offspring cardiometabolic disease. However, the role of genetic inheritance cannot be fully excluded.

Animal models of overnutrition

In line with the first epidemiological studies, animal models initially focused on the impact of maternal undernutrition on offspring health. However, in concert with rising levels of maternal obesity and the understanding that both under- and overnutrition in early life can induce similar outcomes in the offspring, studies have since begun to investigate models of maternal overnutrition. The most common method used to induce maternal obesity has been through the modification of the maternal diet.

Nonhuman primate and ovine models

There are developmental programming models involving nonhuman primates but they are limited especially in relation to understanding the impact on offspring CVD. This is due to the fact that CVD is a condition of age and as nonhuman primates have a long lifespan, this makes studying such long-term outcomes incredibly lengthy and costly. Therefore, observing short-term outcomes such as adiposity and indicators of cardiac dysfunction have been investigated.Reference Lewis, Bertrand and McMahan38, Reference Farley, Tejero and Comuzzie39 Features of premature cardiovascular dysfunction in nonhuman primate offspring have been observed in response to maternal obesity (14–36% fat diet) during pregnancy and lactation, following weaning onto either a control or high fat diet (HFD). Offspring exposed to maternal obesity during pregnancy and lactation with a postnatal HFD had elevated plasma insulin, attenuated vasorelaxation capacity in the renal artery and a thicker intima wall with irregular vascular morphology.Reference Fan, Lindsley and Comstock40

In contrast to nonhuman primates, a variety of cardiovascular outcomes have been investigated in offspring exposed to maternal overnutrition or obesity in sheep. Maternal obesity in ewes induced by administration of an obesogenic diet (150% of the National Research Council recommendations) is a well-described method of inducing obesity. Various studies have observed effects in the fetus showing an increased heart weight and liver lipid levels,Reference George, Uthlaut and Long41 enhanced fetal heart stress signalling, cardiac fibrosisReference Huang, Yan and Zhao42 and impaired contractility in response to a high workload stress.Reference Wang, Ma and Tong43

Larger species that include nonhuman primates and sheep are beneficial to study due to their close similarity to humans. Although these models are often associated with large expenses including high maintenance costs and a long lifespan, the total number of animals required for experimental studies is often significantly less.

Rodent models are the most commonly used and extensively studied and while they show fewer similarities to humans compared with nonhuman primate models, they are preferred due to their short lifespan, relative ease of maintenance and consequently lower cost.

Rodent species – HFD

Rodent models were initially used to investigate the role of maternal overnutrition by manipulating the maternal diet to be high in fat, in particular saturated fat. By manipulating the timing of the insult during pregnancy, lactation and postnatal life, critical developmental windows for offspring disease outcome could be successfully defined. Exposure to a maternal HFD (60%) during gestation in rodents was sufficient to induce features of the metabolic syndrome and hypertension in female offspring, despite being fed a standard postnatal diet.Reference Liang, Oest and Prater44

Rodent offspring exposed to a diet of 20% saturated fat during both pregnancy and lactation showed impaired endothelial relaxation to acetylcholine, indicative of endothelial dysfunction. Offspring had significant lipid abnormalities including raised plasma triglycerides and attenuated HDL. In addition, polyunsaturated fatty acids docosahexaenoic acid and arachidonic acid were reduced in the aorta of offspring fed the HFD, both fatty acids of which have protective effects against CVD.Reference Ghosh, Bitsanis, Ghebremeskel, Crawford and Poston45 Another study investigating HFD exposure during both pregnancy and lactation observed elevated blood pressure and endothelial dysfunction in females. However, if the pre- and postnatal environment of a HFD was maintained in these offspring, endothelial function was improved, although the hypertensive phenotype was unaffected,Reference Khan, Dekou, Hanson, Poston and Taylor46 therefore supporting evidence of the PAR.

Not all investigators feed their dams over a short period prior to mating;Reference Khan, Dekou, Hanson, Poston and Taylor46 this is due to the rationale that long-term high fat feeding (from the weaning of the dams themselves) induces physiological changes in the mother, including alterations in serum lipid levels and body composition. These factors are important as the offspring of such models will be exposed to both maternal overnutrition and obesity, which is more representative of the human exposure.Reference Elahi, Cagampang and Mukhtar47 Exposure of offspring to such long-term high fat feeding during pregnancy and lactation increased both blood pressure and total cholesterol in the offspring. In this study, matching the postnatal environment with high fat feeding reduced blood pressure compared with offspring weaned onto standard chow,Reference Elahi, Cagampang and Mukhtar47 again highlighting the role of the PAR and the benefit of matching the pre- and postnatal environment.

As previously described, maternal hypercholesterolemia is common in overweight and obese mothers. Data from animal models demonstrate that offspring exposed to a HFD supplemented with cholesterol during pregnancy using mice who were homozygous knockout for the LDL receptor (LDLr−/−), showed a doubling of lesion size in the offspring at 3 months of age compared with controls.Reference Napoli, de Nigris and Welch48 Exposure to the high cholesterol levels of ApoE−/− dams led to expression of genes involved in cholesterol biosynthesis in the offspring even following weaning onto standard chow.Reference Goharkhay, Tamayo and Yin49 Also, offspring of ApoE−/− dams have features of endothelial function in the carotid artery, suggesting enhanced susceptibility to later atherosclerosis.Reference Alkemade, Gittenberger-de Groot and Schiel50

Studying HFD exposure alone in rodent models is not sufficient to model maternal obesity as rodents are known to self-regulate their calorie intake in response to fat,Reference Keesey and Hirvonen51 preventing obesity in the dams unless fed for at least 6 weeks before mating.Reference Rooney and Ozanne52 However, rodents are much less able to regulate calorie intake when given a diet rich in simple sugars. Consequently, a diet high in simple sugars and saturated fat (often termed a highly palatable diet) has since been used to model maternal diet-induced obesity. In addition to inducing obesity in rodents, the diet is believed to better represent the Westernized diet.

Rodent models – highly palatable diet

In a recently developed model, administration of the highly palatable diet begins at weaning of the female that is to be mated.Reference Samuelsson, Matthews and Argenton53 Mouse offspring of these dams at 3 months of age display hyperphagia, increased adiposity and endothelial dysfunction. A hypertensive phenotype was observed at 6 months of age.Reference Samuelsson, Matthews and Argenton53 Furthermore, these offspring also have a dysmetabolic phenotype (increased leptin, insulin, body weight, food intake and SBP) and non-alcoholic fatty liver disease.Reference Oben, Mouralidarane and Samuelsson54 Recently published data also from this model demonstrate that offspring have left ventricular cardiac hypertrophy at 8 weeks of age independent of offspring adiposity. This is coupled with increased expression of fetal genes implicated in pathological hypertrophy, suggestive of an irreversible phenotype. Such changes are also coupled with increased phosphorylation of insulin-signalling proteins including Akt, mTOR, ERK and p38MAPK.Reference Fernandez-Twinn, Blackmore and Siggens55

Using the technique of cross-fostering, offspring exposed to maternal diet-induced obesity exclusively during lactation had an enhanced dysmetabolic and non-alcoholic fatty liver phenotype compared with those exposed during both pregnancy and lactation.Reference Oben, Mouralidarane and Samuelsson54 This highlights both the potential role of changes in breast milk composition in development of the offspring phenotype and also highlights the negative impact of nutritional mismatch between gestation and lactation.Reference Oben, Mouralidarane and Samuelsson54

Offspring of a rat model of maternal obesity during pregnancy and lactation showed night-time elevations in mean arterial blood pressure at 3 months of age compared with control offspring, preceding obesity and hyperleptinemia. Underlying mechanisms focused on a sympathetic origin of hypertension, supported by elevated noradrenaline, renin and the inhibition of hypertension following β-adrenergic blockade.Reference Samuelsson, Morris and Igosheva56

Although most models utilize diet to induce obesity as it provides a more representative environment to that of human obesity, there are also models that describe the impact of non-dietary-induced obesity on offspring cardiometabolic disease.

Non-diet-induced maternal obesity

A genetic model of obesity known as the lethal yellow mutation (Ay) in agouti mice has been used to model the long-term effects on offspring exposed to maternal obesity independently of maternal diabetes. Dams with the Ay mutation who are obese, give rise to offspring without the mutation who show an IGT and pancreatic dysfunction.Reference Han, Xu, Epstein and Liu57 Although offspring from this model showed no differences in baseline heart contractility compared with controls measured by electrocardiography, offspring showed an increased susceptibility to ischemia-reperfusion injury following occlusion of the left coronary artery.Reference Calvert, Lefer, Gundewar, Poston and Coetzee58 A significantly greater infarct area and aberrant left ventricular diastolic volume and area supported this observation.

Potential underlying mechanisms

Mechanisms involved in the early life programming of CVD have been well described in relation to the effects of undernutrition. Mechanisms implicated in undernutrition include oxidative stress, changes in morphological organ structure, altered signalling pathways and epigenetic regulation. Although the potential mechanisms involved in exposure to early life overnutrition and offspring CVD are less well established, it is likely that programming of CVD may occur through similar mechanisms as observed in undernutrition due to similarities in offspring phenotype. A summary of the proposed mechanisms involved is summarized in Fig. 2.

Fig. 2

A schematic highlighting possible mechanisms suggested to be involved in the developmental programming of a variety of cardiovascular diseases. CRP, c-reactive protein; NOS, nitric oxide synthase; RAS, renin angiotensin system; ROS, reactive oxygen species; TNF, tumor necrosis factor.

Oxidative stress and inflammation

Obesity and pregnancy per se drive both inflammation and oxidative stress.Reference de Heredia, Gomez-Martinez and Marcos59 Therefore, the combination of the two is likely to have an additive effect. This is supported by studies in sheep showing that the hearts of obese pregnant ewes display elevated levels of oxidative stress.Reference Wang, Ma and Tong43 Human placentae of obese pregnancies demonstrate signs of inflammation and mitochondrial dysfunction both of which could impact on fetal growth.Reference Oliva, Barker and Riley60 Increased oxidative stress has also been demonstrated in the offspring of obese dams. For example, studies in sheep have demonstrated elevated levels of oxidative stress in the heart, accompanied by activation of p38, JNK and attenuated levels of cardioprotective AMPK as a result of maternal obesity. These offspring show functional defects with an impaired cardiac function in response to workload stress.Reference Wang, Ma and Tong43

Inflammation during pregnancy has been suggested to be responsible for impaired myocardial contractility in the offspring.Reference Dong, Zheng, Ford, Nathanielsz and Ren61In vitro studies of feline cardiomyocytes demonstrated that tumor necrosis factor (TNF)-α, an important inflammatory cytokine, negatively impacts on myocardial contractility.Reference Friedrichs, Swillo and Jow62, Reference Oral, Dorn and Mann63 Elevated TNF-α, Vascular Endothelial Growth Factor (VEGF) and Intercellular Adhesion Molecule 1 (ICAM1) levels in sheep offspring exposed pre- and postnatally to a HFD are early markers of atherosclerosis and inflammation.Reference Fan, Lindsley and Comstock40 Cardiac fibrosis in fetal sheep offspring has also been linked to inflammation and TGF-β signalling.Reference Huang, Yan and Zhao42 C-Reactive Protein (CRP) in adult humans is associated with an increased risk of CVD.Reference de Ferranti and Rifai64 Female mice exposed to a HFD during pregnancy, lactation and postnatally, and those exposed postnatally only, showed elevated CRP.Reference Elahi, Cagampang and Mukhtar47 CRP in hypercholesterolemic human mothers has been shown to predict development of atherosclerosis in the offspring, although the association is weaker than for maternal cholesterol.Reference Liguori, D'Armiento, Palagiano, Palinski and Napoli65

Endothelial dysfunction contributes to the pathogenesis of CVD. Nonhuman primate offspring who were exposed to a HFD pre- and postnatally (H/H) developed impaired vasorelaxation of the renal artery. The mRNA expression levels of Endothelial Nitric Oxide Synthase (eNOS) were unchanged in the vessels of these offspring. However, the observation of a positive relationship between the maximal relaxation capacity and eNOS in the H/H offspring may suggest a minor role for attenuated nitric oxide availability in impaired vasorelaxation in these offspring.Reference Fan, Lindsley and Comstock40

Strong evidence supporting the potential causative role of oxidative stress is highlighted by intervention studies. Quercetin, an antioxidant, administered to high fat fed mouse dams during pregnancy prevented hypertension in offspring at 12 months.Reference Liang, Oest and Prater44 Blood glucose level was also restored at 6 and 12 months following treatment. Obesity, a strong risk factor for the development CVD, was prevented in rodent offspring exposed to maternal obesity following treatment with antioxidants, again highlighting the potential role of oxidative stress.Reference Sen and Simmons66 A causal role for lipid peroxidation in hypercholesterolemic pregnant rabbits was supported by a reduction in atherosclerosis at birth following supplementation with Vitamin E.Reference Napoli, Witztum, Calara, de Nigris and Palinski67 Maternal cholesterol itself has also been associated with increased oxidative stress and progression of atherosclerosis.Reference Alkemade, Gittenberger-de Groot and Schiel50

Lipotoxicity and high cholesterol

Lipotoxicity in offspring following exposure to maternal overnutrition has been described in a number of animal models.Reference Jarvie, Hauguel-de-Mouzon and Nelson68, Reference McCurdy, Bishop and Williams69 Recent evidence has demonstrated that mouse offspring exposed during both the pre- and postnatal periods to maternal high fat, have lipid accumulation within the heart.Reference Turdi, Ge, Hu, Bradley and Ren70 This is also coupled with elevated levels of the rate-limiting enzyme important for fat deposition and synthesis, steratoyl-CoA desaturase, swelling of the mitochondria and damage to the double membrane. These animals also show impaired insulin signalling with phosphorylation of both Akt and AMPK in addition to attenuated post receptor signalling.Reference Dong, Zheng, Ford, Nathanielsz and Ren61 Increased activation of the cholesterol pathway in offspring has been observed in response to maternal hypercholesterolemia. Thereby indicating possible programming of enhanced cholesterol biosynthesis, with epigenetic regulation hypothesized to be a cause.Reference Goharkhay, Tamayo and Yin49

The importance of both maternal and offspring levels of cholesterol in development of CVD in the offspring has been strongly supported by intervention studies. Pravastatin administered during the latter stage of pregnancy in female mice fed a high cholesterol diet ameliorated the effects of programming in the offspring. This was supported by a reduction in body weight, improved SBP and increased locomotor activity in the offspring. These changes were dependent on the lipid lowering effect of the statin.Reference Elahi, Cagampang and Anthony71 Hypercholesterolemic pregnant rabbits treated with a statin also resulted in reduced lesion size in the aorta in the offspring.Reference Napoli, Witztum, Calara, de Nigris and Palinski67 Reducing maternal cholesterol with the drug cholestyramine, reduced atherosclerosis at birth in the offspring by 39%.Reference Napoli, Witztum, Calara, de Nigris and Palinski67

Defects in the insulin-signalling pathway

Persistent hyperinsulinemia alone can be used as an independent predictor of MI and has also been associated with mortality.Reference Kannel, Hjortland and Castelli72 Defects in the insulin-signalling pathway have therefore been proposed in numerous studies as a potential mechanism linking maternal overnutrition or diet-induced obesity to offspring CVD. In particular, insulin resistance may play a role in initiating the re-distribution of maternal nutrients to affect the sheep fetus.Reference George, Uthlaut and Long41

Rodent offspring exposed to maternal diet-induced obesity during pregnancy and lactation were hyperinsulinemic independent of obesity. These offspring also showed left ventricular hypertrophy and re-expression of fetal genes.Reference Fernandez-Twinn, Blackmore and Siggens55 The increased activation of insulin-signalling proteins (Akt, ERK and mTOR) has been suggested as a potential mechanism driving the cardiac phenotype in the offspring. Similarly, offspring of a rodent model of maternal overfeeding during lactation had an enlarged heart and hyperinsulinemia coupled with IGT.Reference Martins, Vieira, de Souza and Moura73 A sheep model of maternal overfeeding showed that fetal heart morphometry was altered with the enlargement of both left and right ventricles in the absence of re-expression of fetal genes. Activation of NFATc3, mTOR and FoxO3a were hypothesized as the potential drivers for the hypertrophic phenotype in response to early gestational overfeeding.Reference Fan, Turdi and Ford74

Renin angiotensin system (RAS) and autonomic control

The role of the RAS in the programming of hypertension is well documented in relation to maternal undernutrition and exposure to excessive glucocorticoids.Reference Langley-Evans75 However, this is much less well documented in response to maternal overnutrition. Elevated levels of norepinephrine and renin expression have been observed in renal tissue of rat offspring exposed to obesity.Reference Samuelsson, Morris and Igosheva56 Furthermore, these offspring were hyper responsive to sympathetic action supported by amelioration of an increased blood pressure through α/β adrenergic blockade, in addition to altered baroreceptor function.Reference Samuelsson, Morris and Igosheva56 However, it is important to consider that adipose tissue is an endocrine organ that also secretes angiotensinogen and can induce hypertension.Reference Boscaro, Giacchetti and Ronconi76–Reference Yvan-Charvet, Massiera and Lamande79

Epigenetics

Epigenetics has gained a lot of attention in the field of developmental programming. It has been proposed as a mechanism by which the genome can interact with the environmentReference Gluckman, Hanson, Buklijas, Low and Beedle80 and thereby giving the potential for multiple phenotypes to arise from a single genotype. The key epigenetic modifications include post-translational modifications of histones including among others acetylation, phosphorylation and ubiquitination. Changes in these epigenetic modifications modulate gene transcription. Hypertension, endothelial dysfunction and diabetes in offspring exposed to a low protein diet or uteroplacental insufficiency in early life have all been associated with epigenetic modifications in key regulatory genes (reviewed in Gluckman et al.Reference Gluckman, Hanson, Buklijas, Low and Beedle80). There is currently little data relating maternal overnutrition to alterations in epigenetic modifications in the offspring. Alterations in histone modification have been reported in fetuses exposed to a maternal HFD that display markers of fatty liver disease.Reference Aagaard-Tillery, Grove and Bishop81 This included hyperacetylation of histone H3 concurrent with attenuated activity of a histone deacetylase.

MicroRNA (miR) is a single-stranded RNA capable of inhibiting gene expression by annealing complementary to a specific gene. MicroRNAs have been implicated in a variety of CVDs including heart failure, fibrosis, MI and cardiac hypertrophy.Reference van Rooij and Olson82 Cardiac specific miR208a that is found within an intron of myosin heavy chain 6 (α-myosin heavy chain) is expressed during conditions of cardiac stress.Reference van Rooij, Sutherland and Qi83 Cardiac remodelling following pressure overload was prevented by genetic deletion of cardiac specific miR208a.Reference Montgomery, Hullinger and Semus84

The key aim of future research will be to gather further evidence on epigenetic mechanisms that allow us to understand the programming of adulthood CVD in response to maternal overnutrition and obesity.

Conclusions

There is consistent evidence in both human studies and animal models that exposure to overnutrition and an obesogenic environment in utero programs increased susceptibility to CVD later in life. The mechanisms underlying such an association remain poorly defined. However, in light of the growing prevalence of obesity, especially in women of childbearing age, it is critical that such processes are defined to help combat the transmission of such a phenotype to the next generation.

Acknowledgments

Heather L Blackmore is a British Heart Foundation Phd student (1 + 3 year programme). Susan E Ozanne is a British Heart Fondation senior fellow.

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Figure 0

Fig. 1 Schematic diagram illustrating the theory behind both the predictive adaptive response and the thrifty phenotype. CVD, cardiovascular disease; T2D, type 2 diabetes.

Figure 1

Fig. 2 A schematic highlighting possible mechanisms suggested to be involved in the developmental programming of a variety of cardiovascular diseases. CRP, c-reactive protein; NOS, nitric oxide synthase; RAS, renin angiotensin system; ROS, reactive oxygen species; TNF, tumor necrosis factor.