Skip to main content Accessibility help
×
Home

Information:

  • Access
  • Cited by 34

Actions:

      • Send article to Kindle

        To send this article to your Kindle, first ensure no-reply@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

        Note you can select to send to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

        Find out more about the Kindle Personal Document Service.

        The impact of diet during early life and its contribution to later disease: critical checkpoints in development and their long-term consequences for metabolic health
        Available formats
        ×

        Send article to Dropbox

        To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

        The impact of diet during early life and its contribution to later disease: critical checkpoints in development and their long-term consequences for metabolic health
        Available formats
        ×

        Send article to Google Drive

        To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

        The impact of diet during early life and its contribution to later disease: critical checkpoints in development and their long-term consequences for metabolic health
        Available formats
        ×
Export citation

Abstract

Changes in maternal diet at different stages of reproduction can have pronounced influences on the health and well-being of the resulting offspring, especially following exposure to an obesogenic environment. The mechanisms mediating adaptations in development of the embryo, placenta, fetus and newborn include changes in the maternal metabolic environment. These changes include reductions in a range of maternal counter-regulatory hormones such as cortisol, leptin and insulin. In the sheep, for example, targeted maternal nutrient restriction coincident with the period of maximal placental growth has pronounced effects on the development of the kidney and adipose tissue. As a consequence, the response of these tissues varies greatly following adolescent-onset obesity and ultimately results in these offspring exhibiting all the symptoms of the metabolic syndrome earlier in young adult life. Leptin administration to the offspring after birth can have some long-term differential effects, although much higher amounts are required to cause a response in small compared with large animal models. At the same time, the responsiveness of the offspring is gender dependent, which may relate to the differences in leptin sensitivity around the time of birth. Increasing maternal food intake during pregnancy, either globally or of individual nutrients, has little positive impact on birth weight but does impact on liver development. The challenge now is to establish which components of the maternal diet can be sustainably modified in order to optimise the maternal endocrine environment through pregnancy, thus ensuring feto–placental growth is appropriate in relation to an individual's gender and body composition.

There is a complex interrelationship between dietary composition and changes in food intake in women around the perinatal period. This interaction is accompanied by the substantial endocrine changes that are associated with the establishment of pregnancy(1) and concomitant changes in maternal cardiovascular control. The magnitude of adaptation will be dependent on numerous factors including maternal age, parity, fetal number, ethnicity and body composition(2, 3). Ultimately, the effect of the maternal diet on reproductive outcome will be modulated by each of these components, although their relative impact will vary greatly depending on the stage of gestation(4). One example is the occurrence of morning sickness, which is only experienced by women consuming a Western-style diet and which, in turn, is determined by macronutrient rather than micronutrient intake(5). It is not uncommon for maternal food intake to decrease at some stage in the first trimester and this reduced intake may be an important adaptation that enables changes in maternal body composition to occur through pregnancy whilst ensuring that nutrient flux to the fetus, particularly carbohydrate flux, is maintained(6). However, it may be the subsequent change in maternal body composition, rather than in dietary intake, that is the key factor determining the magnitude of feto–placental adaptations(7). This premise could also explain why preterm birth only appears to result when periconceptional nutrient restriction is accompanied by a pronounced reduction in maternal body weight(8, 9). In contrast, micronutrient intake may only be important in determining some of the later effects on reproduction in early pregnancy. Thus to date, vitamin C is the only individual nutrient for which intake has been positively associated with placental weight at term, although its contribution is small (i.e. <5%)(10).

Dietary challenges during pregnancy: the laboratory v. real life

One factor that has a major influence on the interpretation of outcomes from nutritional interventions is whether they are representative of dietary changes seen in human populations. In addition, the extent to which they may have a substantially greater impact on the particular species or breed under examination compared with human subjects must be considered(11). For example, it has long been established that because of a combination of the large litter size and the short gestation over which fetal growth occurs, protein requirements of the pregnant rat are approximately 30-fold greater than those of larger mammals(12). Thus, it is not unexpected that, in the rat, reductions in the protein content of the diet, concomitant with an increase in a highly-digestible carbohydrate content, result in fetal growth retardation that can have adverse long-term consequences(13). However, such adverse effects of protein restriction in large mammals, with a long-length gestation similar to that of human subjects, have yet to be confirmed. Outside the laboratory, in its natural environment, the rat survives on a very diverse diet of different foods that vary in availability through the seasons. This factor could explain why, experimentally, rats can effectively adapt to such apparently large changes in their diet during reproduction. As a consequence, if the same restricted diet fed through lactation is fed to the offspring then no adverse effects on blood pressure are seen in male offspring(14). Similarly, reducing the amount of food available to the pregnant rat by 50% through pregnancy has only a transient inhibitory effect on the weight of the offspring that is overcome within 3 d of birth(15). The offspring subsequently have a reduction in blood pressure as adults despite having a marked deficit in nephron number.

The pregnant animal has a substantial capacity to effectively adapt to changes in the diet that when suddenly imposed at any time in the reproductive process can be well tolerated without any effect on birth weight of the offspring(16). However, individuals with the same birth weight can exhibit substantial differences in endocrine sensitivity and organ function from birth and throughout later life(17, 18). Moreover, because of the critical periods of organ growth and development from the time of conception through to birth, when approximately 80% of all cell divisions of the life cycle occur, it is not unexpected that changes in the maternal diet can have longer-term effects on the metabolic and cardiovascular health of the resulting offspring(19). These responses normally need to be accompanied by a further challenge to that individual's growth capacity as a result of accelerated postnatal growth and/or in the adolescent period of development(20). At the same time, pronounced adaptations can be found at the cellular level without any gross difference in body composition(18, 21), emphasising the need to make relevant tissue measurements of markers of disease progression.

Conception to embryogenesis

Changes in maternal food intake before pregnancy can have marked effects on the conceptus and these effects appear to be dependent on the magnitude of change in maternal body weight(7). In sheep, therefore, a sudden and maintained reduction in food availability that is sufficient to cause a substantial decline in maternal body weight can result in accelerated maturation of the hypothalamic–pituitary axis of the fetus to the extent that premature birth can occur(22). Interestingly, this outcome only occurs in approximately 30–40% of mothers exposed to this nutritional intervention(8, 22) and may reflect differences in the maternal catabolic response to chronic food deprivation and/or difference in body composition at the start of the study. For example, in one such study a subgroup of the animals exposed to periconceptional nutrient restriction had a baseline doubling in plasma cortisol(23).

The long-term outcomes of being born to mothers exposed to periconceptional nutrient restriction are very modest and those effects, for example on glucose homeostasis, are inconsistent(24, 25). This outcome contrasts with the effect of maternal nutrient restriction commencing from the time of mating, which has no effect on gestational length, birth weight or glucose homeostasis or on the hypothalamic–pituitary axis of the offspring(2628). It does, however, result in a marked leftward shift of the baroreceptor curve relating blood pressure to heart rate(26). The extent to which this type of adaptation may be exacerbated when these individuals are exposed to an obesogenic environment and become hypertensive(29) clearly warrants further investigation.

Placental development and maturation of the kidney

Adaptations within placental structure, as well as in its endocrine sensitivity, have a pronounced influence on the extent to which changes in the maternal diet may adversely affect fetal growth(30, 31). A reduction in maternal food intake, coincident with uterine attachment and invasion of the fetal trophoblast into the syncitium, reduces placental growth as a consequence of reduced cell proliferation(32). This outcome is accompanied by raised glucocorticoid action(32), which appears to be a direct response to the reduction in maternal plasma cortisol(16). At the same time, maternal plasma insulin, thyroid hormones, leptin and insulin-like growth factor-1 are reduced (see Table 1). These adaptations accompany the modest reduction in maternal body weight and the increased plasma NEFA(16) that may be important, in conjunction with the reduction in maternal plasma insulin, in maintaining the concentration of glucose(16, 33), which is the main metabolic substrate required by the fetus. Conversely, increasing the amount of feed consumed by the mother from calculated requirements to ad libitum has very little effect on fetal growth through gestation(34, 35), and at term gestation fetal fat mass can even be reduced(35).

Table 1. Summary of the major maternal endocrine changes following exposure to nutrient restriction between 28 d and 80 d of gestation in the sheep (adapted from Bispham et al.(16) and Symonds et al.(64))

(Values are means with their standard errors for seven sheep per group)

Mean values were significantly different from those for the control diet:

* P<0·05, ***P<0·001.

To date, all organs and mechanisms that have been examined in the adult offspring born to nutrient-restricted mothers appear to be re-set following exposure to this targeted nutritional intervention. However, adaptations that may place in the offspring at increased risk of later adult disease are not seen until individuals are subsequently exposed to an obesogenic environment(18, 21, 36). This outcome is most notable in the kidney in which there is a marked attenuation of both cellular stress and inflammatory responses(18). These responses contrast with other pathways, including apoptosis and glucocorticoid action, that may initially protect the kidney from glomerulersclerosis(29). It is likely that with age the cardiovascular health of these offspring will deteriorate more rapidly(21) and that they will therefore be at increased risk of CVD(37). Indeed, there is further indirect evidence to support this outcome, as if these offspring become obese they show an exacerbated increase in blood pressure with age compared with those born to control-fed mothers(37). Ultimately, these offspring exhibit all the symptoms of the metabolic syndrome including raised plasma TAG, hyperinsulinaemia, hyperleptinaemia and leptin resistance together with ectopic lipid deposition(21, 29, 36).

Fetal and neonatal growth, leptin and maturation of the hypothalamic–pituitary axis

There are substantial differences between both species and nutritional models in the development of a number of organ systems that relate to their critical windows of development. Such differences are also found in the hypothalamic–pituitary axis, which primarily matures after birth in rodents compared with the final third of gestation in sheep and human subjects(11). The importance of this profound difference between species, primarily linked to maturation at birth, has a substantial impact on the magnitude of leptin surge at birth and therefore its relative influence on postnatal growth and development, as summarised in Fig. 1. In small mammals leptin has a primary role in regulating brain development after birth(38); there is currently no evidence of comparable effects in large mammals.

Fig. 1. Comparison of the changes in plasma leptin after birth in mice ()(65), rats (· · ·▪· · ·)(45) and sheep ()(43). Values are means with their standard errors represented by vertical bars for six to eight animals per time point.

In the sheep leptin administration to either the preterm fetus (10 d before birth)(39) or to the neonate(40) has very limited effects on metabolism, which are confined to brown adipose tissue. Interestingly, in the sheep the amount of leptin required to induce the effects that follow an approximately 5–10-fold rise in plasma leptin is 10-fold greater in the fetus(39) compared with the neonate(40) (i.e. 0·48 mg/kg body weight v. 0·04 mg/kg body weight). In the fetal sheep the administration of leptin results in a stability in uncoupling protein 1(39), whereas after birth an increase in body temperature is accompanied by an accelerated loss of uncoupling protein 1(40). Leptin also promotes the loss of uncoupling protein 2 from the lung(41) and pancreas(42) but not adipose tissue(41), although whether this response is a direct effect or is mediated by the concomitant reduction in plasma cortisol remains to be established. These findings emphasise the comparatively modest effects of administering a physiological dose of leptin to a species with a mature hypothalamic–pituitary axis and in which there is an immediate reduction in plasma leptin(43) at birth, as is also seen in the human neonate(44). It is in marked contrast to the rat in which plasma leptin increases 1 week after birth(45) and parallels the postnatal recruitment of non-shivering thermogenesis(46). In neonatal rats a much higher amount of leptin has been used, i.e. 2·5 mg/kg body weight, and a pronounced divergence in effect is observed between males(47) and females(48). This difference is not unexpected given the greater amount of fat present in females(49) across species(50), which is usually reflected in higher plasma leptin in females compared with males(49, 51); a difference that is present from birth in both sheep(40) and human subjects(52).

When a comparatively high dose of leptin is administered to neonatal rats a substantial loss of body weight only results in female pups exhibiting pronounced intrauterine growth retardation and also exposed to the additional stress of cross-fostering (not adopted for controls)(48). Indeed, selective cross-fostering could be a major factor in determining the apparent opposite effects of leptin between nutritional groups in a number of outcomes, including changes in gene expression and methylation relating to glucocorticoid action in the adult liver(53). In males leptin has little effect on body weight(47), possibly because these offspring were still growing at the end of the study (i.e. 170 d after birth) when no ‘protective effect’ of early leptin administration was apparent. In females the change in total fat mass is not however accompanied by a reduction in plasma leptin(48). Furthermore, whether adaptations in the amount of ectopic fat accumulation occur is currently unknown and is clearly important because it is critical in determining the magnitude of adverse metabolic outcomes(54). Given the pronounced differences in maturation at birth and the interaction between fat mass, leptin and gender outlined earlier, the extent to which such effects from using pharmacological amounts of leptin to prevent adverse body composition in the neonate are relevant to the clinical situation remains in doubt.

Increased maternal fat intake and compromised fetal growth

One current concern is the rise in obesity(55), particularly its increased incidence in women of child-bearing age(56). Macrosomic newborns of obese women have an increased amount of body fat(57). However, consistent observations have yet to be produced, as many confounding effects, particularly gender, have yet to be clarified. Indeed, in a recent study of nulliparous obese women in the UK 19% of women had small-for-dates infants compared with 13% producing large-for-dates offspring(58). In mice increasing the amount of dietary fat alone or in combination with other carbohydrates has no effect on birth weight. However, if this dietary intervention is commenced several weeks before pregnancy and is accompanied by increased energy intake, then maternal body weight is raised and subsequent changes in offspring feeding behaviour are observed(59). In the case of non-human primates doubling fat availability in the diet, primarily at the expense of protein content, actually reduces fetal weight(60), with approximately 50% of the subjects being resistant to the effects of the high-fat diet on insulin secretion (and the accompanying increase in maternal body weight). Irrespective of the maternal response, in the fetus there is a consistent effect on hepatic gene expression of enzymes involved in gluconeogenesis, in conjunction with raised hepatic TAG content. This adaptation persists up to 6 months after birth, although the difference is greatly reduced after birth, and as the hepatic TAG content remains lower than in the fetus is not indicative of a disease-like state. Interestingly, the effects seen on hepatic genes are not translated to changes in protein abundance. This outcome is not unexpected as fetal glucose production is only normally activated after birth(61). It may be that raised hepatic gene expression reflects a non-permanent response to the nutritional stress(62) imposed on the mother. This finding is also in accord with the effect of feeding a low-protein high-carbohydrate diet to rodents through pregnancy, which promotes glucocorticoid receptor abundance in a range of fetal tissues including the liver(63).

In the non-human primate study described earlier it was found that placing the mothers back onto the control diet after 4 years alleviates the effects of maternal consumption of a high-fat low-protein diet(60). However, hepatic TAG content in the fetus remain above control values in those mothers no longer consuming the high-fat low-protein diet. Furthermore, non-human primates have very low body fat, which explains the near undetectable plasma leptin in the fetus (approximately 0·5 ng/ml). As their maximal fat mass, recorded at 3 months of age, is only approximately 5% body weight they do not exhibit signs of obesity or metabolic compromise. It would, of course, be highly informative to know how food intake changed with age and through each pregnancy in these studies(60).

Conclusion

In conclusion, changes in maternal diet throughout pregnancy and during the lactation period will modify the mother's endocrine status and can have pronounced effects on the growth and development of the conceptus that are dependent on the stage of gestation of exposure. Increasing evidence links the perinatal dietary environment to cardiometabolic disease development in adulthood. Critically, an increased understanding of these processes and the relative contributions of individual components of the diet to the endocrine status of both the mother and resulting offspring will be important in improving the long-term health of the population.

Acknowledgements

The authors acknowledge the support of the European Union Sixth Framework Programme for Research and Technical Development of the European Community, The Early Nutrition Programming Project (FOOD-CT-2005–007036), in their research. The authors declare no conflict of interest. M. E. S. developed the article outline, conducted the literature search, devised the Table and wrote the article. S. P. S. assisted in the development of the body of the article, devised the Figure and edited all drafts. H. B. edited all drafts.

References

1.Freemark, M (2006) Regulation of maternal metabolism by pituitary and placental hormones: roles in fetal development and metabolic programming. Horm Res 65, Suppl. 3, 4149.
2.Symonds, ME, Pearce, S, Bispham, J et al. (2004) Timing of nutrient restriction and programming of fetal adipose tissue development. Proc Nutr Soc 63, 397403.
3.Hyatt, MA, Budge, H, Walker, D et al. (2007) Effects of maternal parity and late gestational nutrition on mRNA abundance for growth factors in the liver of postnatal sheep. Am J Physiol Regul Integr Comp Physiol 292, R1934R1942.
4.Symonds, ME, Stephenson, T, Gardner, DS et al. (2007) Long-term effects of nutritional programming of the embryo and fetus: mechanisms and critical windows. Reprod Fertil Dev 19, 5363.
5.Pepper, GV & Craig Roberts, S (2006) Rates of nausea and vomiting in pregnancy and dietary characteristics across populations. Proc Biol Sci 273, 26752679.
6.Symonds, ME (2009) Nutrition and its contribution to obesity and diabetes: a life-course approach to disease prevention? Proc Nutr Soc 68, 7177.
7.Gopalakrishnan, GS, Gardner, DS, Dandrea, J et al. (2005) Influence of maternal pre-pregnancy body composition and diet during early-mid pregnancy on cardiovascular function and nephron number in juvenile sheep. Br J Nutr 94, 938947.
8.Bloomfield, FH, Oliver, MH, Hawkins, P et al. (2003) A periconceptional nutritional origin for noninfectious preterm birth. Science 300, 606.
9.Edwards, LJ, McFarlane, JR, Kauter, KG et al. (2005) Impact of periconceptional nutrition on maternal and fetal leptin and fetal adiposity in singleton and twin pregnancies. Am J Physiol Regul Integr Comp Physiol 288, R39R45.
10.Mathews, F, Yudkin, P & Neil, A (1999) Influence of maternal nutrition on outcome of pregnancy: prospective cohort study. Br Med J 319, 339343.
11.Symonds, ME & Budge, H (2009) Nutritional models of the developmental programming of adult health and disease. Proc Nutr Soc 68, 173178.
12.Widdowson, EM (1950) Chemical composition of newly born animals. Nature 116, 626628.
13.Ozanne, SE, Nave, BT, Wang, CL et al. (1997) Poor fetal nutrition causes long-term changes in expression of insulin signaling components in adipocytes. Am J Physiol Regul Integr Comp Physiol 273, E46E51.
14.Fernandez-Twinn, DS, Ekizoglou, S, Wayman, A et al. (2006) Maternal low-protein diet programs cardiac beta-adrenergic response and signaling in 3-mo-old male offspring. Am J Physiol Regul Integr Comp Physiol 291, R429R436.
15.Brennan, KA, Kaufman, S, Reynolds, SW et al. (2008) Differential effects of maternal nutrient restriction through pregnancy on kidney development and later blood pressure control in the resulting offspring. Am J Physiol Regul Integr Comp Physiol 295, R197R205.
16.Bispham, J, Gopalakrishnan, GS, Dandrea, J et al. (2003) Maternal endocrine adaptation throughout pregnancy to nutritional manipulation: consequences for maternal plasma leptin and cortisol and the programming of fetal adipose tissue development. Endocrinology 144, 35753585.
17.Whorwood, CB, Firth, KM, Budge, H et al. (2001) Maternal undernutrition during early- to mid-gestation programmes tissue-specific alterations in the expression of the glucocorticoid receptor, 11b-hydroxysteroid dehydrogenase isoforms and type 1 angiotensin II receptor in neonatal sheep. Endocrinology 142, 17781785.
18.Sharkey, D, Gardner, DS, Fainberg, HP et al. (2009) Maternal nutrient restriction during pregnancy differentially alters the unfolded protein response in adipose and renal tissue of obese juvenile offspring. FASEB J 23, 13141324.
19.McMillen, IC & Robinson, JS (2005) Developmental origins of the metabolic syndrome: prediction, plasticity, and programming. Physiol Rev 85, 571633.
20.Symonds, ME (2007) Integration of physiological and molecular mechanisms of the developmental origins of adult disease: new concepts and insights. Proc Nutr Soc 66, 442450.
21.Chan, LLY, Sebert, SP, Hyatt, MA et al. (2009) Effect of maternal nutrient restriction from early-to-mid gestation on cardiac function and metabolism after adolescent-onset obesity. Am J Physiol Regul Integr Comp Physiol 296, R1455R1463.
22.Bloomfield, FH, Oliver, MH, Hawkins, P et al. (2004) Periconceptional undernutrition in sheep accelerates maturation of the fetal hypothalamic-pituitary-adrenal axis in late gestation. Endocrinology 145, 42784285.
23.Jaquiery, AL, Oliver, MH, Bloomfield, FH et al. (2006) Fetal exposure to excess glucocorticoid is unlikely to explain the effects of periconceptional undernutrition in sheep. J Physiol 572, 109118.
24.Bloomfield, FH, Oliver, MH & Harding, JE (2007) Effects of twinning, birth size, and postnatal growth on glucose tolerance and hypothalamic-pituitary-adrenal function in postpubertal sheep. Am J Physiol Endocrinol Metab 292, E231E237.
25.Todd, SE, Oliver, MH, Jaquiery, AL et al. (2009) Periconceptional undernutrition of ewes impairs glucose tolerance in their adult offspring. Pediatr Res 65, 409413.
26.Gardner, DS, Pearce, S, Dandrea, J et al. (2004) Peri-implantation undernutrition programs blunted angiotensin II evoked baroreflex responses in young adult sheep. Hypertension 43, 12901296.
27.Gardner, DS, Tingey, K, Van Bon, BW et al. (2005) Programming of glucose-insulin metabolism in adult sheep after maternal undernutrition. Am J Physiol Regul Integr Comp Physiol 289, R947R954.
28.Gardner, DS, Van Bon, BW, Dandrea, J et al. (2006) Effect of periconceptional undernutrition and gender on hypothalamic-pituitary-adrenal axis function in young adult sheep. J Endocrinol 190, 203212.
29.Williams, PJ, Kurlak, LO, Perkins, AC et al. (2007) Hypertension and impaired renal function accompany juvenile obesity: the effect of prenatal diet. Kidney Int 72, 279289.
30.Heasman, L, Clarke, L, Firth, K et al. (1998) Influence of restricted maternal nutrition in early to mid gestation on placental and fetal development at term in sheep. Pediatr Res 44, 546551.
31.Heasman, L, Clarke, L, Stephenson, TJ et al. (1999) The influence of maternal nutrient restriction in early to mid-pregnancy on placental and fetal development in sheep. Proc Nutr Soc 58, 283288.
32.Gnanalingham, MG, Williams, P, Wilson, V et al. (2007) Nutritional manipulation between early to mid-gestation: effects on uncoupling protein-2, glucocorticoid sensitivity, IGF-I receptor and cell proliferation but not apoptosis in the ovine placenta. Reproduction 134, 615623.
33.Hay, WW (1995) Current topic: Metabolic interrelationships of placenta and fetus. Placenta 16, 1930.
34.Clarke, L, Heasman, L, Juniper, DT et al. (1998) Maternal nutrition in early-mid gestation and placental size in sheep. Br J Nutr 79, 359364.
35.Budge, H, Bispham, J, Dandrea, J et al. (2000) Effect of maternal nutrition on brown adipose tissue and its prolactin receptor status in the fetal lamb. Pediatr Res 47, 781786.
36.Sebert, SP, Hyatt, MA, Chan, LL et al. (2009) Maternal nutrient restriction between early-to-mid gestation and its impact upon appetite regulation following juvenile obesity. Endocrinology 150, 634641.
37.Symonds, ME, Stephenson, T & Budge, H (2009) Early determinants of cardiovascular disease: the role of early diet in later blood pressure control. Am J Clin Nutr 89, 1518S1522S.
38.Bouret, SG, Draper, SJ & Simerly, RB (2004) Trophic action of leptin on hypothalamic neurons that regulate feeding. Science 304, 108110.
39.Yuen, BS, Owens, PC, Muhlhausler, BS et al. (2003) Leptin alters the structural and functional characteristics of adipose tissue before birth. FASEB J 17, 11021104.
40.Mostyn, A, Bispham, J, Pearce, S et al. (2002) Differential effects of leptin on thermoregulation and uncoupling protein abundance in the neonatal lamb. FASEB J 16, 14381440.
41.Gnanalingham, MG, Mostyn, A, Webb, R et al. (2005) Differential effects of leptin administration on the abundance of UCP2 and glucocorticoid action during neonatal development. Am J Physiol Endocrinol Metab 289, E1093E1100.
42.Gnanalingham, MG, Mostyn, A, Wang, J et al. (2005) Tissue-specific effects of leptin administration on the abundance of mitochondrial proteins during neonatal development. J Endocrinol 187, 8188.
43.Bispham, J, Budge, H, Mostyn, A et al. (2002) Ambient temperature, maternal dexamethasone, and postnatal ontogeny of leptin in the neonatal lamb. Pediatr Res 52, 8590.
44.Masuzaki, H, Ogawa, Y, Sagawa, N et al. (1997) Non-adipose tissue production of leptin: leptin as a novel placenta-derived hormone in humans. Nat Med 3, 10291033.
45.Cottrell, EC, Cripps, RL, Duncan, JS et al. (2009) Developmental changes in hypothalamic leptin receptor: relationship with the postnatal leptin surge and energy balance neuropeptides in the postnatal rat. Am J Physiol Regul Integr Comp Physiol 296, R631R639.
46.Giralt, M, Martin, I, Iglesias, R et al. (1990) Ontogeny and perinatal modulation of gene expression in rat brown adipose tissue. Unaltered iodothyronine 5′-deiodinase activity is necessary for the response to environmental temperature at birth. Eur J Biochem 193, 297302.
47.Vickers, MH, Gluckman, PD, Coveny, AH et al. (2008) The effect of neonatal leptin treatment on postnatal weight gain in male rats is dependent on maternal nutritional status during pregnancy. Endocrinology 149, 19061913.
48.Vickers, MH, Gluckman, PD, Coveny, AH et al. (2005) Neonatal leptin treatment reverses developmental programming. Endocrinology 146, 42114216.
49.Flanagan, DE, Vaile, JC, Petley, GW et al. (2007) Gender differences in the relationship between leptin, insulin resistance and the autonomic nervous system. Regul Pept 140, 3742.
50.Waterland, RA, Travisano, M, Tahiliani, KG et al. (2008) Methyl donor supplementation prevents transgenerational amplification of obesity. Int J Obes (Lond) 32, 13731379.
51.Wong, SL, DePaoli, AM, Lee, JH et al. (2004) Leptin hormonal kinetics in the fed state: effects of adiposity, age, and gender on endogenous leptin production and clearance rates. J Clin Endocrinol Metab 89, 26722677.
52.Laml, T, Preyer, O, Schulz-Lobmeyr, I et al. (2001) Umbilical venous leptin concentration and gender in newborns. J Soc Gynecol Investig 8, 9497.
53.Gluckman, PD, Lillycrop, KA, Vickers, MH et al. (2007) Metabolic plasticity during mammalian development is directionally dependent on early nutritional status. Proc Natl Acad Sci USA 104, 1279612800.
54.Despres, JP & Lemieux, I (2006) Abdominal obesity and metabolic syndrome. Nature 444, 881887.
55.Hedley, AA, Ogden, CL, Johnson, CL et al. (2004) Prevalence of overweight and obesity among US children, adolescents, and adults, 1999–2002. JAMA 291, 28472850.
56.Catalano, PM & Ehrenberg, HM (2006) The short- and long-term implications of maternal obesity on the mother and her offspring. Br J Obstet Gynaecol 113, 11261133.
57.Sewell, MF, Huston-Presley, L, Super, DM et al. (2006) Increased neonatal fat mass, not lean body mass, is associated with maternal obesity. Am J Obstet Gynecol 195, 11001103.
58.Rajasingam, D, Seed, PT, Briley, AL et al. (2009) A prospective study of pregnancy outcome and biomarkers of oxidative stress in nulliparous obese women. Am J Obstet Gynecol 200, 395.e391395.e399.
59.Samuelsson, AM, Matthews, PA, Argenton, M et al. (2008) Diet-induced obesity in female mice leads to offspring hyperphagia, adiposity, hypertension, and insulin resistance: a novel murine model of developmental programming. Hypertension 51, 383392.
60.McCurdy, CE, Bishop, JM, Williams, SM et al. (2009) Maternal high-fat diet triggers lipotoxicity in the fetal livers of nonhuman primates. J Clin Invest 119, 323335.
61.Warnes, DM, Seamark, RF & Ballard, FJ (1977) The appearance of gluconeogenesis at birth in sheep. Activation of the pathway associated with blood oxygenation. Biochem J 162, 627634.
62.Budge, H, Stephenson, T & Symonds, ME (2007) Maternal nutrient restriction is not equivalent to maternal biological stress. Curr Drug Targets 8, 888893.
63.Bertram, CE, Trowern, AR, Copin, N et al. (2001) The maternal diet during pregnancy programs altered expression of the glucocorticoid receptor and type 2 11b-hydroxysteroid dehydrogenase: Potential molecular mechanisms underlying the programming of hypertension in utero. Endocrinology 142, 28412853.
64.Symonds, ME, Budge, H, Mostyn, A et al. (2007) Maternal diet through pregnancy – the key to future good health of the next generation? In Nutrition Research Advances, pp. 223240 [Watkins, SV, editor]. New York: Nova Science Publishers, Inc.
65.Ahima, RS, Prabakaran, D & Flier, JS (1998) Postnatal leptin surge and regulation of circadian rhythm of leptin by feeding. Implications for energy homeostasis and neuroendocrine function. J Clin Invest 101, 10201027.