The dangerous road of catch-up growth

doi:10.1113/jphysiol.2002.024406

The dangerous road of catch-up growth

C. N. Hales and S. E. Ozanne

Department of Clinical Biochemistry, University of Cambridge, Cambridge, UK

ABSTRACT

Many epidemiological studies have now shown a strongly increased risk of developing type 2 diabetes and the metabolic syndrome in adults who as neonates showed signs of poor early (fetal and early postnatal) growth. The thrifty phenotype hypothesis was proposed to provide a conceptual and experimentally testable basis of these relationships. We have used protein restriction of rat dams, as a means to test this hypothesis. In vivo and in vitro studies of the growth-restricted offspring of such pregnancies have provided findings showing remarkable parallels with the human conditions. Permanent changes in the expression of regulatory proteins in liver, muscle and adipose tissue provide at least part of the explanation of the changes observed and offer potential markers for testing in the human context. These studies have also raised the question as to whether 'catch up' growth following early growth retardation may add to the risks posed by this early handicap. Male rats growth-retarded during fetal life and cross-fostered shortly after birth to normal lactating dams reach normal body and organ weights by weaning but have a reduced longevity. This finding raises the possibility that catch up growth, whilst potentially beneficial in the short term, may be detrimental to long-term survival. Human epidemiological studies may point in the same direction. Work by others on other models of early growth restriction have produced similar, although more limited, data. These findings raise the interesting possibility that the response to fetal stress, be it nutritional or other, may evoke a somewhat restricted and uniform pattern of adaptive response.

(Received 15 May 2002; accepted after revision 8 July 2002; first published online 2 August 2002)
Corresponding author C. N. Hales: Department of Clinical Biochemistry, Level 4, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QR, UK. Email: cnh1000{at}cam.ac.uk

INTRODUCTION

The first indication that early development (fetal and in the first year of life) could be involved in subsequent, adult susceptibility to type 2 diabetes came from studies of men in Hertfordshire, UK (Hales et al. 1991). At the mean age of 64 years there was a continuous and reciprocal relationship between the amount of glucose intolerance (impaired glucose tolerance or type 2 diabetes) and birth weight or weight at one year. Although birth weight and weight at one year are related, it could be shown that weight at one year independently contributed. Thus poor growth during the first year of life also appears to be a risk factor. An even stronger relationship was found between birth weight and the presence of the metabolic syndrome (glucose intolerance, hypertension and raised plasma triglyceride concentration). The odds ratio of the lightest compared with the heaviest at birth exhibiting the features of the metabolic syndrome was eighteen (Barker et al. 1993). Subsequently thinness at birth was found to increase the risk of insulin resistance in later life (Phillips et al. 1994).

Since the original findings, these types of relationships have been described in a wide variety of populations worldwide, in females as well as males, in over 30 studies covering an age range of 4-84 years (reviewed by Hales & Barker, 2001). They are therefore reproducible, although the strength of the relationship observed has varied between populations and at the different ages studied. On the whole, the size of the effect seems to increase with age.

In an attempt to provide a conceptual and mechanistic framework to begin to explain these observations, the thrifty phenotype hypothesis was proposed (Hales & Barker, 1992). The term 'thrifty' was derived from an earlier hypothesis, the thrifty genotype hypothesis of Neel (1962). In the latter, Neel proposed that natural selection operating during thousands of years of poor and intermittent nutrition, had selected for genes that conferred a thrifty metabolic state which would aid survival. Diabetes then only emerged when the availability of nutrients became excessive in relation to energy expenditure, leading to obesity.

In contrast, the thrifty phenotype hypothesis proposes that fetal development is sensitive to the nutritional environment. When this is poor, an adaptive response is instigated to optimise the growth of certain organs, such as the brain, to the detriment of others, such as those of the viscera. These adaptations serve to improve the chances of fetal survival. They also lead to an altered postnatal metabolism, which serves the purpose of enhancing postnatal survival under conditions of intermittent and poor nutrition. These adaptations, it was proposed, only become detrimental when nutrition is overabundant and obesity results. Despite the fact that low birth weight is common in many populations worldwide, there may be a very low prevalence of diabetes provided that traditional low-calorie, high-energy expenditure life styles are maintained.

More recent epidemiological findings

Subsequent to these initial studies, more direct evidence has been produced indicating that maternal nutrition does affect subsequent glucose tolerance in the offspring. Adults who were in utero during the Dutch Famine have been found to have significantly worse glucose tolerance than those in utero immediately before or after the famine. The greatest impact of poor fetal nutrition on glucose tolerance was seen in the offspring affected by the famine in the last trimester of pregnancy (Ravelli et al. 1998).

Another environmental influence associated with reduced birth weight is maternal smoking. Recently it has been discovered that offspring of mothers who smoked during pregnancy are more likely to develop type 2 diabetes (Montgomery & Ekbom, 2002).

Although it remains theoretically possible that there is a major genetic cause of type 2 diabetes and that the same genetic defect(s) cause both low birth weight and diabetes, studies of identical twins have shown that the effect of low birth weight can operate independently of a genetic change. Thus in non-concordant monozygotic twins, one of whom has type 2 diabetes, it was the twins with significantly lower mean birth weight that were diabetic (Poulsen et al. 1997). Similar findings have been derived from studies in Italy (Bo et al. 2000).

The thrifty phenotype hypothesis tested in animal models

For the past 10 years we have been studying the effects of fetal and early parental growth restriction in rats in order to test the proposals in the thrifty phenotype hypothesis and also gain insights into the pathways and mechanisms involved. We chose to use maternal dietary protein reduction as a means of inducing growth restriction during fetal life and/or suckling as there is long-standing evidence that protein malnutrition can lead to glucose intolerance (Hales & Barker, 1992). A rat model of reduced protein intake had also been shown to lead to poor growth and replication of $beta$ -cells, poor subsequent insulin secretion and a great reduction in islet vascularisation (Snoeck et al. 1990).

Pregnant and/or lactating rat dams were fed an isocaloric diet containing just under half the normal control protein allocation. We could detect no detrimental effect of the diet on reproductive performance in so far as fertility and litter size were concerned. The rat pups from such pregnancies had a reduced birth weight.

Studies in vivo

Growth. Weight gain after birth and throughout life is very dependent upon postnatal nutrition. Pups from reduced-protein pregnancies that were cross-fostered to normally fed dams rapidly gained weight and by weaning had caught up with the growth of controls. The weight of individual organs, including the brain, liver and kidneys, was also equal to that of controls by 3 months of age (Jennings, 1999). Conversely, animals that were suckled by mothers fed the reduced-protein diet, whether they were the offspring of mothers fed the diet before pregnancy or the offspring of normally fed dams, grew very poorly. Even after weaning onto a normal diet, ad libitum fed animals that grew poorly during lactation failed to catch up in growth throughout life, both in terms of body and individual organ weights, such as the liver and kidneys (Desai et al. 1996). The reduction in size of these organs however, was in proportion to the reduction in body weight. In contrast, brain weight was unaffected in absolute terms, such that when expressed relative to body weight the brain was relatively larger in these animals. The permanent reduction in body growth was accompanied by a reduction in food intake and appeared to be a consequence of a permanent downregulation (programming) of appetite during lactation (Ozanne et al. 2000b).

Longevity. Whilst there may be a natural tendency to consider the restoration of previously reduced body length or weight or the weight of individual organs to normal as beneficial (often referred to as 'catch-up' growth, see Gafni & Baron (2000) for a discussion of the process and possible mechanisms) it is becoming increasingly likely that there may be a price to pay in the long term (e.g. Metcalfe & Monaghan, 2001).

We have found that in male rats, longevity was adversely or beneficially affected according to whether animals exhibited catch-up growth following growth restriction in utero or growth retardation postnatally following a normal pregnancy, respectively (Hales et al. 1996; Jennings et al. 1999). Female rats showed smaller, but insignificant, changes of a similar nature (Hales et al. 1996).

Human populations exhibiting catch-up growth have also been observed to exhibit adverse long-term outcomes in terms of blood pressure (Leon et al. 1996), death from cardiovascular disease (Eriksson et al. 1999) and the occurrence of type 2 diabetes (Forsen et al. 2000; Ong et al. 2000).

One possible mechanism linking catch-up growth with longevity in male rats is differences in rates of telomere shortening. It has been shown that animals that were growth restricted in utero but then experienced postnatal catch-up growth and had a reduced longevity had shorter kidney telomeres (Jennings et al. 1999). In contrast, animals that had been growth restricted postnatally by maternal protein restriction during lactation had longer kidney telomeres and an increased life span.

Glucose tolerance. The glucose tolerance of young animals that were the offspring of rat dams fed a reduced-protein diet during pregnancy and lactation was better than that of controls. This appeared to be due at least in part to an increased sensitivity to insulin, since plasma insulin concentrations were reduced (Shepherd et al. 1997). However, with age the glucose tolerance of these offspring deteriorated more rapidly than that of controls such that by 15 months they had impaired glucose tolerance (Hales et al. 1996) and, by 17 months, frank diabetes (Petry et al. 2001). In these male animals, insulin concentrations were approximately double those of controls during an intravenous glucose tolerance test, clearly indicating insulin resistance.

Blood pressure. The blood pressure of animals that had been growth restricted during early life was greatly influenced by the composition of the post-weaning diet. Animals that were growth restricted by the administration of a reduced-protein diet during pregnancy and lactation to their mothers and which were fed a reduced-protein diet from weaning up to 70 days of age, at which point they were fed a control diet ad libitum, had an elevated blood pressure at 1 year of age (Petry et al. 1997). When these animals were given a highly palatable obesity-inducing diet they became still more hypertensive. Such animals also exhibited impaired glucose tolerance and hypertriglyceridaemia, i.e. the main features of the human metabolic syndrome. Although the effects of early growth restriction and obesity on hypertension were additive, this was not the case for glucose intolerance and hypertriglyceridaemia which, at the age studied (1 year), were the result of obesity predominantly (Petry et al. 1997).

Studies in vitro

Liver. The liver of offspring of reduced-protein pregnancies, both during pregnancy and during lactation, was visibly altered. This was found to be due to fewer but larger liver lobules (Burns et al. 1997). The control of glucose production by livers perfused in vitro and subjected to glucagon or glucagon plus insulin infusion was changed. The glucose output consequent upon glucagon stimulation was reduced at least partly due to a reduction in the expression of glucagon receptors. When insulin was added to the glucagon-containing perfusate, there was an anomalous initial increase in glucose output followed later by the expected reduction. The loss of the initial insulin suppression of glucose output was seen despite an increased expression of the insulin receptor. Hence, it was a post-receptor deficit of unknown basis (Ozanne et al. 1996).

Muscle. The basal glucose uptake of muscle freshly taken from young adult offspring of reduced-protein pregnancies was found to be increased, with the addition of high concentrations of insulin leading to the same glucose uptake as controls. When muscles were pre-incubated in vitro to overcome the effect of endogenous insulin, the basal glucose uptake fell to control levels and the muscles were found to have enhanced sensitivity to insulin. This was due at least in part to the over-expression of the insulin receptor, as was seen in the liver. These changes in insulin action were reversed with age and may at least in part explain the age-dependent changes in glucose tolerance described above. At 15 months of age, insulin was found to stimulate glucose uptake poorly (Ozanne et al. 2000c). This post-receptor defect was related to a decreased expression of protein kinase C zeta (Ozanne et al. 2000c).

Adipose tissue. Isolated adipocytes from young adult offspring showed increased basal glucose uptake but this was not related to endogenous insulin as it occurred an hour after the removal of the tissue from the animal. Insulin-stimulated glucose uptake was also elevated. As in liver and muscle, over-expression of the insulin receptor was observed (Ozanne et al. 1997). A study of post-receptor factors involved in insulin signalling in adipose tissue revealed increased basal and insulin-stimulated insulin receptor 1-associated phosphatidylinositol 3-kinase (PI3 kinase)activity (Ozanne et al. 1997). It has been shown by the use of the inhibitor wortmannin that both insulin's stimulation of glucose uptake and inhibition of lipolysis are mediated by PI3 kinase (Shepherd et al. 1998). However, despite exhibiting an overall increase in insulin-stimulated PI3-kinase activity, fat cells from offspring of reduced-protein pregnancies showed a reduction in insulin's effect to inhibit catecholamine-stimulated lipolysis. The alteration in insulin inhibition of lipolysis was depot selective, being seen in intra-abdominal but not subcutaneous fat cells (Ozanne et al. 2000a). This finding is in striking agreement with changes described in human fat cells (Arner et al. 1999). There was also an enhanced sensitivity to the lipolytic effect of catecholamines, probably in part due to an increased expression of $beta$ -adrenergic receptors.

The manner in which a selective loss of insulin's action is brought about is not known. However, adipose tissue expresses two of the isoforms of the PI3-kinase catalytic subunit, namely p110 $alpha$ and p110 $beta$ . The functional significance of these two forms is not known. Adipose tissue from reduced-protein pregnancies showed a large (over 6-fold) reduction in the expression of the $beta$ -isoform with no change in that of the $alpha$ -isoform. We have speculated that the $alpha$ -isoform may be involved in insulin's stimulation of glucose uptake, whilst the $beta$ -isoform is involved in its antilipolytic action (Ozanne & Hales, 1999).

Whatever the outcome of further studies of these questions, the shift in insulin's action towards enhanced stimulation of glucose uptake whilst fatty acid production is increased, consequent upon its reduced antilipolytic effect and the enhanced sensitivity to catecholamines, could have important consequences for the metabolism of the organism. If food is available only intermittently it would seem advantageous for the uptake and storage of energy to proceed vigorously at times of food availability. Indeed, Neel, in discussing his thrifty genotype hypothesis, proposed that one thrifty gene effect could be a large outpouring of insulin during feeding to achieve just this effect. In our model, enhancement of insulin's action is brought about at least to some extent by the very considerable over-expression of the insulin receptor. One could propose that this is a rather more elegant solution to the need to enhance insulin's action than having to resort to intermittent overproduction of insulin. Furthermore, selective changes in the expression of insulin signalling factors involved in the regulation of different aspects of metabolism allows for subtle changes in the balance of metabolism. In our model, this appears as a shift to glucose storage and subsequent release and oxidation of fat. In this way, one could expect that the organism would be better equipped to cope with prolonged periods of reduced nutrition.

The metabolism of adipose tissue, like muscle, was also found to change with age. At 15 months, adipocytes from reduced-protein pregnancies were resistant both to the effect of insulin to stimulate glucose uptake and to inhibit lipolysis (Ozanne et al. 2001). The increased expression of the insulin receptor had disappeared, it now being comparable to that of controls. The poor action of insulin was associated with impaired activation of PI3-kinase whilst the expression of its $beta$ -catalytic subunit continued to be reduced.

Other animal models involving early growth restriction

A number of studies have been carried out with a view to determining the adult phenotypic consequences of early growth restriction. Whilst the majority of studies carried out thus far have been in the rat (e.g. Simmons et al. 2001; Lane et al. 2001) considerable use has also been made of fetal sheep (e.g. Devaskar et al. 2002) in part because of the possibility of access to the fetal circulation. These include maternal calorie restriction, maternal iron restriction, glucocorticoid administration to pregnant rats and uterine artery ligation (reviewed by Ozanne, 2001; Ozanne & Hales, 2002). These studies therefore allow us to begin to address the issue as to whether there is a diverse set of responses that the fetus can mount during nutritional adversity. Equally important is the question as to whether non-nutritional stresses during pregnancy due to such factors as infection or maternal physical or psychological trauma can lead to consequences for the fetus that are detrimental to health in adult life (Ozanne & Hales, 2002).

There is a need for much more research to be carried out before we can confidently answer these questions. However, such data as exists at present would tend to suggest that the nutritional insults listed do lead to somewhat but not entirely similar phenotypic consequences. One additional question of importance relates to the timing of the insult during pregnancy. The models listed do not all relate to the whole of pregnancy. Uterine artery ligation, for example, was carried out relatively late in pregnancy. It is highly likely that different timing of insults during pregnancy will lead to at least some variation in the long-term consequences for the offspring.

Conclusions

There is no doubt, from observations in both human and animal studies, that growth restriction during early life can have very serious consequences in adult life. Amongst these consequences are type 2 diabetes and the metabolic syndrome. Less clear is the scope for modifying these consequences either for the better or the worse during postnatal life. This question is of great importance for attempts to intervene, which are obviously difficult during pregnancy.

Some evidence exists, again from both human and animal studies, that the trajectory of postnatal growth can have effects on the long-term outcome. Observations involving human epidemiology need to be treated with some caution. Although, as indicated above, there are studies that can be interpreted as indicating that rapid growth, either in terms of height or weight gain or both, can be detrimental on top of early growth restriction, it is not possible to conclude whether the adverse outcome is the cause or consequence of earlier growth restriction-related adult diseases. For example, if receptors for growth factors were over-expressed during fetal life, excessive postnatal growth could simply reflect these earlier events rather than be a separate part of the pathological process. On the other hand, the animal observations discussed show clearly that slowing or accelerating early growth can have either beneficial or detrimental effects, respectively, in terms of longevity.

If late equality or an overshoot of growth is obtained by the imposition of extra growth on a limited endowment of cells, it would not be too surprising if the long-term outcome was detrimental. However, in terms of the survival of the species it could be argued that reproductive success is the only consequence that matters for most species which, in the wild, do not survive to old age. Thus 'buying' survival to reproduction at the expense of adaptations that are detrimental in old age is a strategy which is likely to have positive rather than negative evolutionary value. It is mainly in the human situation, with the increasing potential for long-term survival, that we are being brought to face the price that has to be paid for early-life modifications that aid short-term survival in adverse circumstances.

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This report was presented at The Journal of Physiology Symposium on Fetal Programming: from gene to functional systems, Los Angeles, USA, 20 March 2002. It was commissioned by the Editorial Board and reflects the views of the authors.

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Endocrinology, May 1, 2005; 146(5): 2142 - 2153.
[Abstract] [Full Text] [PDF]

I. C. Mcmillen and J. S. Robinson
Developmental Origins of the Metabolic Syndrome: Prediction, Plasticity, and Programming
Physiol Rev, April 1, 2005; 85(2): 571 - 633.
[Abstract] [Full Text] [PDF]

J. C. Jimenez-Chillaron, M. Hernandez-Valencia, C. Reamer, S. Fisher, A. Joszi, M. Hirshman, A. Oge, S. Walrond, R. Przybyla, C. Boozer, et al.
{beta}-Cell Secretory Dysfunction in the Pathogenesis of Low Birth Weight-Associated Diabetes: A Murine Model
Diabetes, March 1, 2005; 54(3): 702 - 711.
[Abstract] [Full Text] [PDF]

D. S. Fernandez-Twinn, A. Wayman, S. Ekizoglou, M. S. Martin, C. N. Hales, and S. E. Ozanne
Maternal protein restriction leads to hyperinsulinemia and reduced insulin-signaling protein expression in 21-mo-old female rat offspring
Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2005; 288(2): R368 - R373.
[Abstract] [Full Text] [PDF]

J. Schwartz and J. L. Morrison
Impact and mechanisms of fetal physiological programming
Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2005; 288(1): R11 - R15.
[Full Text] [PDF]

J.-H. Chen, K. Stoeber, S. Kingsbury, S. E. Ozanne, G. H. Williams, and C. N. Hales
Loss of Proliferative Capacity and Induction of Senescence in Oxidatively Stressed Human Fibroblasts
J. Biol. Chem., November 19, 2004; 279(47): 49439 - 49446.
[Abstract] [Full Text] [PDF]

D. Brodsky and H. Christou
Current Concepts in Intrauterine Growth Restriction
J Intensive Care Med, November 1, 2004; 19(6): 307 - 319.
[Abstract] [PDF]

N. da Costa, C. McGillivray, Q. Bai, J. D. Wood, G. Evans, and K.-C. Chang
Restriction of Dietary Energy and Protein Induces Molecular Changes in Young Porcine Skeletal Muscles
J. Nutr., September 1, 2004; 134(9): 2191 - 2199.
[Abstract] [Full Text] [PDF]

R. J. Norman, M. Noakes, R. Wu, M. J. Davies, L. Moran, and J. X. Wang
Improving reproductive performance in overweight/obese women with effective weight management
Hum. Reprod. Update, May 1, 2004; 10(3): 267 - 280.
[Abstract] [Full Text] [PDF]

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Ozanne, S. E. (2001). Metabolic programming in adults. In Type 2 Diabetes: The Thrifty Phenotype, ed. Barker, D. J. P., British Medical Bulletin, vol. 60, pp. 143-152. Oxford University Press, Oxford
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				D. S. Fernandez-Twinn, A. Wayman, S. Ekizoglou, M. S. Martin, C. N. Hales, and S. E. Ozanne Maternal protein restriction leads to hyperinsulinemia and reduced insulin-signaling protein expression in 21-mo-old female rat offspring Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2005; 288(2): R368 - R373. [Abstract] [Full Text] [PDF]

				J. Schwartz and J. L. Morrison Impact and mechanisms of fetal physiological programming Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2005; 288(1): R11 - R15. [Full Text] [PDF]

				J.-H. Chen, K. Stoeber, S. Kingsbury, S. E. Ozanne, G. H. Williams, and C. N. Hales Loss of Proliferative Capacity and Induction of Senescence in Oxidatively Stressed Human Fibroblasts J. Biol. Chem., November 19, 2004; 279(47): 49439 - 49446. [Abstract] [Full Text] [PDF]

				D. Brodsky and H. Christou Current Concepts in Intrauterine Growth Restriction J Intensive Care Med, November 1, 2004; 19(6): 307 - 319. [Abstract] [PDF]

				N. da Costa, C. McGillivray, Q. Bai, J. D. Wood, G. Evans, and K.-C. Chang Restriction of Dietary Energy and Protein Induces Molecular Changes in Young Porcine Skeletal Muscles J. Nutr., September 1, 2004; 134(9): 2191 - 2199. [Abstract] [Full Text] [PDF]

				R. J. Norman, M. Noakes, R. Wu, M. J. Davies, L. Moran, and J. X. Wang Improving reproductive performance in overweight/obese women with effective weight management Hum. Reprod. Update, May 1, 2004; 10(3): 267 - 280. [Abstract] [Full Text] [PDF]