Maternal parity and its effect on adipose tissue deposition and endocrine sensitivity in the postnatal sheep

in Journal of Endocrinology

Maternal parity influences size at birth, postnatal growth and body composition with firstborn infants being more likely to be smaller with increased fat mass, suggesting that adiposity is set in early life. The precise effect of parity on fat mass and its endocrine sensitivity remains unclear and was, therefore, investigated in the present study. We utilised an established sheep model in which perirenal–abdominal fat mass (the major fat depot in the neonatal sheep) increases ∼10-fold over the first month of life and focussed on the impact of parity on glucocorticoid sensitivity and adipokine expression in the adipocyte. Twin-bearing sheep of similar body weight and adiposity that consumed identical diets were utilised, and maternal blood samples were taken at 130 days of gestation. One offspring from each twin pair was sampled at 1 day of age, coincident with the time of maximal recruitment of uncoupling protein 1 (UCP1), whilst its sibling was sampled at 1 month, when UCP1 had disappeared. Plasma leptin was lower in nulliparous mothers than in multiparous mothers, and offspring of nulliparous mothers possessed more adipose tissue with increased mRNA abundance of leptin, glucocorticoid receptor and UCP2, adaptations that persisted up to 1 month of age when gene expression for interleukin-6 and adiponectin was also raised. The increase in fat mass associated with firstborn status is therefore accompanied by a resetting of the leptin and glucocorticoid axis within the adipocyte. Our findings emphasise the importance of parity in determining adipose tissue development and that firstborn offspring have an increased capacity for adipogenesis which may be critical in determining later adiposity.

Abstract

Maternal parity influences size at birth, postnatal growth and body composition with firstborn infants being more likely to be smaller with increased fat mass, suggesting that adiposity is set in early life. The precise effect of parity on fat mass and its endocrine sensitivity remains unclear and was, therefore, investigated in the present study. We utilised an established sheep model in which perirenal–abdominal fat mass (the major fat depot in the neonatal sheep) increases ∼10-fold over the first month of life and focussed on the impact of parity on glucocorticoid sensitivity and adipokine expression in the adipocyte. Twin-bearing sheep of similar body weight and adiposity that consumed identical diets were utilised, and maternal blood samples were taken at 130 days of gestation. One offspring from each twin pair was sampled at 1 day of age, coincident with the time of maximal recruitment of uncoupling protein 1 (UCP1), whilst its sibling was sampled at 1 month, when UCP1 had disappeared. Plasma leptin was lower in nulliparous mothers than in multiparous mothers, and offspring of nulliparous mothers possessed more adipose tissue with increased mRNA abundance of leptin, glucocorticoid receptor and UCP2, adaptations that persisted up to 1 month of age when gene expression for interleukin-6 and adiponectin was also raised. The increase in fat mass associated with firstborn status is therefore accompanied by a resetting of the leptin and glucocorticoid axis within the adipocyte. Our findings emphasise the importance of parity in determining adipose tissue development and that firstborn offspring have an increased capacity for adipogenesis which may be critical in determining later adiposity.

Keywords:

Introduction

Worldwide childhood obesity is increasing, an occurrence that is of great concern as it often tracks through to adulthood, suggesting that adiposity is set in early life (Field et al. 2005). The cause of obesity is multifactorial with environmental, biological and genetic factors all having an influence (Rosenbaum et al. 1997), although the relative contribution of each remains uncertain. There is, however, evidence that reduced foetal growth can promote later adiposity, particularly if accompanied by accelerated postnatal growth (Ong et al. 2000, Stettler et al. 2003). Maternal parity can determine birth weight (Lumey & Stein 1997, Gardner et al. 2007), postnatal growth and the longer term health of the offspring (Bai et al. 2002, Ong et al. 2002), resulting in increased fat mass in both school children (Wilkinson et al. 1977) and adolescents (Celi et al. 2003, Wang et al. 2007). Surprisingly, no study to date has looked at the cellular mechanisms mediating this response. We have previously reported the effect of maternal parity on foetal and postnatal development using a sheep model (Hyatt et al. 2007), and found that, like humans, being firstborn is associated with being smaller at birth. These offspring also have pronounced differences in their hepatic GH–insulin-like growth factor (IGF) axis that may impact upon their postnatal growth (Hyatt et al. 2007).

In addition to providing an endogenous energy storage, adipose tissue secretes a number of cytokines and peptides, termed adipokines, which are involved in regulating insulin sensitivity, appetite, energy balance, inflammation and lipid metabolism (see Trayhurn & Wood 2004). Excess fat mass that accompanies obesity appears to be established in early life and is associated with a state of chronic low-grade inflammation where pro-inflammatory cytokines such as interleukin 6 (IL6) are raised, whilst anti-inflammatory markers including adiponectin are decreased in proportion to fat mass (Das 2001). Other important endocrine factors that are susceptible to in utero programming and critical in determining adipose tissue function and later adiposity include the glucocorticoid receptor (GR or NR3C1 as listed in the HUGO Database) and the enzymes 11β-hydroxysteroid dehydrogenase (HSD11B) types 1 and 2 as well as uncoupling protein 2 (UCP2) and peroxisome proliferator-activated receptor γ (PPARG; Whorwood et al. 2001, Bispham et al. 2005, Gnanalingham et al. 2005b, Berthiaume et al. 2007, De Sousa Peixoto et al. 2008). Gene expression and function of these proteins are dependent in part on the maternal diet through pregnancy (Whorwood et al. 2001, Bispham et al. 2005, Gnanalingham et al. 2005b) that can also determine later adipose tissue function. Using our previously established animal model of maternal parity (Hyatt et al. 2007), we have now investigated the impact of maternal parity on adipose tissue development with regard to glucocorticoid sensitivity and adipokine gene expression. Our analysis was focussed on the perirenal–abdominal depot as this is the largest fat depot in the newborn sheep and undergoes rapid growth after birth (Clarke et al. 1997a) that is accompanied by adaptations in its inflammatory and related responses (Sharkey et al. 2009b). We hypothesised that gene expression of key regulators of adipose tissue function and composition would be increased in firstborn offspring during early postnatal development as fat deposition is enhanced over this period.

Materials and Methods

Animals and experimental design

Fifteen twin-bearing (six nulliparous (N) and nine multiparous (M)) Border Leicester X Swaledale sheep that were all reproductively mature adults were entered into the study. Nulliparous sheep were 2 years old and had never been previously mated, whilst the multiparous sheep were aged 3–4 years and had all experienced two previous successful pregnancies, which is important because there is little increase in birth weight after a second pregnancy (Gardner et al. 2007). There were no differences in maternal weight gain or body condition score (BCS) throughout pregnancy as determined by repeated weighing and body condition scoring at fortnightly intervals (e.g. 110 days of gestation – N 80.2±2.4; M 76.5±3.0 kg; BCS – N 2.5±0.2; M 2.6±0.3 and 140 days of gestation – N 82.2±2.8; M 79.5±3.5 kg; BCS – N 2.2±0.2; M 2.4±0.4). Following conception, animals were group-housed, and they consumed 100% of total metabolisable energy requirements for maternal body weight and stage of twin pregnancy. The diet comprised chopped hay and concentrate, and it was provided in a 3:1 weight ratio with all animals having access to a mineral block and fresh water. Offspring were delivered naturally at term (i.e. 145±2 days), and birth weights were recorded. Within 6 h of birth, one twin was randomly selected from each mother to be tissue sampled following humane euthanasia using an i.v. injection of barbiturate (100 mg/kg pentobarbital sodium: Euthatal: RMB Animal Health, Dagenham, UK). The perirenal–abdominal adipose tissue (PAT) depots were completely dissected out and weighed, and a representative sample was stored at −80 °C until further analysis (Hyatt et al. 2007). Mothers were housed with their remaining offspring and were fed a diet of hay ad libitum, together with a fixed amount of concentrate that was sufficient to fully meet their own energy requirements plus that required for lactation. Thus, the remaining twin was reared as a singleton with its mother until tissue sampling at 30 days postnatal age as described above. The resultant groups with regard to gender were 1 day: N, three males: three females; M, four males: five females and 30 days: N, one male: five females; M, six males: three females. There was no effect of gender, either within or between twin sets, on birth weight (<15% difference) irrespective of maternal parity. It should be noted that the aim of this study was not to examine any differential effect of gender on adipose tissue development.

Laboratory measurements

Blood sampling and plasma measurements

All mothers had a jugular vein catheter inserted under local anaesthesia to enable fasted maternal blood sampling (0800 h; 5 ml) to be carried out at 130 days of gestation. A 5-ml venous blood sample from the offspring was also collected into heparinised syringes prior to dissection at 1 and 30 days of age. Blood samples were centrifuged at 800 g at 4 °C for 15 min, and plasma supernatant was transferred to a sterile 1.5-ml Eppendorf tube (within 10 min of collection) and stored at −20 °C. Plasma leptin and cortisol (Coat-a-Count; Euro DPC, Caernarfon, UK) were measured by RIA (Delavaud et al. 2000, Gardner et al. 2006), and plasma IGF1 was assessed by ELISA (OCTEIA IGF1; IDS Ltd, Tyne and Wear, UK). Plasma glucose (Randox GPO-PAP; Randox, Crumlin, UK) and non-esterified fatty acid (NEFA; NEFA-c Kit; Wako Chemicals GmbH, Neuss, Germany) concentrations were assessed spectrophotometrically (Sebert et al. 2009).

Total RNA isolation, reverse transcription and standard curve generation

Total RNA was extracted from 1 g of frozen PAT using Tri-Reagent (Sigma). Total RNA samples were treated for potential genomic DNA contamination with DNase 1 (Promega Ltd), and their A260/A280 ratio was assessed to confirm purity and concentration. cDNA was synthesised from 3 μg RNA using 200 U Superscript II (Invitrogen Ltd) by reverse transcription in accordance with the manufacturer's protocol. For standard curve generation, 1–10−8 ng/μl of primer-specific gel-purified amplicon was used to ensure PCR amplification efficiency (1.95–2.0) as described previously (Williams et al. 2007). 18S rRNA was used as a housekeeping gene, and results were calculated using the 2−ΔCt method (Livak & Schmittgen 2001). Gene expression data are normalised to the 1-day-old group born to multiparous mothers and are presented as a fold change.

Quantitative real-time PCR analysis

The relative abundance of GR, HSD11B-1/2, adiponectin, leptin, IL6, tumour necrosis factor α (TNFα), insulin receptor, PPARA/G, UCP1/2, IGF1 receptor (R), IGF2R, IGF binding protein (BP) and 18S mRNA transcripts were determined by qRT-PCR amplification using a real-time thermocycler (Quantica, Techne Incorporated, Barloworld Scientific Ltd, Stone, UK) and Quantitect SYBR green PCR kit (Qiagen Ltd) as described previously (Williams et al. 2007). Primer sequences have been published previously (Bispham et al. 2005, Hyatt et al. 2007, Muhlhausler et al. 2007, Williams et al. 2007, Sebert et al. 2009) with the exception of HSD11B1 (F: GTG CCA GAT CCC TGT CTG AT, R: AGC GGG ATA CCA CCT TCT TT (60 °C)), HSD11B2 (F: AGC AGG AGA CAT GCC GTT TC, R: AGC GGG ATA CCA CCT TCT TT (60 °C)) and IL6 (F: TGG AGG AAA AAG ATG GAT GC, R: GAC ATG CTG GAG AAG ATG CA (60 °C)). Real-time PCR conditions were set at 95 °C (15 min); 45 cycles of 94 °C (30 s), annealing temperature (30 s) followed by 72 °C (8 min). Melt curves were generated to confirm reaction specificity. Real-time PCRs were performed in duplicate with appropriate positive and negative controls as described previously (Williams et al. 2007).

Protein detection

Mitochondria were prepared from ∼1 g of PAT, and protein content was determined using the Lowry method (Lowry et al. 1951). Western blotting was utilised to measure UCP1 abundance in 10 μg of mitochondrial protein as described previously (Mostyn et al. 2003).

Statistical analysis

All data were explored for normality of their distribution using the Kolmogorov–Smirnov test and were log transformed where necessary (SPSS version 16.0, Chicago, IL, USA). Plasma concentrations and gene abundance were compared by general linear model analysis. The terms fitted to the model were maternal parity, age and parity×age interactions. The present study was neither designed nor powered to analyse the effect of gender, therefore offspring gender was added to the model as a covariate. Where parity×age interactions were present, further independent sample t-tests were performed to identify within which postnatal age group parity differences lay. Data are expressed as mean values with their standard errors. For all comparisons, statistical significance was accepted when a probability of 5% was observed (P<0.05).

Results

Offspring body weight and adiposity

Offspring born to nulliparous mothers were lighter at birth and had significantly more PAT (Table 1). At 30 days after birth, despite achieving a similar body weight, firstborn offspring still possessed greater fat mass.

Table 1

Mean body and adipose tissue weight and plasma insulin-like growth factor 1 (IGF1) and cortisol concentrations of 1-day-old and 30-day-old offspring born to nulliparous and multiparous mothers. Data are given as means with their standard errors (n=5–9 per group). Significant effects of maternal parity and postnatal age were analysed using a two-way ANOVA. Data are presented as means±s.e.m

1 day of age30 days of age
NulliparousMultiparousNulliparousMultiparous
Body weight (kg)3.9±0.2*4.6±0.217.1±0.7*,‡17.9±0.4†,‡
PAT mass (g)17.0±1.611.7±1.3150±2384.3±24.2
Relative PAT (g/kg)4.2±0.2*2.6±0.39.7±1.2*,‡5.3±1.9†,‡
Plasma IGF1 (nmol/l)8.3±1.311.3±1.647.9±3.8*,∥66.2±3.8†,∥
Plasma cortisol (nmol/l)173±18179±2178±1949±13

*,†Different superscripts within an age group denote statistically significant effect of parity (P<0.05). P<0.05, P<0.005 mean values are significantly different from those of the respective 1-day-old group. PAT, perirenal–abdominal adipose tissue.

Maternal and neonatal plasma metabolites

Maternal plasma leptin concentration, as measured in late gestation, was substantially higher in multiparous mothers than in nulliparous mothers (N: 1.1±0.3, M: 5.2±0.9 ng/ml, P<0.005). A similar difference but of much smaller magnitude was also seen in their offspring at birth (N: 0.6±0.2, M: 1.9±0.6 ng/ml, P<0.05). In contrast, parity had no effect upon offspring plasma IGF1 or cortisol concentrations at birth (Table 1). However, plasma IGF1 was lower in 30-day-old offspring born to nulliparous mothers despite increasing with postnatal age in both groups, whilst plasma cortisol decreased with age in all offspring. Neither plasma glucose nor NEFAs were affected by parity (data not shown).

Adipokine gene abundance

Leptin mRNA abundance was persistently higher in offspring born to nulliparous mothers irrespective of sampling age (Table 2; P<0.05). Maternal parity had no effect upon adiponectin or IL6 mRNA abundance at birth, but both were raised in offspring born to nulliparous mothers by 1 month of age. Neither maternal parity nor postnatal age had any effect upon TNFα mRNA abundance.

Table 2

Effect of maternal parity and postnatal age on mitochondrial gene expression (uncoupling protein 1/2 (UCP1/2), peroxisome proliferator-activated receptor α (PPARA) and PPARG) and IGF1R and IGF2R mRNAs. Data are given as means with their standard errors (n=5–9 per group). Significant effects of maternal parity and postnatal age were analysed using a two-way ANOVA. Data are presented as means±s.e.m

1 day of age30 days of age
NulliparousMultiparousNulliparousMultiparous
UCP1 mRNA (a.u)1.0±0.131.0±2.260.01±0.00.012±0.0
UCP2 mRNA (a.u)1.9±0.28*1.0±0.121.14±0.061.32±0.13
UCP1 (% ref)118±3.8*100±2.6ND*,∥10.4±2.6†,∥
Leptin mRNA (a.u)1.9±0.2*1.0±0.21.6±0.3*0.5±0.04
Adiponectin mRNA (a.u)0.9±0.11.0±0.233.1±0.6*1.0±0.13
IL6 mRNA (a.u)1.38±0.41.0±0.2310.48±2.2*,∥1.38±1.0
TNFα mRNA (a.u)0.7±0.21.0±0.41.8±0.67.7±6.7
GR mRNA (a.u)1.9±0.4*1.0±0.336.4±9.5*,∥1.0±0.4†,‡
HSD11B1 mRNA (a.u)1.0±0.61.0±0.30.3±0.11.2±0.5
HSD11B2 mRNA (a.u)2.7±0.5*1.0±0.10.8±0.21.0±0.6
Insulin receptor mRNA (a.u)1.7±0.2*1.0±0.30.5±0.1*,‡1.0±0.2†,‡
IGFBP3 mRNA (a.u)1.8±0.71.0±0.30.4±0.11.0±0.2
PPARA mRNA (a.u)1.1±0.181.0±0.090.82±0.140.43±0.06
PPARG mRNA (a.u)4.0±1.11.0±0.220.54±0.170.34±0.12
IGF1R mRNA (a.u)1.6±0.12*1.0±0.080.1±0.05§0.1±0.02§
IGF2R mRNA (a.u)1.4±0.41.0±0.20.56±0.2§0.3±0.2§

*,†Different superscripts within an age group denote statistically significant effect of parity (P<0.05). P<0.05, §P<0.01, P<0.005 denote statistically significant effect of postnatal age within parity group. PAT, perirenal–abdominal adipose tissue; ND, not detected; a.u, arbitrary units.

GR and HSD11B 1/2 mRNA abundance

Being born to a first-time mother resulted in significantly higher GR and HSD11B2 mRNA abundance in adipose tissue, a difference that only persisted up to 1 month for GR. Consequently, there was an age-related increase in GR together with decreased HSD11B2 gene expression. In contrast, there was no effect of maternal parity or postnatal age on mRNA abundance for HSD11B1.

Insulin receptor and IGF-binding protein 3 mRNA abundance

Insulin receptor and IGF1R mRNAs were significantly higher in adipose tissue sampled from 1-day-old offspring born to nulliparous mothers (Table 2), an adaptation reversed by 1 month of age. Gene expression for both IGF1R and IGF2R was significantly reduced with postnatal age. In contrast, there was no effect of postnatal age or maternal parity on IGF-binding protein 3.

UCP1 and UCP2

There was no effect of maternal parity on UCP1 mRNA, but protein expression was significantly higher in offspring of nulliparous mothers at 1 day of age, a difference that was reversed by 1 month of age as UCP1 content decreased markedly in all offspring over this period (Table 2). In contrast, UCP2 mRNA abundance was significantly higher in adipose tissue sampled from offspring born to nulliparous mothers at 1 day of age, a difference that was no longer apparent by 1 month of age due to a pronounced decrease in its expression in offspring born to nulliparous mothers.

PPARA and PPARG mRNA abundance

There were no differences between maternal groups in PPARA or PPARG gene expression. However, there was a large decrease in mRNA for PPARG over the first month of life compared with a much smaller decline in PPARA (Table 2).

Discussion

We have shown that the increase in fat mass associated with firstborn status is accompanied by a potential resetting of the leptin and glucocorticoid axis within the adipocyte. The enhanced fat mass seen at birth is thus associated with endocrine changes which are likely to have contributed to increased rates of adipogenesis both during late gestation and continuing after birth. These findings further emphasise the importance of the foetal and early postnatal environment in determining both adipose tissue development and later adiposity.

The influence of maternal parity on placental and foetal development and neonatal leptin and adiposity

Our observation that firstborn offspring are lighter at birth is in agreement with findings from other species (Ong et al. 2002, Gardner et al. 2007), including humans, and occurs even when there is no change in maternal body weight and the pregnancy is twin-bearing (Symonds et al. 2004). As size at birth usually reflects the nutritional sufficiency of the in utero environment, the smaller birth weight in first pregnancies is likely to be mediated by reduced placental size (Zalud & Shaha 2008), vascularisation (Campbell & MacGillivray 1984, Khong et al. 2003) and efficiency (Town et al. 2005). Other mechanisms that will determine foetoplacental development include differences in the maternal metabolic and hormonal environment with parity. In the present study, one notable difference between nulliparous and multiparous mothers was in their plasma leptin that was appreciably lower in nulliparous mothers during late gestation. This difference occurred despite no gross differences in energy balance (i.e. comparable food intake, body weight and plasma concentrations of glucose, NEFAs and IGF1) with maternal parity. In the adult sheep, fat mass is the primary regulator of plasma leptin (Delavaud et al. 2000), but this is not necessarily the case during pregnancy (Bispham et al. 2002, 2003) or postnatal development that may be related to changes in insulin sensitivity during this period (Symonds et al. 2009). We also observed significant upregulation of leptin gene expression in adipose tissue of firstborn offspring than in that of multiparous offspring. This finding, although in accordance with increased fat mass, was clearly not related to the lower plasma leptin in these offspring. The loss of any relationship between fat mass and plasma leptin in the postnatal period is not unexpected (Bispham et al. 2002), and could relate in part to different contributions from the mother's milk (Mostyn et al. 2006) and/or differences in energy intake (Ong et al. 2006). In this regard, the higher plasma leptin seen in multiparous mothers than in nulliparous mothers is in accordance with comparable findings in the offspring.

In the humans, pathological conditions, such as pre-eclampsia, result in a pronounced increase in plasma leptin concentration (Mise et al. 1998), but the additional leptin is of placental origin (Laivuori et al. 2000), which makes very little, if any, contribution in the sheep (Bispham et al. 2003). Furthermore, reduced plasma leptin concentration in newborn infants is indicative of catch-up growth (Ong et al. 1999), and is thus in agreement with the present study in which we observed accelerated postnatal growth in firstborn offspring that is associated with later obesity (Ong et al. 2002).

IL6 mRNA abundance was also significantly increased in firstborn offspring at 30 days of age in accordance with increased fat mass, suggesting that inflammation is associated with later obesity (Das 2001, Trayhurn & Wood 2004) and is set in early life (Sharkey et al. 2009a). Adipocyte number of overweight children (Knittle et al. 1979) is raised and tracks into adult life (Spalding et al. 2008). In this regard, we have recently shown, in sheep, that the neonatal period coincides with maximal abundance of adipokines in PAT, which may be important in the transition from brown to white adipose tissue (Sharkey et al. 2009b), and is nutrient sensitive (Sharkey et al. 2009a). Taken together, our findings indicate that the underlying mechanisms of adiposity are established prior to, or soon after, birth.

Offspring of nulliparous mothers possessed more UCP1, which is likely to reflect increased translation of the UCP1 gene to protein following rapid activation at birth (Clarke et al. 1997b). Interestingly, this was accompanied by enhanced UCP2 gene expression and is in accordance with the effect of foetal growth restriction induced by umbilical cord occlusion (Gnanalingham et al. 2005a). It may be that the comparatively restricted in utero environment that accompanies a first pregnancy (Bai et al. 2002) acts to promote both maturation and growth of adipocytes in the foetus. Raised UCP1 would increase its effectiveness in producing heat after birth, an adaptation previously shown to be accompanied by increased fat mass at 1 month after birth in sheep born to chronically cold exposed mothers (Symonds et al. 1992).

Maternal parity influences glucocorticoid and insulin sensitivity of adipose tissue

Local adipose tissue glucocorticoid sensitivity, set during the neonatal period, is nutritionally regulated in utero and can determine later adiposity (Gnanalingham et al. 2005b). In the present study, being born to a nulliparous mother resulted in an increased mRNA abundance of GR and HSD11B2 mRNAs at birth, indicating increased local adipose tissue glucocorticoid sensitivity in the absence of any change in plasma cortisol. Interestingly, this adaptation was no longer apparent by 1 month of age when there is an ∼40-fold increase in GR in conjunction with an age-related decrease in HSD11B2, which are responses predicted to increase risk of later obesity (Watts et al. 2005). Adipocyte differentiation is a complex process that requires coordinated communication between hormones, growth factors and transcription factors. Glucocorticoids, for example, are major stimulators of adipose tissue development and fat accumulation especially in combination with insulin (Brindley 1992) and IGF1R (Mur et al. 2003). These hormones act together to induce expression of metabolic genes (Teruel et al. 1996). However, the precise signalling mechanism and transcription factors involved in GR-, insulin- and IGF1R-regulated adipogenesis and differentiation are still being elucidated. Recent studies have suggested a role for GR-dependent lipin-1 in adipogenesis in both mouse (Zhang et al. 2008) and human adipocytes. Moreover, expression of lipin-1 in differentiating preadipocytes is essential for normal expression of adipogenic transcription factors and for synthesis of triglycerides. In the present study, we observed higher GR and IGF1R mRNA abundance in firstborn offspring at birth that was accompanied by a transient upregulation of the insulin receptor that would promote both differentiation and adipogenesis (Chapman et al. 1985, Rosen & Spiegelman 2000). At 1 month of age, adiponectin mRNA abundance was also increased in perirenal adipose tissue of firstborn offspring, suggesting increased insulin sensitivity (Tsai et al. 2004) despite reduced IR at this stage. In contrast, the rate of loss of both PPARG and PPARA over the first month of life was similar between groups, and confirms that PPARs are not involved in promoting adipose tissue growth after birth (Lomax et al. 2007). Taken together, such adaptations would be predicted to promote fat mobilisation if food supply became limited in later life.

In conclusion, the increase in fat mass of firstborn offspring and the accompanying alterations in adipose tissue endocrine sensitivity may be significant risk factors for obesity in early childhood as well as for the onset of the metabolic syndrome and its associated disorders in later life. Whether this is due to a difference in maternal body composition or pregnancy interval is unclear. Nonetheless, the role of maternal parity in determining offspring adiposity and later metabolic disease is especially important, given that contemporary women in the western world are limiting the size of their families and that this may result in a generation with a greater proportion of firstborn children, thereby exacerbating the current obesity epidemic.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This work was supported by a Wellcome Trust VIP award (MH) and the European Union Sixth Framework for Research and Technical Development of the European Community – The Early Nutrition Programming Project (FOOD-CT-2005-007036).

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  • KhongTYAdemaEDErwichJJHM2003On an anatomical basis for the increase in birth weight in second and subsequent born children. Placenta24348353.

    • Search Google Scholar
    • Export Citation
  • KnittleJLTimmersKGinsberg-FellnerFBrownREKatzDP1979The growth of adipose tissue in children and adolescents. Cross-sectional and longitudinal studies of adipose cell number and size. Journal of Clinical Investigation63239246.

    • Search Google Scholar
    • Export Citation
  • LaivuoriHKaajaRKoistinenHKaronenSLAnderssonSKoivistoVYlikorkalaO2000Leptin during and after preeclamptic or normal pregnancy: its relation to serum insulin and insulin sensitivity. Metabolism49259263.

    • Search Google Scholar
    • Export Citation
  • LivakKJSchmittgenTD2001Analysis of relative gene expression data using real-time quantitative PCR and the 2T method. Methods25402408.

    • Search Google Scholar
    • Export Citation
  • LomaxMASadiqFKaramanlidisGKaramitriATrayhurnPHazleriggDG2007Ontogenic loss of brown adipose tissue sensitivity to beta-adrenergic stimulation in the ovine. Endocrinology148461468.

    • Search Google Scholar
    • Export Citation
  • LowryOHRosenbroughNJFarrALRandallRJ1951Protein measurement with the Folin phenol reagent. Journal of Biological Chemistry193265275.

  • LumeyLHSteinAD1997Offspring birthweights after maternal intrauterine undernutrition: a comparison within sibships. American Journal of Epidemiology146810819.

    • Search Google Scholar
    • Export Citation
  • MiseHSagawaNMatsumotoTYuraSNannoHItohHMoriTMasuzakiHHosodaKOgawaY1998Augmented placental production of leptin in preeclampsia: possible involvement of placental hypoxia. Journal of Clinical Endocrinology and Metabolism8332253229.

    • Search Google Scholar
    • Export Citation
  • MostynAWilsonVDandreaJYakubuDPBudgeHAlves-GuerraMCPecqueurCMirouxBSymondsMEStephensonT2003Ontogeny and nutritional manipulation of mitochondrial protein abundance in adipose tissue and the lungs of postnatal sheep. British Journal of Nutrition90323328.

    • Search Google Scholar
    • Export Citation
  • MostynASebertSLittenJCPerkinsKSLawsJSymondsMEClarkeL2006Influence of porcine genotype on the abundance of thyroid hormones and leptin in sow milk and its impact on growth, metabolism and expression of key adipose tissue genes in the offspring. Journal of Endocrinology190631639.

    • Search Google Scholar
    • Export Citation
  • MuhlhauslerBSDuffieldJAMcMillenIC2007Increased maternal nutrition stimulates peroxisome proliferator activated receptor-gamma, adiponectin, and leptin messenger ribonucleic acid expression in adipose tissue before birth. Endocrinology148878885.

    • Search Google Scholar
    • Export Citation
  • MurCArribasMBenitoMValverdeAM2003Essential role of insulin-like growth factor I receptor in insulin-induced fetal brown adipocyte differentiation. Endocrinology144581593.

    • Search Google Scholar
    • Export Citation
  • OngKKAhmedMLSherriffAWoodsKAWattsAGoldingJDungerDB1999Cord blood leptin is associated with size at birth and predicts infancy weight gain in humans, ALSPAC Study Team. Avon Longitudinal Study of Pregnancy and Childhood. Journal of Clinical Endocrinology and Metabolism8411451148.

    • Search Google Scholar
    • Export Citation
  • OngKKAhmedMLEmmettPMPreeceMADungerDB2000Association between postnatal catch-up growth and obesity in childhood: prospective cohort study. BMJ320967971.

    • Search Google Scholar
    • Export Citation
  • OngKKPreeceMAEmmettPMAhmedMLDungerDB2002Size at birth and early childhood growth in relation to maternal smoking, parity and infant breast-feeding: longitudinal birth cohort study and analysis. Pediatric Research52863867.

    • Search Google Scholar
    • Export Citation
  • OngKKEmmettPMNobleSNessADungerDB2006Dietary energy intake at the age of 4 months predicts postnatal weight gain and childhood body mass index. Pediatrics117e503e508.

    • Search Google Scholar
    • Export Citation
  • RosenEDSpiegelmanBM2000Molecular regulation of adipogenesis. Annual Review of Cell and Development Biology16145171.

  • RosenbaumMLeibelRLHirschJ1997Obesity. New England Journal of Medicine337396407.

  • SebertSPHyattMAChanLLPatelNBellRCKeislerDStephensonTBudgeHSymondsMEGardnerDS2009Maternal nutrient restriction between early-to-mid gestation and its impact upon appetite regulation following juvenile obesity. Endocrinology150634641.

    • Search Google Scholar
    • Export Citation
  • SharkeyDGardnerDSFainbergHPWilsonVSebertSBosPBellRSymondsMEBudgeH2009aMaternal nutrient restriction during pregnancy differentially alters the unfolded protein response in adipose and renal tissue of obese juvenile offspring. FASEB Journal2313141324.

    • Search Google Scholar
    • Export Citation
  • SharkeyDSymondsMEBudgeH2009bAdipose tissue inflammation: developmental ontogeny and consequences of gestational nutrient restriction in offspring. Endocrinology15039133920.

    • Search Google Scholar
    • Export Citation
  • SpaldingKLArnerEWestermarkPOBernardSBuchholzBABergmannOBlomqvistLHoffstedtJNaslundEBrittonT2008Dynamics of fat cell turnover in humans. Nature453783787.

    • Search Google Scholar
    • Export Citation
  • StettlerNKumanyikaSKKatzSHZemelBSStallingsVA2003Rapid weight gain during infancy and obesity in young adulthood in a cohort of African Americans. American Journal of Clinical Nutrition7713741378.

    • Search Google Scholar
    • Export Citation
  • SymondsMEBryantMJClarkeLDarbyCJLomaxMA1992Effect of maternal cold exposure on brown adipose tissue and thermogenesis in the neonatal lamb. Journal of Physiology455487502.

    • Search Google Scholar
    • Export Citation
  • SymondsMEGardnerDSPearceSStephensonT2004Endocrine responses to fetal undernutrition: the growth hormone (GH):insulin-like growth factor (IGF) axis. In Fetal Origins of Adult Disease: Programming of Chronic Disease Through Fetal Exposure to Undernutrition pp 353380. Ed. Langley-EvansSC. Oxford: CAB International.

    • Search Google Scholar
    • Export Citation
  • SymondsMESebertSPBudgeH2009The impact of diet during early life and its contribution to later disease: critical checkpoints in development and their long-term consequences for metabolic health. Proceedings of the Nutrition Society68416421.

    • Search Google Scholar
    • Export Citation
  • TeruelTValverdeAMBenitoMLorenzoM1996Insulin-like growth factor I and insulin induce adipogenic-related gene expression in fetal brown adipocyte primary cultures. Biochemical Journal319627632.

    • Search Google Scholar
    • Export Citation
  • TownSCPattersonJLPereiraCZGourleyGFoxcroftGR2005Embryonic and fetal development in a commercial dam-line genotype. Animal Reproduction Science85301316.

    • Search Google Scholar
    • Export Citation
  • TrayhurnPWoodIS2004Adipokines: inflammation and the pleiotropic role of white adipose tissue. British Journal of Nutrition92347355.

  • TsaiP-JYuC-HHsuS-PLeeY-HChiouC-HHsuY-WHoS-CChuC-H2004Cord plasma concentrations of adiponectin and leptin in healthy term neonates: positive correlation with birthweight and neonatal adiposity. Clinical Endocrinology618893.

    • Search Google Scholar
    • Export Citation
  • WangHSekineMChenXKanayamaHYamagamiTKagamimoriS2007Sib-size, birth order and risk of overweight in junior high school students in Japan: results of the Toyama Birth Cohort Study. Preventative Medicine444551.

    • Search Google Scholar
    • Export Citation
  • WattsLMManchemVPLeedomTARivardALMcKayRABaoDNeroladakisTMoniaBPBodenmillerDMCaoJX-C2005Reduction of hepatic and adipose tissue glucocorticoid receptor expression with antisense oligonucleotides improves hyperglycemia and hyperlipidemia in diabetic rodents without causing systemic glucocorticoid antagonism. Diabetes5418461853.

    • Search Google Scholar
    • Export Citation
  • WhorwoodCBFirthKMBudgeHSymondsME2001Maternal undernutrition during early to midgestation programs tissue-specific alterations in the expression of the glucocorticoid receptor, 11beta-hydroxysteroid dehydrogenase isoforms, and type 1 angiotensin ii receptor in neonatal sheep. Endocrinology14228542864.

    • Search Google Scholar
    • Export Citation
  • WilkinsonPWParkinJMPearlsonJPhilipsPRSykesP1977Obesity in childhood: a community study in Newcastle upon Tyne. Lancet1350352.

  • WilliamsPJKurlakLOPerkinsACBudgeHStephensonTKeislerDSymondsMEGardnerDS2007Hypertension and impaired renal function accompany juvenile obesity: the effect of prenatal diet. Kidney International72279289.

    • Search Google Scholar
    • Export Citation
  • ZaludIShahaS2008Three-dimensional sonography of the placental and uterine spiral vasculature: influence of maternal age and parity. Journal of Clinical Ultrasound 36391396.

    • Search Google Scholar
    • Export Citation
  • ZhangPO'LoughlinLBrindleyDNReueK2008Regulation of lipin-1 gene expression by glucocorticoids during adipogenesis. Journal of Lipid Research4915191528.

    • Search Google Scholar
    • Export Citation

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  • BisphamJGopalakrishnanGSDandreaJWilsonVBudgeHKeislerDHBroughton PipkinFStephensonTSymondsME2003Maternal endocrine adaptation throughout pregnancy to nutritional manipulation: consequences for maternal plasma leptin and cortisol and the programming of fetal adipose tissue development. Endocrinology14435753585.

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  • BisphamJGardnerDSGnanalinghamMGStephensonTSymondsMEBudgeH2005Maternal nutritional programming of fetal adipose tissue development: differential effects on messenger ribonucleic acid abundance for uncoupling proteins and peroxisome proliferator-activated and prolactin receptors. Endocrinology14639433949.

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  • ClarkeLHeasmanLFirthKSymondsME1997bInfluence of route of delivery and ambient temperature on thermoregulation in newborn lambs. American Journal of Physiology. Regulatory Integrative and Comparative Physiology272R1931R1939.

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  • DasUN2001Is obesity an inflammatory condition?Nutrition17953966.

  • DelavaudCBocquierFChilliardYKeislerDHGertlerAKannG2000Effect of sheep nutritional status and body fatness on plasma leptin concentration assessed by a specific RIA. Journal of Endocrinology165519526.

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  • De Sousa PeixotoRATurbanSBattleJHChapmanKESecklJRMortonNM2008Preadipocyte 11beta-hydroxysteroid dehydrogenase type 1 is a keto-reductase and contributes to diet-induced visceral obesity in vivo. Endocrinology14918611868.

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  • FieldAECookNRGillmanMW2005Weight status in childhood as a predictor of becoming overweight or hypertensive in early adulthood. Obesity Research13163169.

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  • GardnerDSVan BonBWDandreaJGoddardPJMaySFWilsonVStephensonTSymondsME2006Effect of periconceptional undernutrition and gender on hypothalamic–pituitary–adrenal axis function in young adult sheep. Journal of Endocrinology190203212.

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  • GardnerDSButteryPJDanielZSymondsME2007Factors affecting birth weight in sheep: maternal environment. Reproduction133297307.

  • GnanalinghamMGGiussaniDASivathondanPForheadAJStephensonTSymondsMEGardnerDS2005aChronic umbilical cord compression results in accelerated maturation of lung and brown adipose tissue in the sheep fetus during late gestation. American Journal of Physiology. Endocrinology and Metabolism289E456E465.

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  • GnanalinghamMGMostynASymondsMEStephensonT2005bOntogeny and nutritional programming of adiposity in sheep: potential role of glucocorticoid action and uncoupling protein-2. American Journal of Physiology. Regulatory Integrative and Comparative Physiology289R1407R1415.

    • Search Google Scholar
    • Export Citation
  • HyattMABudgeHWalkerDStephensonTSymondsME2007Effects of maternal parity and late gestational nutrition on mRNA abundance for growth factors in the liver of postnatal sheep. American Journal of Physiology. Regulatory Integrative and Comparative Physiology292R1934R1942.

    • Search Google Scholar
    • Export Citation
  • KhongTYAdemaEDErwichJJHM2003On an anatomical basis for the increase in birth weight in second and subsequent born children. Placenta24348353.

    • Search Google Scholar
    • Export Citation
  • KnittleJLTimmersKGinsberg-FellnerFBrownREKatzDP1979The growth of adipose tissue in children and adolescents. Cross-sectional and longitudinal studies of adipose cell number and size. Journal of Clinical Investigation63239246.

    • Search Google Scholar
    • Export Citation
  • LaivuoriHKaajaRKoistinenHKaronenSLAnderssonSKoivistoVYlikorkalaO2000Leptin during and after preeclamptic or normal pregnancy: its relation to serum insulin and insulin sensitivity. Metabolism49259263.

    • Search Google Scholar
    • Export Citation
  • LivakKJSchmittgenTD2001Analysis of relative gene expression data using real-time quantitative PCR and the 2T method. Methods25402408.

    • Search Google Scholar
    • Export Citation
  • LomaxMASadiqFKaramanlidisGKaramitriATrayhurnPHazleriggDG2007Ontogenic loss of brown adipose tissue sensitivity to beta-adrenergic stimulation in the ovine. Endocrinology148461468.

    • Search Google Scholar
    • Export Citation
  • LowryOHRosenbroughNJFarrALRandallRJ1951Protein measurement with the Folin phenol reagent. Journal of Biological Chemistry193265275.

  • LumeyLHSteinAD1997Offspring birthweights after maternal intrauterine undernutrition: a comparison within sibships. American Journal of Epidemiology146810819.

    • Search Google Scholar
    • Export Citation
  • MiseHSagawaNMatsumotoTYuraSNannoHItohHMoriTMasuzakiHHosodaKOgawaY1998Augmented placental production of leptin in preeclampsia: possible involvement of placental hypoxia. Journal of Clinical Endocrinology and Metabolism8332253229.

    • Search Google Scholar
    • Export Citation
  • MostynAWilsonVDandreaJYakubuDPBudgeHAlves-GuerraMCPecqueurCMirouxBSymondsMEStephensonT2003Ontogeny and nutritional manipulation of mitochondrial protein abundance in adipose tissue and the lungs of postnatal sheep. British Journal of Nutrition90323328.

    • Search Google Scholar
    • Export Citation
  • MostynASebertSLittenJCPerkinsKSLawsJSymondsMEClarkeL2006Influence of porcine genotype on the abundance of thyroid hormones and leptin in sow milk and its impact on growth, metabolism and expression of key adipose tissue genes in the offspring. Journal of Endocrinology190631639.

    • Search Google Scholar
    • Export Citation
  • MuhlhauslerBSDuffieldJAMcMillenIC2007Increased maternal nutrition stimulates peroxisome proliferator activated receptor-gamma, adiponectin, and leptin messenger ribonucleic acid expression in adipose tissue before birth. Endocrinology148878885.

    • Search Google Scholar
    • Export Citation
  • MurCArribasMBenitoMValverdeAM2003Essential role of insulin-like growth factor I receptor in insulin-induced fetal brown adipocyte differentiation. Endocrinology144581593.

    • Search Google Scholar
    • Export Citation
  • OngKKAhmedMLSherriffAWoodsKAWattsAGoldingJDungerDB1999Cord blood leptin is associated with size at birth and predicts infancy weight gain in humans, ALSPAC Study Team. Avon Longitudinal Study of Pregnancy and Childhood. Journal of Clinical Endocrinology and Metabolism8411451148.

    • Search Google Scholar
    • Export Citation
  • OngKKAhmedMLEmmettPMPreeceMADungerDB2000Association between postnatal catch-up growth and obesity in childhood: prospective cohort study. BMJ320967971.

    • Search Google Scholar
    • Export Citation
  • OngKKPreeceMAEmmettPMAhmedMLDungerDB2002Size at birth and early childhood growth in relation to maternal smoking, parity and infant breast-feeding: longitudinal birth cohort study and analysis. Pediatric Research52863867.

    • Search Google Scholar
    • Export Citation
  • OngKKEmmettPMNobleSNessADungerDB2006Dietary energy intake at the age of 4 months predicts postnatal weight gain and childhood body mass index. Pediatrics117e503e508.

    • Search Google Scholar
    • Export Citation
  • RosenEDSpiegelmanBM2000Molecular regulation of adipogenesis. Annual Review of Cell and Development Biology16145171.

  • RosenbaumMLeibelRLHirschJ1997Obesity. New England Journal of Medicine337396407.

  • SebertSPHyattMAChanLLPatelNBellRCKeislerDStephensonTBudgeHSymondsMEGardnerDS2009Maternal nutrient restriction between early-to-mid gestation and its impact upon appetite regulation following juvenile obesity. Endocrinology150634641.

    • Search Google Scholar
    • Export Citation
  • SharkeyDGardnerDSFainbergHPWilsonVSebertSBosPBellRSymondsMEBudgeH2009aMaternal nutrient restriction during pregnancy differentially alters the unfolded protein response in adipose and renal tissue of obese juvenile offspring. FASEB Journal2313141324.

    • Search Google Scholar
    • Export Citation
  • SharkeyDSymondsMEBudgeH2009bAdipose tissue inflammation: developmental ontogeny and consequences of gestational nutrient restriction in offspring. Endocrinology15039133920.

    • Search Google Scholar
    • Export Citation
  • SpaldingKLArnerEWestermarkPOBernardSBuchholzBABergmannOBlomqvistLHoffstedtJNaslundEBrittonT2008Dynamics of fat cell turnover in humans. Nature453783787.

    • Search Google Scholar
    • Export Citation
  • StettlerNKumanyikaSKKatzSHZemelBSStallingsVA2003Rapid weight gain during infancy and obesity in young adulthood in a cohort of African Americans. American Journal of Clinical Nutrition7713741378.

    • Search Google Scholar
    • Export Citation
  • SymondsMEBryantMJClarkeLDarbyCJLomaxMA1992Effect of maternal cold exposure on brown adipose tissue and thermogenesis in the neonatal lamb. Journal of Physiology455487502.

    • Search Google Scholar
    • Export Citation
  • SymondsMEGardnerDSPearceSStephensonT2004Endocrine responses to fetal undernutrition: the growth hormone (GH):insulin-like growth factor (IGF) axis. In Fetal Origins of Adult Disease: Programming of Chronic Disease Through Fetal Exposure to Undernutrition pp 353380. Ed. Langley-EvansSC. Oxford: CAB International.

    • Search Google Scholar
    • Export Citation
  • SymondsMESebertSPBudgeH2009The impact of diet during early life and its contribution to later disease: critical checkpoints in development and their long-term consequences for metabolic health. Proceedings of the Nutrition Society68416421.

    • Search Google Scholar
    • Export Citation
  • TeruelTValverdeAMBenitoMLorenzoM1996Insulin-like growth factor I and insulin induce adipogenic-related gene expression in fetal brown adipocyte primary cultures. Biochemical Journal319627632.

    • Search Google Scholar
    • Export Citation
  • TownSCPattersonJLPereiraCZGourleyGFoxcroftGR2005Embryonic and fetal development in a commercial dam-line genotype. Animal Reproduction Science85301316.

    • Search Google Scholar
    • Export Citation
  • TrayhurnPWoodIS2004Adipokines: inflammation and the pleiotropic role of white adipose tissue. British Journal of Nutrition92347355.

  • TsaiP-JYuC-HHsuS-PLeeY-HChiouC-HHsuY-WHoS-CChuC-H2004Cord plasma concentrations of adiponectin and leptin in healthy term neonates: positive correlation with birthweight and neonatal adiposity. Clinical Endocrinology618893.

    • Search Google Scholar
    • Export Citation
  • WangHSekineMChenXKanayamaHYamagamiTKagamimoriS2007Sib-size, birth order and risk of overweight in junior high school students in Japan: results of the Toyama Birth Cohort Study. Preventative Medicine444551.

    • Search Google Scholar
    • Export Citation
  • WattsLMManchemVPLeedomTARivardALMcKayRABaoDNeroladakisTMoniaBPBodenmillerDMCaoJX-C2005Reduction of hepatic and adipose tissue glucocorticoid receptor expression with antisense oligonucleotides improves hyperglycemia and hyperlipidemia in diabetic rodents without causing systemic glucocorticoid antagonism. Diabetes5418461853.

    • Search Google Scholar
    • Export Citation
  • WhorwoodCBFirthKMBudgeHSymondsME2001Maternal undernutrition during early to midgestation programs tissue-specific alterations in the expression of the glucocorticoid receptor, 11beta-hydroxysteroid dehydrogenase isoforms, and type 1 angiotensin ii receptor in neonatal sheep. Endocrinology14228542864.

    • Search Google Scholar
    • Export Citation
  • WilkinsonPWParkinJMPearlsonJPhilipsPRSykesP1977Obesity in childhood: a community study in Newcastle upon Tyne. Lancet1350352.

  • WilliamsPJKurlakLOPerkinsACBudgeHStephensonTKeislerDSymondsMEGardnerDS2007Hypertension and impaired renal function accompany juvenile obesity: the effect of prenatal diet. Kidney International72279289.

    • Search Google Scholar
    • Export Citation
  • ZaludIShahaS2008Three-dimensional sonography of the placental and uterine spiral vasculature: influence of maternal age and parity. Journal of Clinical Ultrasound 36391396.

    • Search Google Scholar
    • Export Citation
  • ZhangPO'LoughlinLBrindleyDNReueK2008Regulation of lipin-1 gene expression by glucocorticoids during adipogenesis. Journal of Lipid Research4915191528.

    • Search Google Scholar
    • Export Citation