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Academic Division of Child Health (J.B., G.S.G., J.D., V.W., H.B., T.S., M.E.S.) and Academic Division of Obstetrics and Gynecology (F.B.P.), School of Human Development, University Hospital, Nottingham NG7 2UH, United Kingdom; and Department of Animal Sciences (D.H.K.), University of Missouri, Columbia, Missouri 65201
Address all correspondence and requests for reprints to: Dr. Michael E. Symonds, Academic Division of Child Health, School of Human Development, Queen’s Medical Centre, University Hospital, Nottingham NG7 2UH, United Kingdom. E-mail: Michael.Symonds{at}nottingham.ac.uk.
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Introduction |
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The precise molecular mechanisms underlying the programming of adult disease by maternal nutrient restriction remain a matter of debate. A severe period of nutrient restriction in late gestation results in an appreciable decrease in maternal plasma IGF-I concentration and reduced placental and fetal size (7). More modest changes in nutrient intake can influence the plasma concentration of a range of counter regulatory metabolic hormones, including those secreted from the adrenal and thyroid glands, the pituitary, as well as leptin release from adipose tissue (8, 9, 10, 11). The extent to which these may have an overriding effect on maternal metabolism so that the partition of nutrients to the fetus is altered has not been established. Recent experimental studies have suggested that fetal overexposure to maternal glucocorticoids triggers programming events in utero that lead to hypertension and persistent increases in glucocorticoid action throughout life (12, 13). However, in nonpregnant adult sheep, 4 d of food withdrawal has no effect on plasma cortisol (14), and in late gestation, a 50% reduction in maternal food intake only causes a transient rise in maternal plasma cortisol and has no effect on cortisol in the fetus (8). Whether other metabolic hormones, particularly leptin, may be consistently affected by undernutrition during pregnancy also remains unclear. In pregnant sheep, the effect of undernutrition on plasma leptin appears to be dependent on both the stage of gestation (15) and animal age (16). For growing adolescent sheep made pregnant by embryo transfer and fed a pelleted diet twice daily, either an increase or decrease in maternal nutrition up to 50 or 100 d gestation results in parallel changes in maternal leptin (16). In contrast, in ewes fed a mixture of roughage and concentrate, nutrient restriction in late gestation has no effect on maternal plasma leptin (17).
The aim of the present study was to examine whether nutrient restriction of pregnant ewes sufficient to meet 60% of their metabolizable energy (ME) requirements between 28 and 80 d gestation alters maternal leptin or cortisol status. This period was chosen because it is after the time of embryo development, coincides with the main period of placental growth (18), and is coincident with the stage at which maternal plasma leptin concentrations are near maximal (16). The effects of nutrition on other important metabolic hormones during pregnancy (IGF-I, prolactin, and T4) together with glucose, nonesterified fatty acid (NEFA), and urea nitrogen were also examined. At the same time, we determined whether fetal adipose tissue endocrine sensitivity, as evidenced by mRNA abundance of leptin and IGF-I and IGF-II and their receptors, may also be reprogrammed as a consequence of nutrient restriction.
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Materials and Methods |
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60% of ME requirements) or 8.7–9.9 MJ/d of ME in the group fed to appetite (150% of ME requirements). The amount of feed given to each ewe was increased at 43 and 61 d gestation to meet the higher energy requirements associated with growth of the conceptus (20). The diet comprised chopped hay that had an estimated ME content of 7.91 MJ/kg dry matter and a crude protein content (nitrogen x 6.25) of 69 g/kg dry matter and a barley-based concentrate that had an estimated ME content of 11.6 MJ/kg dry matter and a crude protein content of 162 g/kg dry matter. The proportion of hay to concentrate fed was approximately 3:1 with respect to dry weight. All diets contained adequate minerals and vitamins. Body condition score was measured every 2 wk. After 80 d gestation, equal numbers of ewes from each group either were fed to appetite and consumed between 8–10.9 MJ/d of ME (150% of ME requirements) up to 140 d gestation (term = 147 d) or were offered sufficient feed to meet 100% of the ME requirements as calculated to produce a 4.5-kg newborn lamb. These animals consumed between 6.5 and 7.5 MJ/d of ME. For all of these animals, the amount of feed provided was increased at 100 and 120 d gestation to meet the increased ME requirements that accompany the increase in fetal weight with gestation.
Experimental design
Maternal blood sampling.
Approximately 2 wk before mating and at individual housing at 28 d gestation, blood samples were taken by venepuncture from all ewes. At approximately 20-d intervals between 41 and 139 d gestation, jugular venous catheters were inserted into seven NR ewes and seven ewes fed to appetite, and blood samples taken hourly the following day from 0800 h until 1600 h, with feeding at approximately 0900 h. This protocol was confined to those ewes that were fed to appetite after 80 d gestation. All samples were taken into heparinized syringes, transferred into ice-cold tubes, and centrifuged at 3000 rpm for 30 min. The plasma was removed and stored at -20 C until analyzed.
Tissue sampling.
At 80 d gestation, six NR ewes and five well-fed ewes were euthanized by administration of 100 mg/kg pentobarbital sodium (euthatal). The entire uterus was removed, and the fetus was killed with barbiturate. From each ewe, a number of randomly chosen A type placentomes [which represent the majority of placentomes (21, 22)] were immediately dissected. These were then separated into their maternal and fetal components, placed in liquid nitrogen, and stored at -80 C until analyzed together with a sample of maternal omental adipose tissue from each ewe. In addition, whole placentomes were fixed in 10% (wt/vol) formalin and embedded in paraffin wax for histological analysis. Total placental weights were recorded as previously published by Dandrea et al. (23). At 140 d gestation, the same sampling procedure was repeated on 10 previously NR ewes and 10 ewes fed to appetite, of which half of each group had been fed to requirements from 80 d gestation. At this stage, the fetus was also weighed and dissected to enable sampling and storage of perirenal adipose tissue (which constitutes 80% of adipose tissue in a fetal sheep) and the hypothalamic region. All operative procedures and experimental protocols had the required Home Office approval as designated by the Animals (Scientific Procedures) Act (1986).
RNA analysis
Total RNA was isolated from adipose and placental tissue using Tri-Reagent (Sigma, Poole, UK) as previously described by Bispham et al. (24). Each set of cDNA primers is described in Table 1
, and mRNA abundance was determined using RT-PCR with the same protocol as outlined by Bispham et al. (24). In the case of increasing the RT-PCR conditions to detect mRNA for the leptin receptor in adipose tissue and the placenta, the number of cycles was increased to 40, and temperature ranges from 58.2–60.7 C were examined. Agarose gel electrophoresis (2.0%) and ethidium bromide staining confirmed the presence of both the amplicon under test and 18S products of the expected sizes. Each assay was performed in triplicate on all samples from each group of ewes. In the case of placental analysis, a mean value of the maternal and fetal placental leptin mRNA abundance measured separately from each ewe was used in subsequent statistical analyses.
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Metabolite and hormone analysis
Plasma concentrations of glucose and NEFA were measured enzymatically, and T4 was measured by RIA as described by Clarke et al. (21). The concentration of IGF-I was determined by ELISA as described by Heasman et al. (26). Plasma prolactin was also analyzed by RIA using the methods described by McMillen et al. (27). Plasma concentrations of prolactin were assayed in duplicate after a 1:10 and a 1:50 dilution using a rabbit antiovine prolactin primary antibody, iodinated ovine prolactin, and goat antirabbit secondary antibody. The intra- and interassay coefficients of variation for the assay were 3 and 9% (n = 5), respectively. Leptin was determined using a validated double antibody RIA as described by Delavaud et al. (28). Plasma concentrations of leptin were assayed in duplicate 200-µl samples using a rabbit antiovine leptin primary antibody, iodinated ovine leptin, and sheep antirabbit secondary antibody. The leptin intra- and interassay coefficients of variation were 4 and 11% (n = 5), respectively. Total cortisol was measured by coated-tube RIA (Coat-a-count, Diagnostic Products Corp. Ltd., Caernarfon, UK) and urea nitrogen by UV ELISA [BUN (Endpoint), Sigma Diagnostics, Gillingham, UK].
Statistical analysis
Plasma metabolite and hormone profiles throughout gestation were analyzed for effect of diet, gestational age, and their interaction by a general linear model (SPSS version 9.0, SPSS Inc., Chicago, IL). This combines ANOVA with regression, allowing analysis of a dependent variable against one or more qualitative independent variables without any assumption about the nature of their relationship. We performed a repeated-measure general linear model that analyses the independent differences between groups of related data that have been measured more than twice, considering the effects both alone and as interactions. Significant differences in ewe body weights, body condition score, and plasma leptin concentration between preconception and 28 d gestation were assessed by Mann-Whitney U test.
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Results |
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). As a result, both body weight and condition score were significantly higher (P < 0.01) in the group fed to appetite from 42–100 d gestation (Fig. 2). After 80 d gestation, when all of these ewes were offered the same amount of feed, intake gradually increased in previously NR ewes to plateau at around 109 d gestation. There was no difference in food intake between groups when all ewes were fed to appetite.
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). This effect was no longer apparent once the diet of the NR group was restored. Notably, there was an increase in plasma cortisol between 80 and 100 d gestation in both groups of ewes, irrespective of previous nutritional regime.
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). As a consequence, plasma leptin was significantly lower (P < 0.002) in NR ewes compared with well-fed ewes at all sampling points with the exception of 140 d gestation.
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). Irrespective of feeding group, an increase in plasma T4 and IGF-I occurred in all ewes after 80 d gestation, to peak at 140 d gestation. Plasma prolactin was, however, similar between groups over the period of nutrient restriction and increased in both groups up to 140 d gestation (Table 2).
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). Plasma NEFA concentrations were significantly higher (P < 0.01) in NR ewes compared with those fed to appetite at 42, 60, and 80 d gestation (Fig. 6). There was no difference between groups in plasma urea nitrogen concentration (Table 2
), which remained unchanged throughout gestation before declining at 140 d gestation.
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). Irrespective of weight at birth, fetuses sampled from ewes NR between 28 and 80 d gestation had significantly more (P < 0.05) adipose tissue than those sampled from ewes fed to appetite. This effect was irrespective of maternal nutrition in the second half of gestation, although fetuses of ewes fed to appetite in late gestation had less adipose tissue than those fed only to 100% of ME requirements.
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). This response was unaffected by maternal nutrition in late gestation and was in the absence of any effect on IGF-I or IGF-II mRNA (Table 3). Leptin mRNA abundance was, however, not influenced by maternal nutrition in early gestation and was reduced in fetuses sampled from ewes fed to appetite in late gestation (Fig. 8).
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), and the leptin receptor was only detectable in the hypothalamus. Similarly, although leptin could be detected in adipose tissue by immunocytochemistry, it was not present in the placenta (Fig. 10). Neither maternal nutrition nor stage of gestation had any influence on the abundance of leptin mRNA in maternal adipose tissue (e.g. fed to appetite, 80 d gestation, 30 ± 8; 140 d gestation, 40 ± 11 leptin mRNA as a percentage of 18S rRNA). There was no difference in leptin mRNA expression in placenta of NR ewes and ewes fed to appetite at either sampling age or between 80 and 140 d gestation (e.g. 80 d gestation, NR, 59 ± 5; fed to appetite, 55 ± 6 leptin mRNA as a percentage of 18S rRNA) or between the maternal and fetal components of the placenta at either gestational age (results not shown).
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Discussion |
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Maternal nutrition and cortisol
The finding of a reduction in maternal cortisol during a prolonged period of nutrient restriction is likely to be due to a decrease in maternal cortisol secretion. A reduction in maternal cortisol, together with lower plasma leptin, IGF-I, and T4, may act to reduce maternal carbohydrate oxidation and promote lipolysis, as indicated by the rise in maternal NEFA, thereby maximizing potential glucose supply to the growing placenta and fetus. Despite this adaptation, placental growth is still compromised at 80 d gestation (21, 23), although total fetal weight remains very similar to controls. Furthermore, fetal weight was actually lowest in those sheep fed to appetite up to 80 d and then fed to requirements for the remainder of gestation. This suggests that the calculated total energy requirements in late gestation, necessary to produce a 4.5-kg newborn lamb, may be underestimated for ewes that have previously been fed to appetite.
The reason why maternal nutrient restriction has a markedly different effect on cortisol between early to mid gestation compared with late gestation (8) may be due to the much higher fetal glucose demands in late gestation (30). It is notable that there was a significant rise in plasma cortisol between 80 and 100 d gestation in all ewes. This was coincident with the time in which plasma leptin decreased in the well-fed group and was not accompanied with any change in maternal plasma IGF-I, prolactin, or T4. It is also the stage of gestation at which placental growth, in terms of an increase in tissue weight, ceases but large changes in placental vasculature occur (31). These adaptations within the placenta are critical in enabling the increased metabolic demands of the fetus to be met during late gestation, a process that may be promoted by the concomitant rise in maternal cortisol.
Chronic maternal cortisol infusion during late gestation results in a reduction in placental size (32). Previous studies have proposed that excess fetal cortisol exposure is the mechanism by which fetal development is programmed after nutrient restriction, thereby resulting in an increased predisposition to adult CVD (33, 34). An adaptation of this kind has been suggested to be due to increased maternal cortisol and/or a reduction in the capacity of the placenta to inactivate cortisol via the enzyme 11ß-hydroxysteroid dehydrogenase (11ßHSD) type 2. Using the same nutritional manipulation as adopted in the present study, it has previously been shown that placental 11ßHSD type 2 activity is reduced at 80 d gestation (35). It is not known whether such an effect would persist up to term when 11ßHSD type 2 activity normally decreases (36). Moreover, infusion of cortisol into the fetus results in reduced 11ßHSD type 2 activity. The finding that maternal cortisol is actually decreased by nutrient restriction suggests that the lower placental 11ßHSD type 2 previously observed (35) may be a specific adaptation to lower rather than higher maternal cortisol. This would also explain the lack of any difference in cord plasma cortisol at 80 d gestation between nutritional groups (37).
The regulation of leptin during pregnancy
Lower plasma cortisol concentrations in NR ewes were accompanied by reduced leptin, IGF-I, and T4 concentrations. The failure of NR ewes to increase plasma leptin up to 80 d gestation is likely to reflect the mobilization of body fat because leptin mRNA abundance was very low and leptin protein was undetectable in the ovine placenta. The apparent dissociation between leptin mRNA and protein data from the placenta as determined by immunocytochemistry suggests that either leptin mRNA is not being translated into protein, or that the protein is only present in very low amounts and therefore immunocytochemistry is not sufficiently sensitive to detect it.
Previous studies have indicated that mRNA for the leptin receptor is expressed in the ovine placenta (16), a finding we could not confirm. The primer sequences used in this earlier publication did not extend over an intron-spanning domain and, hence, the potential confounding effect of nonspecific detection of genomic DNA may explain why leptin receptor mRNA appeared to be detected. We used two different sets of primers, both of which included an intron-spanning domain. Each detected appreciable amounts of leptin receptor mRNA in the hypothalamus, the primary site of expression, but neither was able to detect mRNA within the placenta in either nutrition group, at either mid or late gestation. We, therefore, conclude that leptin secretion from the placenta does not have a major local endocrine role in the sheep. This suggestion is in accord with findings in the ob/ob mouse for which leptin is essential for conception and implantation but not fetal development (38). Leptin secretion by the fetus may therefore only act as a nutritional modulator of energy balance in response to increased or decreased maternal food intake in late gestation (17).
The increase in plasma leptin up to 80 d gestation in ewes fed to appetite is in accord with findings by others (15, 16). It has been proposed that this effect is due to increased secretion from maternal adipose tissue depots for which a rise in mRNA abundance occurs with gestation within tail adipose tissue (15). This is, however, only a minor site of adipose deposition for sheep. We could detect no difference in leptin mRNA abundance between nutritional groups at 80 d gestation using samples taken from the omental region (which represent 20% of total maternal adipose tissue). It is possible that changes in blood flow to maternal adipose tissue, as a result of the increased mobilization of fat stores by NR ewes, may have prevented any increase in maternal leptin with gestational age. Adaptations in maternal adipose tissue metabolism during nutrient restriction may be mediated by low maternal plasma T4 that decreased in parallel with leptin after dietary restriction.
Maternal nutrition and the programming of fetal adipose tissue development
The enhanced adipose tissue deposition in near-term fetuses sampled from previously NR ewes is further evidence that fetal adiposity can be programmed in utero (17). Our findings suggest that the increased incidence of obesity in adults born to mothers exposed to the Dutch famine during early pregnancy (29) may be a direct consequence of adaptations in the endocrine sensitivity of fetal adipose tissue. In both sheep and humans, fetal adipose tissue is primarily deposited during the final third of gestation (39). Over this period, there is an increased abundance of circulating hormones within the fetal circulation that are important in regulating fetal adipose tissue development (40), and these include IGF-I and leptin (41, 42). The extent to which mRNA abundance within adipose tissue was increased or decreased between nutritional groups at term was determined by maternal nutrition both in the first and second halves of gestation. A reduction in maternal nutrition between early to mid gestation, therefore, resulted in increased mRNA abundance for both the IGF-I and IGF-II receptors in conjunction with enhanced adipose tissue deposition, irrespective of the level of maternal nutrition in late gestation. In vitro, IGF-I has been shown to have an anabolic effect on fetal adipose tissue growth (41). Fetal plasma concentration of IGF-I is normally positively related to fetal glucose supply (43) for which an increase in nutrient flux may also contribute to greater mRNA abundance for the receptor, thereby promoting tissue sensitivity to IGF-I. As a consequence, IGF-I may have an anabolic effect on growth of specific tissues in the absence of a significant change in plasma concentration. This may also explain the loss of the normal relationship between fetal dimensions and organ weights at term and plasma IGF-I we have previously described in NR offspring (26). A reduction in IGF-II receptor mRNA abundance within a range of fetal tissues including the liver, kidney, heart, and muscle have been positively associated with fetal overgrowth after in vitro fertilization of sheep (44). It has, therefore, been suggested that reduced abundance of the IGF-II receptor acts to remove some of the fetal constraints on growth, although whether this extends to adipose tissue growth is not known. Our findings, therefore, indicate that although IGF-I and IGF-II mRNA are both already highly abundant within adipose tissue, an up-regulation of their receptor mRNA can promote adipose tissue deposition.
Plasma leptin is normally low in the late gestation ovine fetus and does not respond to changes in maternal nutrition over the final month of gestation (17), but it is positively correlated with both body weight and leptin mRNA abundance in perirenal adipose tissue in some (24, 42), but not all (45), studies to date. It has been further suggested that leptin may act as a signal of unilocular fat mass in the fetus when maternal nutrient intake is fixed at or above maintenance (46), although fetal plasma leptin concentrations in the latter were much higher than all other studies to date, i.e. 2–9 ng/ml compared with 1–1.5 ng/ml (17, 24). The finding in the present study that adipose tissue deposition was reduced in conjunction with a lower abundance of leptin mRNA may be representative of the normal physiological situation because ewes were allowed to eat to appetite throughout the second half of gestation and were not subjected to any fetal surgery. Any extra available energy may be used to promote the growth of fetal tissues other than adipose tissue, which has a much greater energetic requirement than all other tissues. The role of leptin in the fetus remains to be established, although it is interesting to note that intracerebroventricular infusion of leptin dampens the increase in fetal ACTH and cortisol pulses near to term (47). The fetus, however, has no direct regulation of food intake, and its growth is limited by nutrient availability with an increase promoting somatotrophic growth rather than fat deposition. The extent to which a reduction in leptin secretion from fetal adipose tissue would potentially benefit the fetus at a time when nutrient supply is not limited remains to be investigated.
It has been established that glucocorticoid receptor mRNA abundance is enhanced in adipose tissue of NR offspring, in conjunction with decreased mRNA and activity for 11ßHSD type 1 (35). The enzyme 11ß-HSD type 1 acts predominantly as an 11-oxoreductase catalyzing the conversion of cortisone to bioactive cortisol (48, 49), and transgenic mice in which 11ß-HSD type 1 is overexpressed show substantially increased visceral adipose tissue deposition at 18 wk of age (50). The extent to which altered abundance of mRNA for leptin, IGF-I, or IGF-II receptors may be mediated by an increased sensitivity and/or production of cortisol within adipocytes of NR offspring remains to be confirmed. Chronic infusion of cortisol into the fetus has no effect on leptin in adipose tissue (51). It is, therefore, possible that the effects of cortisol on tissue growth may differ depending on whether cortisol exposure is increased by an endocrine or paracrine route. Alternatively, the relationship between fetal plasma leptin and cortisol may be changed after intrauterine growth retardation because the study in which these two indices were positively correlated involved small fetuses with minimal amounts of perirenal adipose tissue (i.e. approximately 8 g compared with 20 g in the present study) and very low plasma leptin, i.e. 0.2–0.5 ng/ml (52) compared with 1–1.5 ng/ml published by others (17, 24).
In conclusion, maternal nutrient restriction over the period of rapid placental growth does not result in a maternal stress response as plasma cortisol is reduced. After the restoration of maternal nutrition over the second half of gestation, fetal adipose tissue development is enhanced, which may act to place these individuals at increased risk of obesity in later life. In contrast, allowing the mother to feed to appetite over the second half of gestation promotes fetal growth while limiting adipose tissue growth.
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Acknowledgments |
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Footnotes |
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Abbreviations: CVD, Cardiovascular disease; 11ßHSD, 11ß-hydroxysteroid dehydrogenase; ME, metabolizable energy; NEFA, nonesterified fatty acid; NR, nutrient-restricted.
Received March 13, 2003.
Accepted for publication April 24, 2003.
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 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]
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K A Brennan, G S Gopalakrishnan, L Kurlak, S M Rhind, C E Kyle, A N Brooks, M T Rae, D M Olson, T Stephenson, and M E Symonds Impact of maternal undernutrition and fetal number on glucocorticoid, growth hormone and insulin-like growth factor receptor mRNA abundance in the ovine fetal kidney Reproduction, February 1, 2005; 129(2): 151 - 159. [Abstract] [Full Text] [PDF]
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L. J. Edwards, J. R. McFarlane, K. G. Kauter, and I. C. McMillen Impact of periconceptional nutrition on maternal and fetal leptin and fetal adiposity in singleton and twin pregnancies Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2005; 288(1): R39 - R45. [Abstract] [Full Text] [PDF]
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M. Desai, D. Gayle, J. Babu, and M. G. Ross Programmed obesity in intrauterine growth-restricted newborns: modulation by newborn nutrition Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2005; 288(1): R91 - R96. [Abstract] [Full Text] [PDF]
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K. L. Kind, C. T. Roberts, A. I. Sohlstrom, A. Katsman, P. M. Clifton, J. S. Robinson, and J. A. Owens Chronic maternal feed restriction impairs growth but increases adiposity of the fetal guinea pig Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2005; 288(1): R119 - R126. [Abstract] [Full Text] [PDF]
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F. H. Bloomfield, M. H. Oliver, P. Hawkins, A. C. Holloway, M. Campbell, P. D. Gluckman, J. E. Harding, and J. R. G. Challis Periconceptional Undernutrition in Sheep Accelerates Maturation of the Fetal Hypothalamic-Pituitary-Adrenal Axis in Late Gestation Endocrinology, September 1, 2004; 145(9): 4278 - 4285. [Abstract] [Full Text] [PDF]
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G. S. Gopalakrishnan, D. S. Gardner, S. M. Rhind, M. T. Rae, C. E. Kyle, A. N. Brooks, R. M. Walker, M. M. Ramsay, D. H. Keisler, T. Stephenson, et al. Programming of adult cardiovascular function after early maternal undernutrition in sheep Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2004; 287(1): R12 - R20. [Abstract] [Full Text] [PDF]
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 H. Budge, L.J. Edwards, I.C. McMillen, A. Bryce, K. Warnes, S. Pearce, T. Stephenson, and M.E. Symonds Nutritional Manipulation of Fetal Adipose Tissue Deposition and Uncoupling Protein 1 Messenger RNA Abundance in the Sheep: Differential Effects of Timing and Duration Biol Reprod, July 1, 2004; 71(1): 359 - 365. [Abstract] [Full Text] [PDF]
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 Gastroenterology, hepatology, and nutrition Arch. Dis. Child., April 1, 2004; 89(suppl_1): A13 - A16. [Full Text] [PDF]
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Endocrinology and diabetes Arch. Dis. Child., April 1, 2004; 89(suppl_1): A51 - A53. [Full Text] [PDF]
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