Paper | Published:

Programming of obesity and cardiovascular disease

International Journal of Obesity volume 28, pages S46S53 (2004) | Download Citation

Subjects

Abstract

BACKGROUND: There is evidence that malnutrition in early life induces a growth retardation leading, in adult life, to manifest components of the metabolic syndrome. However, the impact on obesity seems less clearly established.

OBJECTIVE: To review the effects of foetal and postnatal malnutrition on the programming of obesity in the context of the metabolic syndrome, as well as the link between central obesity and cardiovascular diseases.

METHODS: Included in the review were recent papers exploring the mechanisms linking maternal nutrition with impaired foetal growth and later obesity, cardiovascular disease, hypertension and diabetes in humans and animals.

RESULTS: The programming of obesity during foetal and early postnatal life depends of the timing of maternal malnutrition as well as the postnatal environment. Obesity arises principally in offspring submitted to malnutrition during early stages of gestation and which presented early catch-up growth. The programming may involve the dysregulation of appetite control or the hormonal environment leading to a context favourable to obesity development (hypersecretion of corticosteroids, hyperinsulinaemia and hyperleptinaemia and anomalies in the IGF axis). Adipose tissue secretes actively several factors implicated in inflammation, blood pressure, coagulation and fibrinolysis. The programmed development of intra-abdominal obesity after early growth restriction may thus favour higher prevalence of hypertension and cardiovascular diseases.

CONCLUSIONS: Abdominal obesity appears in malnourished offspring and is aggravated by early catch-up growth. Higher rates of intra-abdominal obesity observed after growth restriction may participate to hypertension and create atherothrombotic conditions leading to the development of cardiovascular diseases.

Introduction

A foetal or perinatal origin of adult disease is hypothesised to contribute to the explosive epidemic of the metabolic syndrome. Solid relations have been established between rate of early growth and the development of glucose intolerance, insulin resistance and hypertension. Animal models are available that are helping to elucidate cellular and molecular mechanisms implicated in these relationships. As far as obesity is concerned, a recent European Commission Obesity Workshop highlighted the need to prove or disprove a perinatal link to obesity, along with the critical time windows and mechanisms of programming.1 The purpose of this overview is to examine in recent data of the literature the progress that has been made in this matter. We shall focus on the effects of the early nutritional environment of the foetus and neonate on the susceptibility to develop obesity in the context of the metabolic syndrome, as well as the link between central obesity and cardiovascular diseases.

The programming of the metabolic syndrome

The metabolic syndrome or syndrome X consists in a cluster of metabolic abnormalities including raised blood pressure, atherogenic dyslipidaemia, glucose intolerance and insulin resistance. The metabolic syndrome culminates in the development of diabetes, central obesity and cardiovascular disease. It is increasingly common in the world and it is anticipated that the syndrome will become an epidemic in the next 20 y. The surprising explosive increase in occurrence of the metabolic syndrome indicates that the pathogenesis is not based on genetic defects (the thrifty genotype), albeit they may amplify it, but on environmental causes like change in postnatal habits and also as an adaptation during early development.

The important and fruitful concept of a foetal origin of the metabolic syndrome started originally from human epidemiological studies. A decisive step has been the study of a population born in Hertfordshire for which the birth weight data were available, and which showed an increased death rate from ischaemic heart disease, impaired glucose tolerance and noninsulin-dependent diabetes in men with low birth weight and weight at 1 y of age.2, 3 Since these original descriptions, the findings of relationships between birth weight or thinness at birth and later development of components of the metabolic syndrome have been replicated in a variety of populations around the world.4

In order to explain such correlations, the Thrifty Phenotype hypothesis has been proposed.5 It postulates that a nutritionally deprived foetus adapts two strategies to ensure survival. First, the foetus diverts nutrients to critical organs such as the brain at the expense of peripheral tissues such as muscle. Second, metabolic adaptations occur that maximise the chances of survival under poor nutrition, but they become detrimental in case of normal or plentiful nutrition. This programming may then lead to the metabolic syndrome in adult life. In a more global way, the Early Programming hypothesis proposes that a stimulus or insult acting during critical periods of growth and development may permanently alter tissue structure and function.

The widening of the hypothesis in explaining the facilitation of adult degenerative diseases is necessitated by several facts. Not only does foetal exposure to malnutrition need to be considered but also the postnatal development. For example, after foetal undernutrition, if a period of early catch-up growth due to abundance of nutrients gives opposite information to the developing newborn, the metabolic conflict may dramatically modify the programming.6 According the tissue or organ, the time of maximal effect of the input on early programming may be different, defining the concept of critical windows, as is well known, in another context, for the differential vulnerability of different organs to teratogens. Finally, not only bulk undernutrition may predispose to metabolic anomalies but also overnutrition, as in the case of gestational diabetes or high-fat diet, and even changes in specific food components.

From a biological point of view, the concept of early programming of adult disease is not surprising. Starting from the zygote, the growth and development of the organism involves cell proliferation, and then a proportion of cells undergo usually several steps of commitment, which progressively restrict the variety of the differentiation potential. Mitotic runs accompany these commitments. The lineage then evolves towards a differentiated, functional state, either definitely or reversibly. During development, not only cell divisions and differentiation occur but also programmed cell death that suppresses unnecessary cells or cells with damaged DNA. During that period of coordinated growth and progressive acquiring of function, it may be expected that alterations of the milieu would have permanent consequences. They would indeed modify pools of precursors, changing the future potentiality of the organ.

Animal models support the concept and have the potentiality to explain the mechanisms of programming

Experimental research in animals supports these notions of causal link between malnutrition or adverse events in utero and early life, leading to alterations in foetal growth and increased risk of chronic degenerative diseases. Mechanistic studies aimed at determining the key factors involved in these correlations are obviously impossible in humans. However, we need to know how nutrition programmes the structure and functions of the organs, and ultimately by what molecular mechanisms nutrients alter gene expression. Therefore, models of maternal malnutrition in rodent have been established as the major paradigm for finding mechanisms of early programming of adult disease. Sheep having the advantage of exhibiting similar rates of pre- and postnatal growth as humans and producing one or two offspring of 3–6 kg, the same as in human, has also been used and to a lesser extent, guinea pig and non-human primates.

Different modes of malnutrition occurring during different periods of development were set up: calorie restriction, protein restriction, uterine artery ligation, gestational diabetes and high-fat diet were the most used. In each model, alterations in organ development were observed and later consequences for the health of the progeny were reported. Detailed information can be found elsewhere.7, 8, 9, 10 Only selected examples will be cited here to illustrate the relevance of rodent models of foetal undernutrition.

Maternal low protein models of foetal programming have been used to investigate the mechanisms linking maternal nutrition with impaired foetal growth and later cardiovascular disease, hypertension and diabetes. Depending on the source of carbohydrate, fat content, fatty acid composition and methionine, hypertension was observed at adulthood or not.11, 12 If the low protein diet was restricted to the preimplantation period,13 hypertension was also observed.

Proteins play a key role in the development of the islets of Langherhans in utero. Foetuses and neonates from dams fed 8% protein instead of 20% exhibited a poor development of the endocrine pancreas including its vascularisation, β-cell mass being reduced due to lower proliferation rate, more apoptosis and less insulin-like growth factors (IGFs).14 Islet insulin secretion was reduced at least by 50% in response to different secretagogues.15 Despite feeding the animals with a normal diet after weaning, the adult offspring showed a lower plasma insulin level and insulin secretion after glucose challenge.16 A maternal low protein diet also induced changes in zonation and enzyme activity in the liver of the pups that was not restored at adulthood even when the animals were fed a normal diet. An increased sensitivity of peripheral organs to insulin was observed in young adulthood, but which deteriorated, and the insulin resistance appeared in later life.17

Calorie restriction during pregnancy in rat led to similar results. When giving 50% of ad libitum intake the last week of pregnancy, the β-cell mass was also reduced, insulin secretion was blunted at 3 months and glucose intolerance appeared later.18 More severe maternal undernutrition throughout pregnancy in rat results in obesity, hypertension, hyperinsulinaemia and hyperleptinaemia in the offspring when they reach adulthood.19, 20 These two models of protein- and calorie-restriction highlighted also that the lasting consequences are not limited to the first generation, but persist in the next generation. The offspring malnourished in early life becoming pregnant manifest metabolic anomalies giving its foetuses again an altered intrauterine environment.

Foetal malnutrition as a consequence of uteroplacental insufficiency also programmes the development of the endocrine pancreas and the glucose metabolism later in life. Bilateral uterine artery ligation mimics that situation. The adult offspring develops glucose intolerance and insulin resistance, as well as obesity at a later stage,21 but contrasting to the majority of other animal models, this treatment was not associated with hypertension.22

It is thus obvious that these and others animal models are needed to reveal the specific mechanism by which foetomaternal nutrition leads to degenerative disease in order to pave the way for simple nutritional preventive intervention.

The programming of obesity

The relation between foetal growth and obesity in later life is a complicated one.23, 24 Several studies showed that people who were heavy at birth or at 1 y of age tended to be slightly more obese as adults, as measured by body mass index (BMI).24, 25 The Pima Indians study proposes another example of programming, in which intrauterine diabetic environment confers risks for childhood and adult obesity in the offspring, independently of birth weight.26 Alternatively, there are also indications that those who were light as babies tended to have a more truncal or abdominal fat distribution as adults, independently of overall fatness.23, 24 In the same line, maternal smoking during pregnancy is associated with childhood27 and adolescence obesity, probably linked to the lighter weight at birth.28 Finally, some studies report a J- or U-shaped relation, with a higher prevalence of obesity seen for the lowest and highest birth weights.23, 24

It is true that there seems less evidence that the development of obesity is itself a manifestation of the thrifty phenotype, at least with regard to the effects of foetal and early-life programming, which are less strong in terms of adiposity than might be expected given the evidence of other metabolic changes. This observation might be explained by the fact that obesity is a highly multifactorial syndrome in which social, behavioural and environmental influences might over-ride some of the underlying metabolic pressures entrained as part of the thrifty phenotype.29

The difficulty in highlighting the relation to low birth weight and obesity is illustrated for instance by the epidemiological studies on the offspring of the Dutch Famine in 1944–1945, which support the hypothesis of components of the metabolic syndrome like glucose intolerance, atherogenic lipid profile and frequency of coronary heart disease having a possible origin in utero due to undernutrition. It revealed a subordination upon its timing during gestation and on the tissues and systems undergoing critical periods of development at that time.30 However, the relation with obesity is less clear. In this cohort, Ravelli et al31 demonstrated an association between maternal malnutrition during early gestation and higher BMI and waist circumference in 50-y-old women, but not in men, although this association had been previously demonstrated in young men in the same cohort.32 Such an association between prenatal exposure to famine and obesity was not detected in subjects born in Leningrad during the Siege in 1941–1944, which may indicate the importance of catch-up growth during early childhood, a situation that occurred in the Netherlands but not in Leningrad.33 A catch-up growth experienced between birth and 2 y of age, in infants who were growth restricted in utero, increases their fatness and the central fat deposition at 5 y.6 Clearly, the distribution of fat must be considered, as for example in Jamaica, children stunted in early childhood had less fat and lower BMI than nonstunted children, but had more central fat distribution that was partially explained by their lower birth weights.34

The importance of catch-up growth also appears in the data from studies in India.35 For a given BMI, Indians have a higher percentage of body fat and more visceral fat than members of other populations. This thin-fat phenotype due to poor muscle and small abdominal viscera is present at birth. Accelerated childhood growth seems a risk factor for adiposity and insulin resistance, especially in children born small. Adolescents are old enough for the amplification of programming effects but not so old as to incur a large contribution of lifestyle factors. In United Kingdom, a study in adolescents suggested that low birth weight programs in fact a smaller proportion of lean mass rather than fat mass later in life.36 This would result from viscera and muscle sacrifice in case of undernutrition. Therefore, ensuing lower metabolic activity in adolescents could in the presence of an energy-dense diet, predispose to greater adiposity later in life in the adults of low birth weight.

Recently, based on animal studies that will be described in the next section, it has been proposed that unnoticed changes in fatty acid composition of ingested fats over the last decades could be important determinants in the increasing prevalence of childhood overweight and obesity.37 An overconsumption of n-6 polyunsaturated fatty acids (PUFA), in association with a high linoleic acid/linolenic acid ratio, may indeed favour the adipogenesis during the dynamic phase of pregnancy-lactation. The increased size of precursor pools may subsequently lead to children and adult obesity owing to continuous intake of the n-6 PUFA-enriched diets.

Thus, many different possible factors may induce an early programming of obesity, such as global nutrition or specific food components like sugar, fatty acids, or placental deficiencies, smoking, etc. In addition, the programming may occur at different levels: appetite regulation, creation of a hormonal context favourable to obesity and genesis of an altered population of fat cell precursors. Since experiments in that matter are obviously impossible in humans, animal studies are needed to solve that complexity.

Animal models for programming of obesity

The offspring of protein malnourished rats features obvious modifications in (central) adipocytes metabolism: increased insulin receptor expression, higher glucose uptake and utilisation in response to hyperinsulinaemia, but selective resistance to the antilipolytic action of insulin, which can be related to different expression or activity of molecules of the insulin stimulation pathways like the catalytic subunit of PI 3-kinase and protein kinase B.38, 39 Despite such anomalies, the demonstration that the low protein diet favours the later development of obesity in rat has been rather elusive. Even after giving high-fat high-sucrose ‘cafeteria’ diet, the low protein progeny does not appear to become more obese than rats that were fed normally in utero.38, 40 In mice however, offspring of dams fed a low protein diet during pregnancy and caught up during lactation by nursing by control dams gained more weight when given free access to a cafeteria diet.41 Our recent results (unpublished data) underline the importance of an early catch-up growth after intrauterine nutrient shortage, since in these conditions, rats develop a higher obesity rate than controls, both after protein or calorie restriction, whereas they do not in the absence of rapid catch-up growth.

Another rat model, in which severe maternal calorie restriction is applied throughout gestation and followed by nursing by normal dams, provokes profound adult hyperphagia. Programmed offspring also develops obesity, hyperinsulinism, hyperleptinaemia, hypertension during adult life, and postnatal hypercaloric nutrition amplifies the metabolic anomalies induced by programming.42 A similar pattern has been observed in another model in which catch-up growth of nutrient-restricted foetuses was induced during the last week of rat gestation.43, 44 In sheep, maternal nutrient restriction over the period of rapid placental growth followed by restoration of maternal nutrition over the second half of gestation enhances the adipose tissue development at the end of gestation, which was thought to increase the risk of obesity in later life.45 However, this does not lead to significant increase in adipose and fat mass at adulthood.46

Bilateral uterine artery ligation performed on day 19 of gestation in rat leads to intrauterine growth retardation (IUGR). In this model, IUGR offspring remained growth retarded until 7 weeks after birth, after which they began to recover a normal body weight. They developed marked fasting hyperglycaemia and hyperinsulinaemia at 10 weeks that deteriorated into glucose intolerance and insulin resistance at 15 weeks. By 26 weeks of age, the IUGR rats were obese.21 This model shows that growth restriction even late in gestation may induce obesity at adulthood.

Still another model of obesity programming is the mice fed high-fat diet rich in linoleic acid, a precursor of arachidonic acid, during the pregnancy and lactation. The adult progeny featured a higher weight and adiposity in the group fed linoleic acid than in animals fed other mixture of fat containing both n-3 and n-6 fatty acids, while prostacyclin receptor-deficient mice did not show this effect, which then is suspected to be produced by this pathway.47

Three programming pathways for obesity: appetite regulation, hormonal context and fat cell precursors

In humans, programming of obesity may be consistent with perturbations of appetite regulation, but there is no causal demonstration yet. Rats programmed by maternal calorie restriction have an elevated food intake at an early postnatal age.42 Among the variety of appetite-stimulating or -suppressing hormones and neurotransmitters, leptin is a candidate deserving interest. Hyperleptinaemia and hyperinsulinism have been linked with leptin resistance at the level both of the hypothalamus and the pancreatic β cell. A permanent dysregulation of the adipoinsular feedback system, leading to prolonged elevation of plasma leptin and insulin concentrations, is suggested in this rat model.19 This defect as well as alterations in hypothalamic circuitry induced by programming may be restored by IGF-1 administration in adults.20 In human, low leptin levels in cord blood closely reflected decreased adiposity at birth and strongly predicted high rates of weight gain in infancy and catch-up growth.48

Growth restriction in utero may lead to permanent changes in hormonal status that may confer a propensity to develop obesity. Although the nature of the endocrine adaptations that underlie this long-term effect of malnutrition are poorly understood, one may highlight in addition to leptin evoked just above, three main changes: the glucocorticoid axis, insulin and the IGF axis.

A number of observations indicate an involvement in obesity of the hypothalamo-pituitary-adrenal (HPA) axis.49 Preliminary human studies have shown an inverse association between birth weight and both basal cortisol and adrenal responsivity to ACTH in adults.50 Animal models show that exposure to a variety of stressors during pregnancy, including malnutrition, also results in the birth of offspring with elevated basal or stress-induced glucocorticoids. Increased corticosterone levels found in foetuses of calorie-51 or protein-restricted52 rats have been implicated in growth retardation and disturb the development of the HPA axis. Foetal growth retardation and its consequences in case of maternal protein restriction may occur however without overexposure to glucocorticoids.53 One mechanism supposed to participate to the high level of foetal glucocorticoids is the downregulation of 11β-hydroxysteroid dehydrogenase gene expression, an enzyme that inactivates the maternal physiological glucocorticoids during their passage across the placenta.51 Programming of the HPA axis has been linked to permanent changes in hippocampal corticosteroid receptor populations, reducing glucocorticoid feedback in this area.54 Hypertension, hyperglycaemia and impaired glucose tolerance may be consequences of this programming, as well as a facilitation to develop obesity.

Glucose intolerance and diabetes are obviously a major facet of foetal programming highlighted by epidemiological studies. The link of insulin production and activity with obesity is supported in a few animal experiments. As described above, in offspring of calorie-restricted dams,42 obesity is accompanied by hyperinsulinism. Adipocytes isolated from young adult low protein offspring feature changes in metabolism that render the response to insulin favourable to fat accumulation.38, 39

IGFs are among the most important regulators of growth, and together with insulin, of the partition to lean mass. IGF axis has been poorly studied in models of IUGR. Calorie restriction has been found to either decrease or not IGF levels at birth and to increase or not IGF binding proteins (IGFBPs).55, 56 Protein restriction decreased plasma IGF-1 levels in the progeny at birth,57, 58 as well as augmented the abundance of IGFBP-1 and -2, the liver production of which being regulated in part by insulin and glucocorticoids.58

A third pathway of generating obesity in children and adult is a modification in the population of fat cell precursors. If an enlargement of the adipose cell due to fat accumulation may contribute to obesity, the multiplication and differentiation of precursor cells has a much greater influence. These cells are unfortunately present throughout life, but the size of the pools of cells at different steps of commitment in the lineage are not known since there are no markers for their identification. Early age is supposed to be a period very sensitive to nutritional or hormonal factors susceptible to modulate the fat cell precursors multiplication and (pre)differentiation, since it corresponds to a large expansion of the depots.37 Recently, we tested the hypothesis that the capacity for proliferation and differentiation of fat cell precursors could be modified by maternal protein malnutrition. For that purpose, stromal–vascular fraction of adipose tissues in foetus, neonate and weaned rats, which contains precursor cells, was cultured, and the result did not comfort that hypothesis, at least for that specific nutritional treatment.59

The balance of contradictory signals experienced by precursors influences whether the cells undergo adipogenesis. In addition to the endocrine system, these signals originate from the precursors themselves or operate as part of a feedback loop involving mature adipocytes. The signals are either positive or negative and promote or block a cascade of transcription factors that induce differentiation.60 Among the positive factors are found corticosteroids, insulin, IGFs and prostacyclins, each of which having been cited earlier in this overview.

Programmed hypertension: fat tissue, kidney, brain?

In a systematic review of 80 studies, which included 444 000 subjects aged from 0 to 84 y and of all races, smaller size at birth was associated with an increase in blood pressure and more prevalent hypertensive disease during adult life.71 These associations are graded, and are seen across the normal range of birth weights in populations where the infants and children are otherwise seen as normal. Little is known about the mechanistic basis of this relationship, but candidate pathways are under study.

Molecules potentially contributive to hypertension are secreted by adipose tissue, like endothelin-1, the most potent vasopressor known, but which may play a role in the regulation of adiponectin secretion and whole body energy metabolism.72 All the components of the renin–angiotensin system are expressed in adipose tissue and angiotensinogen is abnormally high in obese patients, which suggested an important role of the adipocyte-derived angiotensinogen and the adipose renin–angiotensin system in obesity-related hypertension.73 Leptin itself has direct central effects that activate the sympathetic nervous system and its outflow to the kidneys, as well as a direct effect on the kidneys, resulting in increased sodium reabsorption leading to hypertension. The new concept of leptin resistance suggests the maintenance of leptin-induced sympathetic activation in obesity, despite resistance to leptin metabolic effects.74

There are several other ways of programming hypertension in early life than by programming excessive adipose tissue development. The maternal nutritional status appeared to programme expression of the renal angiotensin II type 2 receptor. This may play a key role in the impairment of renal development and the elevation of blood pressure noted in rats exposed to intrauterine protein restriction.75 The feeding of low protein diets or other insults in pregnancy that have an impact upon the development of cardiovascular functions also appears to impact upon nephron number. In the sheep, nephron number is related to weight at birth following nutrient restriction,76 and in the rat low protein diets reduce nephron number by approximately 30%.77 However, it is possible that hypertension and reduced renal reserve merely coincide and are not causally associated. Indeed, in rats fed low protein diets supplemented with additional nitrogen sources, while only glycine could reverse the hypertensive effects of low protein diets, all supplements could normalise nephron number. The evidence thus suggests that prenatal undernutrition may programme renal structure in later life, but that renal programming is not one of the primary mechanisms leading to hypertension.77

At the brain level, when examining the possible programming favouring hypertension, there is evidence of alterations in the components of the hippocampal/hypothalamic/pituitary/adrenal axis in some rat models, whereas in others (sheep) there are alterations in the expression of angiotensinogen (hypothalamus) and angiotensin II receptor type I (AT1) in the medulla oblongata.76, 78

Conclusion

Despite the complexity of the problem due to the many confounding factors and the multifactorial nature of obesity, a body of arguments is growing to indicate that truncal/abdominal hyperadiposity arise in malnourished offspring, and is aggravated by early catch-up growth. Some animal models are available to mimic the human situation and to study the cellular and molecular mechanisms by which is established the link between early malnutrition and central obesity. The programming may involve definitive dysregulation of appetite, the generation of a hormonal context which is favourable to adipogenesis and which may include high levels of corticosteroids, hyperinsulinaemia and anomalies in IGF axis, as well as the genesis of an abnormal population of fat cell precursors in the depots. Such central obesity is detrimental to the cardiovascular system, since it may participate to hypertension and create atherothrombotic conditions caused by a multiplicity of regulatory secretions from adipocytes and their stroma.

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  1. Laboratory of Cell Biology, Institute of Life Science, Université Catholique de Louvain, Louvain-la-Neuve, Belgium

    • C Remacle
    • , F Bieswal
    •  & B Reusens

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https://doi.org/10.1038/sj.ijo.0802800

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