Experimental models of developmental programming: consequences of exposure to an energy rich diet during development
1 Maternal and Fetal Research Unit, Division of Reproductive Health, Endocrinology and Development, GKT School of Medicine, St Thomas' Hospital, Lambeth Palace Road, London SE1 7EH, UK
Abstract
Studies in both humans and experimental animals addressing the ‘Fetal Origins of Adult Disease’ hypothesis have established a relationship between an adverse intrauterine environment and offspring disease in adult life. This phenomenon, termed ‘fetal programming’ describes a process whereby a stimulus in utero establishes a permanent response in the fetus leading to enhanced susceptibility to later disease. However, the environment, during periods of developmental plasticity in postnatal life, can also ‘programme’ function. Thus, the terms ‘developmental programming’ and the ‘Developmental Origins of Adult Health and Disease’ are preferentially utilized. The ‘Thrifty Phenotype’ hypothesis explained the association between insufficient in utero nutrition and the later development of Type 2 diabetes. Most recently the ‘Predictive Adaptive Response’ hypothesis proposes that the degree of mismatch between the pre- and postnatal environments is an important determinant of subsequent disease. Epidemiological studies have indicated that fetal growth restriction correlates with later disease, implying that fetal nutritional deprivation is a strong programming stimulus. This prompted the development of experimental animal models using controlled maternal calorie, protein or macronutrient deficiency during key periods of gestation. However, in many societies, maternal and postnatal nutrition are either sufficient or excessive. Here, we examine findings from a range of nutritional studies examining maternal and/or postnatal nutritional excess. There is supportive evidence from a limited number of studies to test the ‘Predictive Adaptive Response’ hypothesis. These suggest that maternal over-nutrition is deleterious to the health of offspring and can result in a phenotype of the offspring that is characteristic of metabolic syndrome.
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Introduction
Obesity is increasing to epidemic proportions in human populations. In the USA 20.9% of the total population have a body mass index > 30 (Mokdad et al. 2003). This is explained in part by excessive fat intake in most western diets: in 2001 the European average was 32.1% of calorie intake from all fat (Office for National Statistics UK, 2003) and in the UK, women of average childbearing age (24–35 years) consumed 35.4% of calories from fat, of which saturated fats accounted for 13.2% of energy (Office for National Statistics UK, 2003). More and more women are therefore obese and consuming a calorific or fat-rich diet when pregnant. Other than the immediate risk to the mother's health and to pregnancy outcome, for example the increased risk of gestational diabetes and pre-eclampsia (Ostlund et al. 2004), there are other potential consequences. In particular, there is increasing evidence, predominantly from studies in animals, to suggest that the fetus may be prone to development of cardiovascular disease in later life through exposure to the excesses of maternal nutrition. This short review summarizes the literature which is supportive of this hypothesis.
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Historical perspective from fetal origins to predictive adaptive responses
The contribution of maternal nutrition to the fetal origins hypothesis (Barker, 1997) has been studied extensively in both human populations and in experimental animals. Earlier studies focused on the effect of under-nutrition, and the association of smallness at birth and later adult cardiovascular disease (Osmond & Barker, 2000). The ‘Thrifty Phenotype’ hypothesis proposed that poor nutrition in utero led to fetal adaptations that produced permanent changes in insulin and glucose metabolism, thus increasing the risk of adult Type 2 diabetes and the metabolic syndrome (Hales & Barker, 2001). Although well supported by maternal nutrient restriction studies, that reported altered pancreatic morphology and function (Snoeck et al. 1990) and insulin homeostasis (Hales & Barker, 2001), this hypothesis did not provide a mechanism for altered function of adult offspring following maternal over-nutrition.
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Extending upon the ‘Thrifty Phenotype’ hypothesis, the ‘Predictive Adaptive Response’ hypothesis (Gluckman & Hanson, 2004a, b, c) proposes that the fetus makes adaptations in utero (or in the early postnatal developmental period) based on the predicted postnatal environment. When this predictive adaptive response (PAR) is appropriate, the phenotype is normal; however, where mismatch occurs between the predicted and actual environment, disease manifests. Unlike previous programming hypotheses, it contends that in response to a given in utero or early postnatal nutritional plane (either high or low), cellular processes are tuned to cope with the predicted environment and that these adaptations are not necessarily advantageous in utero. Thus it is proposed that disease only manifests when the actual adult diet diverges from this plane to which the fetus has ‘predicted’. This is an intriguing concept and one supported by the small number of studies to have directly addressed the hypothesis.
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Evidence from population based studies for developmental programming through maternal dietary excess
Few studies have directly assessed the relationship between maternal over-nutrition and cardiovascular phenotype of the offspring. In a post-mortem study from an Italian population, Napoli et al. have demonstrated that fetuses and children born to hypercholesterolaemic mothers exhibit accelerated development of fatty streaks in the aorta (Napoli et al. 1997, 1999). The study did not ascertain whether this was attributable to familial hypercholesterolaemia and maternal dietary intake was not known; therefore we may only assume that mothers were hypercholesterolaemic due to dietary intake of fat rather than altered fat metabolism. Another study from a Scottish cohort suggested programming of raised blood pressure and perturbed glucose homeostasis in adult offspring of women who consumed a high carbohydrate : protein ratio in the diet (Campbell et al. 1996; Shiell et al. 2000). Indirectly, and potentially of relevance through diet and obesity, there is overwhelming evidence from studies of Pima Indians to suggest that women who have diabetes in pregnancy are likely to convey a predisposition to insulin resistance in their children (Pettitt et al. 1988).
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Evidence from animal studies for developmental programming through maternal nutritional excess
Whilst deprivation studies are relatively straightforward in experimental rodent models, delivery of supranormal nutrition is not, as rodents demonstrate a robust homeostatic regulation of food intake and energy expenditure to maintain body weight (Keesey & Hirvonen, 1997). Leptin and insulin are known peripheral signalling moieties that target hypothalamic regulatory sites that lead to appetite modulation (Keesey & Hirvonen, 1997; Hellstrom et al. 2004). The existence of a ‘body weight set-point’ in rodents and humans is established, whereby body weight reduction or increase is corrected by altered food intake and energy expenditure to defend the target body weight (Keesey & Hirvonen, 1997).
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Pregnant rats fed a fat-rich but normal carbohydrate diet reduce their intake of energy-dense diet to maintain similar calorie intake compared with controls, but derive more calories from fat (Guo & Jen, 1995; Langley-Evans, 1996; Del Prado et al. 1997; Taylor et al. 2003). Thus, it is likely that the phenotype of offspring from fat-fed dams is determined by increased exposure to the dietary fat rather than maternal energy intake per se.
Maternal high-fat or cholesterol over-feeding during pregnancy and lactation in rodents results in a phenotype of the offspring that closely resembles the human metabolic syndrome (Armitage et al. 2004b). Abnormal glucose homeostasis (Guo & Jen, 1995; Taylor et al. 2005), increased blood pressure (Langley-Evans, 1996; Khan et al. 2003), abnormal serum lipid profiles (Karnik et al. 1989; Guo & Jen, 1995; Khan et al. 2003), increased adiposity (Guo & Jen, 1995; Khan et al. 2004a) pro-atherogenic lesions (Palinski et al. 2001), reduced acetylcholine-induced vasodilatation (Khan et al. 2004a,b; Taylor et al. 2004) and hyperleptinaemia (Taylor et al. 2005) have all been reported.
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The cellular or molecular mechanisms that underlie the phenotype arising from maternal nutritional excess are under increasing scrutiny and will facilitate a fuller understanding of cardiovascular disease aetiology. Microarray gene expression studies of aortas from offspring of lard-fed rats reveal alterations (2-fold or greater) in the expression of over 200 genomic and mitochondrial-specific mRNA sequences, compared with that of control offspring (Taylor et al. 2005). Genes altered by exposure to maternal lard-rich diets included those encoding for collagen and elastin, endothelial and inducible nitric oxide synthase (Armitage et al. 2004a) and a reduction in mitochondrial copy number (Taylor et al. 2005). Similar studies have been carried out in aortas from offspring of LDL receptor knockout mice. Compared with offspring from control-fed dams, the offspring of high-cholesterol-fed LDL receptor knockout mice demonstrated altered expression of over 130 genes encoding for proteins involved in mitochondrial function, extracellular matrix function, the oestrogen-related receptor, cytokine signalling and antioxidant defence (Napoli et al. 2002). In addition to the gene array studies that suggest alterations to the expression of mitochondrial genome encoded proteins, we have also shown reductions in mitochondrial copy number in kidneys from offspring of lard-fed dams, compared with control offspring (Taylor et al. 2005).
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The hyperinsulinaemia and hyperglycaemia observed in adult offspring of lard-fed rat dams is accompanied by reduced whole body insulin sensitivity, impaired pancreatic cell insulin secretion and pancreatic ultrastructural changes (Taylor et al. 2005) suggesting that islet cell exhaustion occurs due to high insulin demand secondary to skeletal muscle insulin insensitivity. This is consistent with observations from animal models of mild maternal diabetes, in which perinatal hyperinsulinaemia, due to hypertrophy of the endocrine pancreas, results in impaired pancreatic function and glucose tolerance in the adult (Van Assche et al. 2001). Indeed, fat-feeding during pregnancy produces maternal hyperinsulinaemia that may contribute to the programming stimulus in this model (Taylor et al. 2003).
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Blood pressure changes in female offspring of lard-fed rat dams appear to be linked to altered baroreceptor sensitivity in offspring and not to small artery endothelial dysfunction (Khan et al. 2003). Male offspring of coconut oil (saturated fat)-fed rats demonstrate increased blood pressure but do not show evidence of altered hypothalamic-pituitary-adrenal axis (HPA) axis activation (Langley-Evans, 1996), suggesting that HPA hyperactivity, associated with hypertension in offspring of protein-deprived rats, is not involved in elevation of the blood pressure in offspring of fat-fed dams.
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The blunted endothelial-dependent vasodilatation observed in small mesenteric arteries from offspring of lard-fed dams appears to be underpinned by a reduction in endothelial-derived hyperpolarizing factor (EDHF) rather than a nitric oxide or prostacyclin deficit (Taylor et al. 2004). The reduced arachidonic acid and docosahexaenoic concentrations that we have observed in aortas from offspring of lard-fed dams (Ghosh et al. 2001) may underlie the EDHF defect as these fatty acids are precursors of a putative EDHF.
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There is no evidence for hyperphagia, or reduced locomotor activity (Khan et al. 2003) in offspring of lard-fed rat dams, therefore increased body mass and adiposity that we have reported (Khan et al. 2003) may be maintained by reduced basal metabolic activity. This would be compatible with the reduced mitochondrial copy number that we have reported in the kidney in this model (Taylor et al. 2005).
Either the high fat intake per se or the ingestion of specific fatty acids is likely to be responsible for the development of the phenotype of the offspring. Maternal high-saturated-fat intake (from coconut oil) results in offspring with pancreatic cell loss and glucose intolerance by oral glucose tolerance test. However, raised maternal polyunsaturated fatty acid intake (from fish oil) did not perturb the phenotype of the offspring compared with controls (Siemelink et al. 2002). Moreover, in a recent study we have shown that blood pressure in offspring of high polyunsaturated-fat-fed rats (25% corn oil) is 20 mmHg lower than that of offspring of saturated-fat (20% palm oil + 5% corn oil)-fed rats (Jensen et al. 2004). Taken together, these studies suggest that it is the saturated fatty acid component of the lard-rich diet which is deleterious to the offspring, and also imply that maternal polyunsaturated fatty acids may be of benefit in the development of the fetal cardiovascular system. Whilst the benefits of maternal long chain omega-3 polyunsaturated fatty acids in development of the CNS have long been recognized (Uauy et al. 2001; Vingrys et al. 2001), the potential benefit to the developing cardiovascular system is relatively novel. Indeed, previous observations from the laboratory of one of the authors show that essential fatty acid deprivation during development in the rat is associated with subtle yet permanent changes in brain membrane fatty acid composition in adult offspring (Armitage et al. 2003) associated with a programmed increase in blood pressure of the offspring (Weisinger et al. 2001).
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Nutritional supply during suckling
The majority of the studies described above have not discriminated between the effects of the maternal diet during pregnancy or in the suckling period, as most protocols include provision of the diet to the dam until weaning. The maternal diet during the suckling period may, however, be crucial, because significant maturation occurs early in life. This is more marked in altricial species such as rats, that undergo rapid maturation of most organ systems after birth, but precocial species including humans, born at a more advanced stage of development are also prone to programming stimuli during the suckling period. Extended breast feeding in primates (Mott et al. 1990) and humans (Leeson et al. 2001), which would lead to prolonged ingestion of fat-rich milk in early life, is reported to lead to increased cardiovascular risk in later life. We have also reported that a maternal lard-rich diet during the suckling period alone leads to elevation of blood pressure, depressed endothelial function and abnormal glucose homeostasis in adult rat offspring (Khan et al. 2004a). In contrast to gestational intake, maternal energy intake during suckling is higher when dams are fed a lard-rich diet (Khan et al. 2003); it would seem that the energy homeostatic mechanism previously described does not apply during suckling. Therefore both increased gross energy and fat intake during this period may influence the phenotype of the offspring (Del Prado et al. 1997; Khan et al. 2003). The important influence of the sucking period is supported by other rodent studies, in which culling rat litters (typically to 4–6 pups from 10–16) increases milk availability per pup and results in offspring with dyslipidaemia (Hahn, 1984), hyperinsulinaemia, hyperleptinaemia, increased body mass index (BMI) and fat pad mass and an altered growth trajectory (Schmidt et al. 2001).
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By providing highly palatable semipurified diets high in fat and sugars, increased energy delivery together with increased food intake is achievable in rodents (Ozanne et al. 2004). ‘Cafeteria diets’, such as these have been used to study the effects of maternal obesity and gestational diabetes (Holemans et al. 2004) or as a postnatal diet in offspring that were subjected to prior under-nutrition (see later). The phenotype of the offspring from ‘cafeteria’-fed dams is yet to be investigated, but one might hypothesize a similar phenotype to that described for offspring of diabetic dams (Holemans et al. 1999).
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Predictive adaptive responses (PARs) and maternal nutritional excess
We (Khan et al. 2004b) have also reported supporting evidence for the existence of PARs in a maternal lard-feeding model in the rat. Offspring of Sprague-Dawley dams fed a lard-based diet during pregnancy and suckling and weaned on a control diet showed blunted endothelium-dependent dilatation and increased serum triglyceride and plasma glucose concentrations compared with offspring weaned onto the same fat-rich diet. This is a clear example of an appropriate PAR with regard to endothelial dilatation, glucose and triglyceride homeostasis. However, these rats still developed hypertension, obesity and hyperinsulinaemia suggesting that the predictive adaptive response was not appropriate with regard to the mechanisms responsible for the development of those parameters (Khan et al. 2004b). This discordance of PARs is not readily explainable and illustrates the need for further studies in order to better characterize and validate the theoretical framework.
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In another study, evidence to support the PARs hypothesis was reported in an experimental pig model. Sows were fed either a control or pro-atherogenic diet during pregnancy and suckling; then the piglets were fed either the same diet as their mother or crossed to the opposite diet. Pigs exposed to the atherogenic diet in utero appeared to be protected from the development of aortic fatty streaks when fed an atherogenic diet in postnatally, compared with those that were exposed to the control diet in utero and the atherogenic diet postnatally (Norman & LeVeen, 2001).
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As predicted by the PARs hypothesis, post-weaning hypercalorific intakes have been shown to have deleterious effects on animal cardiovascular health when superimposed upon prenatal nutrient restriction. Offspring of rats subject to calorie restriction during pregnancy demonstrated hypertension, hyperleptinaemia, hyperinsulinaemia, and increased retroperitoneal fat pad mass that was exacerbated by a postnatal cafeteria diet (Vickers et al. 2000). In another relevant study, Ozanne & Hales (2004) have reported shorter life-span in mice offspring of dams subject to protein restriction during pregnancy, worsened by postnatal cafeteria diet feeding (Ozanne & Hales, 2004). Whilst few studies have set out to investigate the role of carbohydrate loading in developmental programming, the protein-restricted diets are carbohydrate loaded to maintain energy yield, and the resultant increase in glycaemic index may compound the effects of protein restriction in the developing fetus.
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The role of neural circuits in programming of obesity in offspring
To date, the role of altered neuro-anatomy or neurochemistry in development of the phenotype in offspring of fat-fed dams has not been studied in the same detail as the role of peripheral organ function. However, insulin, raised in offspring of fat-fed dams (Taylor et al. 2005), and insulin-like growth factors, are thought to be pivotal to neuronal differentiation and synapse formation and consolidation in the hypothalamus (Plagemann et al. 1999a). Additionally, it is proposed that increased concentrations of insulin or neuropeptide Y acting at the arcuate nucleus of the hypothalamus, could result in ‘metabolic imprinting’ of neural circuits early in life and therefore increase the body weight homeostatic set-point, stimulate appetite and result in obesity in the offspring (Levin, 2000). A reduction in density of noradrenergic neurones in the hypothalamic paraventricular nucleus has also been found in obese offspring of obese rat dams (Levin, 2000). Our studies suggest that altered basal metabolic activity, rather than changes in central regulation of appetite, occur in obese offspring of fat-fed rats (Khan et al. 2003; Taylor et al. 2005). However, there is evidence to support a role for altered CNS function and hypothalamic insulin concentration in over-fed neonatal rats that grow up to demonstrate a metabolic syndrome-like phenotype (Plagemann et al. 1999b).
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Conclusions
In summary, maternal over-nutrition is a stimulus to the programming of metabolic syndrome-like characteristics in adult rat offspring. There is growing evidence that fat intake per se does not predict phenotype, but that saturated fatty acid intake is deleterious. Both the brain and peripheral organs appear to be affected. Inappropriate PARs appear to result in disease when the nutritional plane was predicted to be low in utero but was high in the postnatal period and there is some evidence to support PARs in the situation of maternal nutritional excess. Experiments focusing on maternal over-nutrition in pregnancy and in the offspring will provide data applicable to the dietary habits in the Western world. Maternal restriction followed by adult over-nutrition offers a model in which to study the conditions seen more often in developing nations, immigrant populations and as a consequence of in utero growth restriction from placental disease. The PARs hypothesis unifies both of these scenarios and detailed investigations as to the acceptable range of dietary intake are required and will enable us to move closer towards providing meaningful dietary advice in humans.
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Abstract
Studies in both humans and experimental animals addressing the ‘Fetal Origins of Adult Disease’ hypothesis have established a relationship between an adverse intrauterine environment and offspring disease in adult life. This phenomenon, termed ‘fetal programming’ describes a process whereby a stimulus in utero establishes a permanent response in the fetus leading to enhanced susceptibility to later disease. However, the environment, during periods of developmental plasticity in postnatal life, can also ‘programme’ function. Thus, the terms ‘developmental programming’ and the ‘Developmental Origins of Adult Health and Disease’ are preferentially utilized. The ‘Thrifty Phenotype’ hypothesis explained the association between insufficient in utero nutrition and the later development of Type 2 diabetes. Most recently the ‘Predictive Adaptive Response’ hypothesis proposes that the degree of mismatch between the pre- and postnatal environments is an important determinant of subsequent disease. Epidemiological studies have indicated that fetal growth restriction correlates with later disease, implying that fetal nutritional deprivation is a strong programming stimulus. This prompted the development of experimental animal models using controlled maternal calorie, protein or macronutrient deficiency during key periods of gestation. However, in many societies, maternal and postnatal nutrition are either sufficient or excessive. Here, we examine findings from a range of nutritional studies examining maternal and/or postnatal nutritional excess. There is supportive evidence from a limited number of studies to test the ‘Predictive Adaptive Response’ hypothesis. These suggest that maternal over-nutrition is deleterious to the health of offspring and can result in a phenotype of the offspring that is characteristic of metabolic syndrome.
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Introduction
Obesity is increasing to epidemic proportions in human populations. In the USA 20.9% of the total population have a body mass index > 30 (Mokdad et al. 2003). This is explained in part by excessive fat intake in most western diets: in 2001 the European average was 32.1% of calorie intake from all fat (Office for National Statistics UK, 2003) and in the UK, women of average childbearing age (24–35 years) consumed 35.4% of calories from fat, of which saturated fats accounted for 13.2% of energy (Office for National Statistics UK, 2003). More and more women are therefore obese and consuming a calorific or fat-rich diet when pregnant. Other than the immediate risk to the mother's health and to pregnancy outcome, for example the increased risk of gestational diabetes and pre-eclampsia (Ostlund et al. 2004), there are other potential consequences. In particular, there is increasing evidence, predominantly from studies in animals, to suggest that the fetus may be prone to development of cardiovascular disease in later life through exposure to the excesses of maternal nutrition. This short review summarizes the literature which is supportive of this hypothesis.
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Historical perspective from fetal origins to predictive adaptive responses
The contribution of maternal nutrition to the fetal origins hypothesis (Barker, 1997) has been studied extensively in both human populations and in experimental animals. Earlier studies focused on the effect of under-nutrition, and the association of smallness at birth and later adult cardiovascular disease (Osmond & Barker, 2000). The ‘Thrifty Phenotype’ hypothesis proposed that poor nutrition in utero led to fetal adaptations that produced permanent changes in insulin and glucose metabolism, thus increasing the risk of adult Type 2 diabetes and the metabolic syndrome (Hales & Barker, 2001). Although well supported by maternal nutrient restriction studies, that reported altered pancreatic morphology and function (Snoeck et al. 1990) and insulin homeostasis (Hales & Barker, 2001), this hypothesis did not provide a mechanism for altered function of adult offspring following maternal over-nutrition.
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Extending upon the ‘Thrifty Phenotype’ hypothesis, the ‘Predictive Adaptive Response’ hypothesis (Gluckman & Hanson, 2004a, b, c) proposes that the fetus makes adaptations in utero (or in the early postnatal developmental period) based on the predicted postnatal environment. When this predictive adaptive response (PAR) is appropriate, the phenotype is normal; however, where mismatch occurs between the predicted and actual environment, disease manifests. Unlike previous programming hypotheses, it contends that in response to a given in utero or early postnatal nutritional plane (either high or low), cellular processes are tuned to cope with the predicted environment and that these adaptations are not necessarily advantageous in utero. Thus it is proposed that disease only manifests when the actual adult diet diverges from this plane to which the fetus has ‘predicted’. This is an intriguing concept and one supported by the small number of studies to have directly addressed the hypothesis.
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Evidence from population based studies for developmental programming through maternal dietary excess
Few studies have directly assessed the relationship between maternal over-nutrition and cardiovascular phenotype of the offspring. In a post-mortem study from an Italian population, Napoli et al. have demonstrated that fetuses and children born to hypercholesterolaemic mothers exhibit accelerated development of fatty streaks in the aorta (Napoli et al. 1997, 1999). The study did not ascertain whether this was attributable to familial hypercholesterolaemia and maternal dietary intake was not known; therefore we may only assume that mothers were hypercholesterolaemic due to dietary intake of fat rather than altered fat metabolism. Another study from a Scottish cohort suggested programming of raised blood pressure and perturbed glucose homeostasis in adult offspring of women who consumed a high carbohydrate : protein ratio in the diet (Campbell et al. 1996; Shiell et al. 2000). Indirectly, and potentially of relevance through diet and obesity, there is overwhelming evidence from studies of Pima Indians to suggest that women who have diabetes in pregnancy are likely to convey a predisposition to insulin resistance in their children (Pettitt et al. 1988).
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Evidence from animal studies for developmental programming through maternal nutritional excess
Whilst deprivation studies are relatively straightforward in experimental rodent models, delivery of supranormal nutrition is not, as rodents demonstrate a robust homeostatic regulation of food intake and energy expenditure to maintain body weight (Keesey & Hirvonen, 1997). Leptin and insulin are known peripheral signalling moieties that target hypothalamic regulatory sites that lead to appetite modulation (Keesey & Hirvonen, 1997; Hellstrom et al. 2004). The existence of a ‘body weight set-point’ in rodents and humans is established, whereby body weight reduction or increase is corrected by altered food intake and energy expenditure to defend the target body weight (Keesey & Hirvonen, 1997).
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Pregnant rats fed a fat-rich but normal carbohydrate diet reduce their intake of energy-dense diet to maintain similar calorie intake compared with controls, but derive more calories from fat (Guo & Jen, 1995; Langley-Evans, 1996; Del Prado et al. 1997; Taylor et al. 2003). Thus, it is likely that the phenotype of offspring from fat-fed dams is determined by increased exposure to the dietary fat rather than maternal energy intake per se.
Maternal high-fat or cholesterol over-feeding during pregnancy and lactation in rodents results in a phenotype of the offspring that closely resembles the human metabolic syndrome (Armitage et al. 2004b). Abnormal glucose homeostasis (Guo & Jen, 1995; Taylor et al. 2005), increased blood pressure (Langley-Evans, 1996; Khan et al. 2003), abnormal serum lipid profiles (Karnik et al. 1989; Guo & Jen, 1995; Khan et al. 2003), increased adiposity (Guo & Jen, 1995; Khan et al. 2004a) pro-atherogenic lesions (Palinski et al. 2001), reduced acetylcholine-induced vasodilatation (Khan et al. 2004a,b; Taylor et al. 2004) and hyperleptinaemia (Taylor et al. 2005) have all been reported.
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The cellular or molecular mechanisms that underlie the phenotype arising from maternal nutritional excess are under increasing scrutiny and will facilitate a fuller understanding of cardiovascular disease aetiology. Microarray gene expression studies of aortas from offspring of lard-fed rats reveal alterations (2-fold or greater) in the expression of over 200 genomic and mitochondrial-specific mRNA sequences, compared with that of control offspring (Taylor et al. 2005). Genes altered by exposure to maternal lard-rich diets included those encoding for collagen and elastin, endothelial and inducible nitric oxide synthase (Armitage et al. 2004a) and a reduction in mitochondrial copy number (Taylor et al. 2005). Similar studies have been carried out in aortas from offspring of LDL receptor knockout mice. Compared with offspring from control-fed dams, the offspring of high-cholesterol-fed LDL receptor knockout mice demonstrated altered expression of over 130 genes encoding for proteins involved in mitochondrial function, extracellular matrix function, the oestrogen-related receptor, cytokine signalling and antioxidant defence (Napoli et al. 2002). In addition to the gene array studies that suggest alterations to the expression of mitochondrial genome encoded proteins, we have also shown reductions in mitochondrial copy number in kidneys from offspring of lard-fed dams, compared with control offspring (Taylor et al. 2005).
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The hyperinsulinaemia and hyperglycaemia observed in adult offspring of lard-fed rat dams is accompanied by reduced whole body insulin sensitivity, impaired pancreatic cell insulin secretion and pancreatic ultrastructural changes (Taylor et al. 2005) suggesting that islet cell exhaustion occurs due to high insulin demand secondary to skeletal muscle insulin insensitivity. This is consistent with observations from animal models of mild maternal diabetes, in which perinatal hyperinsulinaemia, due to hypertrophy of the endocrine pancreas, results in impaired pancreatic function and glucose tolerance in the adult (Van Assche et al. 2001). Indeed, fat-feeding during pregnancy produces maternal hyperinsulinaemia that may contribute to the programming stimulus in this model (Taylor et al. 2003).
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Blood pressure changes in female offspring of lard-fed rat dams appear to be linked to altered baroreceptor sensitivity in offspring and not to small artery endothelial dysfunction (Khan et al. 2003). Male offspring of coconut oil (saturated fat)-fed rats demonstrate increased blood pressure but do not show evidence of altered hypothalamic-pituitary-adrenal axis (HPA) axis activation (Langley-Evans, 1996), suggesting that HPA hyperactivity, associated with hypertension in offspring of protein-deprived rats, is not involved in elevation of the blood pressure in offspring of fat-fed dams.
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The blunted endothelial-dependent vasodilatation observed in small mesenteric arteries from offspring of lard-fed dams appears to be underpinned by a reduction in endothelial-derived hyperpolarizing factor (EDHF) rather than a nitric oxide or prostacyclin deficit (Taylor et al. 2004). The reduced arachidonic acid and docosahexaenoic concentrations that we have observed in aortas from offspring of lard-fed dams (Ghosh et al. 2001) may underlie the EDHF defect as these fatty acids are precursors of a putative EDHF.
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There is no evidence for hyperphagia, or reduced locomotor activity (Khan et al. 2003) in offspring of lard-fed rat dams, therefore increased body mass and adiposity that we have reported (Khan et al. 2003) may be maintained by reduced basal metabolic activity. This would be compatible with the reduced mitochondrial copy number that we have reported in the kidney in this model (Taylor et al. 2005).
Either the high fat intake per se or the ingestion of specific fatty acids is likely to be responsible for the development of the phenotype of the offspring. Maternal high-saturated-fat intake (from coconut oil) results in offspring with pancreatic cell loss and glucose intolerance by oral glucose tolerance test. However, raised maternal polyunsaturated fatty acid intake (from fish oil) did not perturb the phenotype of the offspring compared with controls (Siemelink et al. 2002). Moreover, in a recent study we have shown that blood pressure in offspring of high polyunsaturated-fat-fed rats (25% corn oil) is 20 mmHg lower than that of offspring of saturated-fat (20% palm oil + 5% corn oil)-fed rats (Jensen et al. 2004). Taken together, these studies suggest that it is the saturated fatty acid component of the lard-rich diet which is deleterious to the offspring, and also imply that maternal polyunsaturated fatty acids may be of benefit in the development of the fetal cardiovascular system. Whilst the benefits of maternal long chain omega-3 polyunsaturated fatty acids in development of the CNS have long been recognized (Uauy et al. 2001; Vingrys et al. 2001), the potential benefit to the developing cardiovascular system is relatively novel. Indeed, previous observations from the laboratory of one of the authors show that essential fatty acid deprivation during development in the rat is associated with subtle yet permanent changes in brain membrane fatty acid composition in adult offspring (Armitage et al. 2003) associated with a programmed increase in blood pressure of the offspring (Weisinger et al. 2001).
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Nutritional supply during suckling
The majority of the studies described above have not discriminated between the effects of the maternal diet during pregnancy or in the suckling period, as most protocols include provision of the diet to the dam until weaning. The maternal diet during the suckling period may, however, be crucial, because significant maturation occurs early in life. This is more marked in altricial species such as rats, that undergo rapid maturation of most organ systems after birth, but precocial species including humans, born at a more advanced stage of development are also prone to programming stimuli during the suckling period. Extended breast feeding in primates (Mott et al. 1990) and humans (Leeson et al. 2001), which would lead to prolonged ingestion of fat-rich milk in early life, is reported to lead to increased cardiovascular risk in later life. We have also reported that a maternal lard-rich diet during the suckling period alone leads to elevation of blood pressure, depressed endothelial function and abnormal glucose homeostasis in adult rat offspring (Khan et al. 2004a). In contrast to gestational intake, maternal energy intake during suckling is higher when dams are fed a lard-rich diet (Khan et al. 2003); it would seem that the energy homeostatic mechanism previously described does not apply during suckling. Therefore both increased gross energy and fat intake during this period may influence the phenotype of the offspring (Del Prado et al. 1997; Khan et al. 2003). The important influence of the sucking period is supported by other rodent studies, in which culling rat litters (typically to 4–6 pups from 10–16) increases milk availability per pup and results in offspring with dyslipidaemia (Hahn, 1984), hyperinsulinaemia, hyperleptinaemia, increased body mass index (BMI) and fat pad mass and an altered growth trajectory (Schmidt et al. 2001).
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By providing highly palatable semipurified diets high in fat and sugars, increased energy delivery together with increased food intake is achievable in rodents (Ozanne et al. 2004). ‘Cafeteria diets’, such as these have been used to study the effects of maternal obesity and gestational diabetes (Holemans et al. 2004) or as a postnatal diet in offspring that were subjected to prior under-nutrition (see later). The phenotype of the offspring from ‘cafeteria’-fed dams is yet to be investigated, but one might hypothesize a similar phenotype to that described for offspring of diabetic dams (Holemans et al. 1999).
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Predictive adaptive responses (PARs) and maternal nutritional excess
We (Khan et al. 2004b) have also reported supporting evidence for the existence of PARs in a maternal lard-feeding model in the rat. Offspring of Sprague-Dawley dams fed a lard-based diet during pregnancy and suckling and weaned on a control diet showed blunted endothelium-dependent dilatation and increased serum triglyceride and plasma glucose concentrations compared with offspring weaned onto the same fat-rich diet. This is a clear example of an appropriate PAR with regard to endothelial dilatation, glucose and triglyceride homeostasis. However, these rats still developed hypertension, obesity and hyperinsulinaemia suggesting that the predictive adaptive response was not appropriate with regard to the mechanisms responsible for the development of those parameters (Khan et al. 2004b). This discordance of PARs is not readily explainable and illustrates the need for further studies in order to better characterize and validate the theoretical framework.
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In another study, evidence to support the PARs hypothesis was reported in an experimental pig model. Sows were fed either a control or pro-atherogenic diet during pregnancy and suckling; then the piglets were fed either the same diet as their mother or crossed to the opposite diet. Pigs exposed to the atherogenic diet in utero appeared to be protected from the development of aortic fatty streaks when fed an atherogenic diet in postnatally, compared with those that were exposed to the control diet in utero and the atherogenic diet postnatally (Norman & LeVeen, 2001).
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As predicted by the PARs hypothesis, post-weaning hypercalorific intakes have been shown to have deleterious effects on animal cardiovascular health when superimposed upon prenatal nutrient restriction. Offspring of rats subject to calorie restriction during pregnancy demonstrated hypertension, hyperleptinaemia, hyperinsulinaemia, and increased retroperitoneal fat pad mass that was exacerbated by a postnatal cafeteria diet (Vickers et al. 2000). In another relevant study, Ozanne & Hales (2004) have reported shorter life-span in mice offspring of dams subject to protein restriction during pregnancy, worsened by postnatal cafeteria diet feeding (Ozanne & Hales, 2004). Whilst few studies have set out to investigate the role of carbohydrate loading in developmental programming, the protein-restricted diets are carbohydrate loaded to maintain energy yield, and the resultant increase in glycaemic index may compound the effects of protein restriction in the developing fetus.
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The role of neural circuits in programming of obesity in offspring
To date, the role of altered neuro-anatomy or neurochemistry in development of the phenotype in offspring of fat-fed dams has not been studied in the same detail as the role of peripheral organ function. However, insulin, raised in offspring of fat-fed dams (Taylor et al. 2005), and insulin-like growth factors, are thought to be pivotal to neuronal differentiation and synapse formation and consolidation in the hypothalamus (Plagemann et al. 1999a). Additionally, it is proposed that increased concentrations of insulin or neuropeptide Y acting at the arcuate nucleus of the hypothalamus, could result in ‘metabolic imprinting’ of neural circuits early in life and therefore increase the body weight homeostatic set-point, stimulate appetite and result in obesity in the offspring (Levin, 2000). A reduction in density of noradrenergic neurones in the hypothalamic paraventricular nucleus has also been found in obese offspring of obese rat dams (Levin, 2000). Our studies suggest that altered basal metabolic activity, rather than changes in central regulation of appetite, occur in obese offspring of fat-fed rats (Khan et al. 2003; Taylor et al. 2005). However, there is evidence to support a role for altered CNS function and hypothalamic insulin concentration in over-fed neonatal rats that grow up to demonstrate a metabolic syndrome-like phenotype (Plagemann et al. 1999b).
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Conclusions
In summary, maternal over-nutrition is a stimulus to the programming of metabolic syndrome-like characteristics in adult rat offspring. There is growing evidence that fat intake per se does not predict phenotype, but that saturated fatty acid intake is deleterious. Both the brain and peripheral organs appear to be affected. Inappropriate PARs appear to result in disease when the nutritional plane was predicted to be low in utero but was high in the postnatal period and there is some evidence to support PARs in the situation of maternal nutritional excess. Experiments focusing on maternal over-nutrition in pregnancy and in the offspring will provide data applicable to the dietary habits in the Western world. Maternal restriction followed by adult over-nutrition offers a model in which to study the conditions seen more often in developing nations, immigrant populations and as a consequence of in utero growth restriction from placental disease. The PARs hypothesis unifies both of these scenarios and detailed investigations as to the acceptable range of dietary intake are required and will enable us to move closer towards providing meaningful dietary advice in humans.
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