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J Physiol. Jun 15, 2010; 588(Pt 12): 2219–2237.
Published online Apr 26, 2010. doi:  10.1113/jphysiol.2010.187682
PMCID: PMC2911222

Sex- and age-specific effects of nutrition in early gestation and early postnatal life on hypothalamo-pituitary-adrenal axis and sympathoadrenal function in adult sheep

Abstract

The early-life environment affects risk of later metabolic disease, including glucose intolerance, insulin resistance and obesity. Changes in hypothalamo-pituitary-adrenal (HPA) axis and sympathoadrenal function may underlie these disorders. To determine consequences of undernutrition in early gestation and/or immediately following weaning on HPA axis and sympathoadrenal function, 2- to 3-year-old Welsh Mountain ewes received 100% (C, n= 39) or 50% nutritional requirements (U, n= 41) from 1–31 days gestation, and 100% thereafter. From weaning (12 weeks) to 25 weeks of age, male and female offspring were then either fed ad libitum (CC, n= 22; UC, n= 19) or were undernourished (CU, n= 17; UU, n= 22) such that body weight was reduced to 85% of their individual target, based on a growth trajectory calculated from weights taken between birth and 12 weeks. From 25 weeks, ad libitum feeding was restored for all offspring. At 1.5 and 2.5 years, adrenocorticotropic hormone (ACTH) and cortisol concentrations were measured at baseline and in response to corticotropin-releasing factor (CRF) (0.5 μg kg−1) plus arginine vasopressin (AVP) (0.1 μg kg−1). At 2.5 years, HPA axis and sympathoadrenal (catecholamine) responses to a transport and isolation stress test were also measured. In females, post-weaning undernutrition reduced pituitary output (ACTH) but increased adrenocortical responsiveness (cortisol:ACTH area under curve) during CRF/AVP challenge at 1.5 years and increased adrenomedullary output (adrenaline) to stress at 2.5 years. In males, cortisol responses to stress at 2.5 years were reduced in those with slower growth rates from 12 to 25 weeks. Early gestation undernutrition was associated with increased adrenocortical output in 2.5-year-old females only. Pituitary and adrenal responses were also related to adult body composition. Thus, poor growth in the post-weaning period induced by nutrient restriction has sex- and age-specific effects on HPA and sympathoadrenal function. With altered glucose tolerance previously reported in this model, this may have long-term detrimental effects on metabolic homeostasis and cardiovascular function.

Introduction

Epidemiological studies have demonstrated that part of an individual's risk of developing the metabolic syndrome can be attributed to the environment in early life (Gluckman & Hanson, 2004). Low weight or thinness at birth are associated with an increased risk of impaired glucose tolerance, insulin resistance and hypertension (Barker et al. 1989; Hales et al. 1991; Phillips et al. 1994). Since low birth weight is also associated with increased hypothalamo-pituitary-adrenal (HPA) axis activity in children and adults (Clark et al. 1996; Phillips et al. 2000), it has been suggested that changes in the HPA axis may underlie the association between the early environment and the metabolic syndrome (Phillips et al. 1998). Certainly, patients with an overactive HPA axis (Cushing's syndrome) show features of the metabolic syndrome, namely insulin resistance, glucose intolerance, hypertension, dyslipidaemia and obesity (Pivonello et al. 2005). Chronically elevated glucocorticoids have a diabetogenic effect, interfering with the action of insulin at several levels (Rizza et al. 1982) and promoting fat accumulation (Buren et al. 2002). Alterations in sympathoadrenal system function may also contribute to the aetiology of the metabolic syndrome given its role in the regulation of metabolic and cardiovascular activity (Phillips & Barker, 1997; Young, 2002b). Indeed, a hypercortisolaemic or hyperadrenergic state may be early features linking low birth weight and later metabolic and cardiovascular disease (Phillips & Barker, 1997; Levitt et al. 2000).

Animal studies have shown that HPA axis activity can be influenced not only by the prenatal environment, e.g. by maternal stress, undernutrition or glucocorticoid exposure (Weinstock et al. 1992; Langley-Evans et al. 1996a; Sloboda et al. 2002; Bloomfield et al. 2003), but also by the early postnatal environment, e.g. by maternal care, maternal separation and neonatal handling (Meaney et al. 1993). Similar pre- and postnatal factors also affect the sympathoadrenal system and may be associated with changes in body composition (Coulter et al. 1998; Young, 2000, 2002a). These effects are life-long, often sex-specific and depend on the nature and timing of the insult. For example, rat studies show that maternal stress increases HPA function in 28-day-old offspring, particularly in females (Weinstock et al. 1992), while handling of rat pups in the neonatal period decreases stress-induced HPA activity of the adult offspring (Meaney et al. 1989). The mechanisms linking the early environment and altered HPA axis function include changes in cortisol metabolism via 11β-hydroxysteroid dehydrogenase, altered negative feedback of the axis and altered tissue sensitivity to glucocorticoids (Meaney et al. 1989; Maccari et al. 1995; Bertram et al. 2001) and altered adrenal catecholamine synthetic ability (Adams et al. 1998). These effects may be induced by epigenetic modification of expression of key transcription factors such as the glucocorticoid receptor (GR), which have been shown to be influenced by early nutrition or behaviour in rats (Weaver et al. 2004; Lillycrop et al. 2005).

The effect of maternal nutrition at different stages of development has been studied in offspring exposed to the Dutch Hunger Winter of 1945/5. While the risk of coronary heart disease was increased in those exposed in early gestation (Roseboom et al. 2000), HPA responses to stressors were not different between unexposed individuals and those exposed at either early, mid or late gestation (de Rooij et al. 2006a,b;). Our laboratory has investigated the effects of discrete periods of nutrient restriction in sheep, a species with a similar developmental trajectory to humans, and a similar maturation of the HPA axis in late gestation. In sheep, undernutrition even in early gestation, from conception until after implantation (1–31 days of gestation), has long-term effects on homeostasis of endocrine and cardiovascular systems (Edwards & McMillen, 2002; Bloomfield et al. 2003; Cleal et al. 2007a,b;). However, the long-term effects of undernutrition in postnatal life have been little studied in large animal models. Recently, we demonstrated that the period immediately following weaning is critical in sheep in terms of later metabolic homeostasis (Poore et al. 2007). Undernutrition from 12 to 25 weeks of age induced improved glucose tolerance, in females but not males, which persisted until at least 2.5 years of age, but this was not influenced by the early gestation undernutrition regime (Poore et al. 2007). The aim of the current study was to determine if undernutrition immediately following weaning, with or without exposure to undernutrition in early gestation, affects pituitary and adrenal responses to challenge: stimulation with corticotropin-releasing factor (CRF)/arginine vasopressin (AVP) in young (1.5 years) and mature (2.5 years) adult life and a stress test induced by transport and isolation in mature adult life. Thus, we aimed to gain insight into whether changes in HPA axis function could be associated with altered metabolic homeostasis.

Methods

Animals

All procedures were carried out in accordance with the regulations of the UK Animals (Scientific Procedures) Act 1986. The data in this study come from the same cohort of sheep previously studied by us and for which other data have been published elsewhere (Cleal et al. 2007a,b; Poore et al. 2007). Eighty Welsh Mountain ewes in their second or third parity (2–3 years old) and of uniform good body condition score (BCS; ~3 on a scale of 1–5; Russel et al. 1969) were used in this study. Full details about ewe mating, ewe and lamb housing and diets are as presented elsewhere (Poore et al. 2007). All manipulations of ewes and of lambs until 1.5 years of age took place at the Royal Veterinary College.

Before conception, ewes were randomly assigned to a control or a dietary restricted group. Control ewes (prenatal control, C, n= 39) received 100% nutritional requirements before and throughout gestation (Fig. 1). From 1 to 31 days gestation (term = 147 days), ewes in the dietary restricted group (prenatal undernutrition, U, n= 41) received 50% nutritional requirements and then 100% requirements for the remainder of gestation (Fig. 1). From −7 days, ewes were weighed weekly. The starting pelleted diet ration for each ewe was calculated using RUMNUT software (Ruminant Nutrition) v. 5 for sheep (AT Chamberlain, Mountwood House, Shedfield, Southampton, UK) based on initial body weight. This ration was adjusted weekly according to their weight measurement. The RUMNUT software was based on AFRC guidelines for pregnant sheep (Agricultural and Food Research Council, 1993) and incorporated adjustments for weight gain according to gestational age. Water was provided ad libitum. Ewes were individually penned from −7 to 37 days gestation and group housed thereafter with animals at a similar gestational age. Ewes delivered and suckled lambs naturally while receiving 100% nutritional requirements, with further feed ration adjustments according to lactational needs (Agricultural and Food Research Council, 1993). Lambs were weaned at 12 weeks, after gradual introduction of the post-weaning diet (Poore et al. 2007).

Figure 1
Schematic diagram of the experimental protocol

Lambs from C and U ewes were grouped with approximately 10 others of similar body weight and postnatal treatment group in open barns. For each lamb, an individual linear weight trajectory was calculated for the period 12–25 weeks that was based on weights taken at birth, 4, 8 and 12 weeks. Lambs in the postnatal control group (prenatal control/postnatal control, CC, n= 22; prenatal undernutrition/postnatal control, UC, n= 19) were fed 100% nutritional requirements to follow their individual trajectory from 12 to 25 weeks (Fig. 1). Lambs in the postnatal undernutrition group (prenatal control/postnatal undernutrition, CU, n= 17; prenatal undernutrition/postnatal undernutrition, UU, n= 22) were fed a restricted pelleted diet such that body weight was reduced to 85% of their individual target weight from 12 to 25 weeks (Fig. 1). Lambs had free access to hay throughout. To keep body weight on the desired trajectory, lambs were monitored individually by weekly weighing and feed ration adjustment. If necessary, lambs were temporarily removed to individual pens to maintain body weight at the desired level.

From 25 weeks onwards, lambs were returned to larger group housing and received 100% nutritional requirements (Fig. 1). All lambs were weighed at 35 weeks and just prior to experiments (see below) at 16.5 ± 0.1 months (1.5 years) and 29.6 ± 0.2 months (2.5 years) of age. At each experimental age, BCS was assessed manually and fat and muscle depths were measured by ultrasound in the third lumbar region by small number of experienced animal technicians, as described previously (Poore et al. 2007).

Each group contained approximately equal numbers of males and females and the ratio of singleton to twin lambs was approximately 4:6 (see Table 1). Results for basal and stimulated adrenocorticotropic hormone (ACTH) and cortisol concentrations (from CRF/AVP challenges, see below) were obtained from all animals, at 1.5 and 2.5 years. Results for basal and stimulated adrenaline and noradrenaline concentrations (from TI test, see below) were obtained from a subset of animals at 2.5 years only (Table 1). Organ weights recorded at postmortem at 2.5 years were obtained from all animals (Table 1).

Table 1
Number of observations in each group for each data set

Surgical techniques

As described previously (Poore et al. 2007), surgery at 9.9 months (to create carotid artery loops for repeated arterial access and to vasectomise male lambs) and experiments at 1.5 years of age were performed at the Royal Veterinary College. At 1.5 years, sheep were moved into individual cages and acclimatised for 4 days, with no change in their feeding regime. After an overnight fast, temporary indwelling carotid artery (via the loop) and jugular vein catheters were inserted under general anaesthesia (2–4% halothane in O2 by face mask) and antibiotic treatment was administered (15 mg kg−1, i.m.; Betamox). CRF/AVP challenges (see below) were performed 1 day after catheterisation. Indwelling catheters were maintained for a total of 3 days and then removed at the completion of the experiments. Sheep were then returned to group housing.

At 2.5 years, sheep were moved to the University of Southampton facilities for the remaining experiments. They were housed in individual cages on wheels, with the same feeding regime, and allowed 6 days to recover from the change in location. After an overnight fast, general anaesthesia was induced by thiopentone sodium (10 mg kg−1, i.v.) and maintained by halothane (2–4% in O2) and indwelling carotid artery (via the loop) and jugular vein catheters were inserted. Antibiotic treatment was administered (15 mg kg−1, i.m.; Betamox) and catheters were maintained for up to 17 days. CRF/AVP challenges (see below) were performed 6 days after catheterisation.

Experimental protocol

At 1.5 and 2.5 years, a CRF/AVP challenge was performed to test pituitary responsiveness to hypothalamic factors and adrenal responsiveness to the subsequent ACTH output. CRF (0.5 μg (kg body weight)−1) combined with AVP (0.1 μg (kg body weight)−1) was administered as a rapid intravenous bolus at ~13.00 h, at least 4 h after feeding. Arterial blood samples (9 ml into chilled EDTA tubes) were collected for analysis of plasma ACTH and cortisol concentrations at 30 min, 15 min and immediately (0 min) before and 10, 30, 60, 120 and 180 min after the CRF/AVP bolus (time 0).

At 2.5 years, at least 7 days after the CRF/AVP challenge and 3 days after experiments performed for studies not reported here, adrenocortical and adrenomedullary responses to a stress test were assessed by a transport and isolation (TI) test, as follows: Still contained in their individual wheeled cages, sheep were moved from their normal communal holding room to a different empty room (~2 min duration, starting at time 0) followed by 30 min isolation. Arterial blood samples (10 ml into chilled EDTA tubes) were collected for analysis of plasma noradrenaline and adrenaline concentrations 15 min and immediately (0 min) before, and 10, 20 and 30 min after, the start of the transport (time 0). Blood samples were centrifuged immediately (10 min, 4°C) and plasma was stored in multiple aliquots at −20°C. All experiments were performed at approximately 08.00 h, before the morning ration of pelleted feed. For technical/facility reasons, this experiment could not be performed at 1.5 years.

Postmortem

At the completion of all experimental protocols, sheep were killed by barbiturate (pentobarbitone sodium) overdose. Pituitary and adrenal (left and right) glands were removed and weighed and corrected for current body weight.

Biochemical analyses

ACTH and cortisol concentrations were measured in unextracted plasma using an Immulite auto-analyser (Immulite, Siemens Healthcare Diagnostics, Camberley, UK). ACTH was measured in 75 μl plasma by a sequential immunometric assay (2 × 30 min incubation cycles). Cortisol was measured in 10 μl plasma by a solid-phase, competitive chemiluminescence enzyme immunoassay (1 × 30 min incubation cycle). The Immulite system was validated by us for use with sheep plasma by (1) comparing results with a radioimmunoassay developed for sheep plasma by Dr P. Wood, Department of Chemical Pathology, Southampton General Hospital, (2) demonstrating linearity following serial dilution of a known sample (y= 8.3x− 0.54, r=+0.98), and (3) demonstrating that sheep plasma did not interfere with recovery of known concentrations of human cortisol and ACTH added to sheep plasma (recoveries both >96%). Samples were assayed in singleton after demonstration of a high reproducibility of the auto-analyser. The sensitivity of the cortisol assay was 0.2 ng ml−1 and the inter- and intra-assay coefficients of variation for the assay were 7.9% and 4.6%, respectively. The sensitivity of the ACTH assay was 9 pg ml−1 and the inter- and intra-assay coefficients of variation for the assay were 4.6% and 1.1%, respectively.

Plasma noradrenaline and adrenaline concentrations were measured using a commercially available radioimmunoassay kit (2 CAT RIA, Labor Diagnostika Nord, Nordham, Germany). The sensitivity of the assay for noradrenaline was 12.5 pg ml−1 and the interassay coefficient of variation for the assay was 21.1% at a value of 1179 pg ml−1. The sensitivity of the assay for adrenaline was 2.5 pg ml−1 and the interassay coefficient of variation for the assay was 14.2% at a value of 218 pg ml−1.

Data analysis

For each of the CRF/AVP challenges and TI tests, basal ACTH and cortisol concentrations were derived from average pre-experiment (−30 to 0 min for CRF/AVP challenge and −15 to 0 min for TI test) concentrations. At 1.5 years, basal ACTH and cortisol concentrations presented are from the CRF/AVP challenge. At 2.5 years, basal ACTH and cortisol concentrations prior to the CRF/AVP and TI test were highly correlated (P < 0.05 and P < 0.005, respectively), and therefore the values presented are the average of both pre-experiment values. For each animal, the maximum ACTH and cortisol concentration achieved (Δ peak) and the area under the response curve (AUC) following CRF/AVP administration (integrated concentrations 10–180 min) and during the TI test (integrated concentrations 10–30 min) were calculated relative to basal concentrations calculated for each particular experiment. Adrenocortical sensitivity (basal and stimulated) was given by the ratio of cortisol to ACTH concentrations (basal and AUC, respectively).

Basal noradrenaline and adrenaline concentrations were derived from average pre-TI (−15 to 0 min) concentrations. For each animal, the maximum noradrenaline and adrenaline concentration achieved (Δ peak) and the AUC (integrated concentrations 10–30 min) during the TI test were calculated relative to basal concentrations (provided that an increase was observed).

Data are expressed as means ±s.e.m. The effects of four main factors were examined: prenatal diet, postnatal diet, sex and litter size. The time courses of hormone responses to CRF/AVP challenge or TI test were first tested using multifactorial analyses of variance for repeated measures (RM ANOVA), with time as the repeated measure. Summary measures (basal, Δ peak and AUC) taken from each experiment were also analysed using analysis of variance (ANOVA), with the same four factors: prenatal diet, postnatal diet, sex and litter size. If there was a significant effect of a main factor or interactions between the main factors, further analyses were performed within subsets of the data. Linear regression analysis was used to examine relationships between two factors: this was done separately within each sex, across all nutritional groups. Statistical analyses were performed using GraphPad Prism v. 3.0 and SPSS v. 8 (GraphPad Software Inc., La Jolla, CA, USA; SPSS Inc., Chicago, IL, USA). Significance was accepted at P < 0.05 and a trend was noted when 0.05 < P < 0.1.

Results

Postnatal growth patterns and body composition

Data on body weight and composition and on postnatal growth patterns in this cohort of sheep have been published previously (Poore et al. 2007). Briefly, there was no effect of early gestation undernutrition on birth weight or size. Regardless of sex, weight gain between 12 and 25 weeks was reduced by post-weaning undernutrition and then these animals showed an accelerated growth rate from 25 to 35 weeks. No difference in body weights between the four nutritional groups was observed at 1.5 or 2.5 years. Female sheep were lighter but fatter than male sheep at both postnatal ages. Fat depth was increased in UU females compared to the other groups at 1.5, but not 2.5, years (Poore et al. 2007).

Basal ACTH, cortisol and catecholamine concentrations

At both 1.5 and 2.5 years, basal cortisol concentrations and the ratio of basal cortisol to ACTH concentrations were significantly (P < 0.05) higher in female compared to male sheep (Tables 2 and and3).3). At 1.5 years there were no significant effects of early gestation or post-weaning nutrition, or singleton or twin birth on basal ACTH or cortisol concentrations, or the basal cortisol:ACTH ratio (Tables 2 and and3).3). In 2.5-year-old females, basal cortisol concentrations were significantly (P < 0.05) higher in those prenatally undernourished compared to prenatal controls (Table 3).

Table 3
Basal and stimulated ACTH, cortisol and catecholamine concentrations, pituitary and adrenal gland weights in female sheep
Table 2
Basal and stimulated ACTH, cortisol and catecholamine concentrations, pituitary and adrenal gland weights in male sheep

For basal adrenaline concentrations prior to the TI test at 2.5 years, there were significant (P < 0.05) interactions between prenatal nutrition, postnatal nutrition and litter size across all animals. The interaction between prenatal nutrition and postnatal nutrition (P= 0.006) persisted in singleton offspring such that there was an effect of postnatal undernutrition on basal adrenaline concentrations in those with control prenatal nutrition (CU, 138.3 ± 22.4 pg ml−1vs. CC, 66.5 ± 21.2 pg ml−1, P= 0.037) but not in those that received prenatal undernutrition (UU, 65.7 ± 7.4 pg ml−1vs. UC, 94.4 ± 23.8 pg ml−1, P > 0.05).

CRF/AVP challenges at 1.5 and 2.5 years of age

ACTH and cortisol responses

ACTH and cortisol concentrations were significantly (P < 0.0001; RM ANOVA over time) increased following CRF/AVP administration in all animals at 1.5 and 2.5 years (Figs 2 and and3).3). In 1.5-year-old females, analysis of the ACTH response over time (RM ANOVA) showed that ACTH output following CRF/AVP administration was reduced (P < 0.05) in postnatally undernourished animals, regardless of the prenatal nutritional regime, when compared to those with control postnatal nutrition (Fig. 2B). In addition, there was a reduction (P < 0.05) in Δ peak and AUC for ACTH concentrations in postnatally undernourished females compared to postnatal control females (Table 3). Although in the RM ANOVA of the cortisol response over time there was an interaction (P < 0.05) between time and postnatal nutritional regime at 1.5 years (Fig. 2D), Δ peak cortisol and cortisol AUC were not significantly reduced in postnatally undernourished females (Table 3). Consequently, the ratio of cortisol to ACTH AUC was significantly increased (P < 0.01) in postnatally undernourished compared to postnatal control females at 1.5 years (Table 3). There were no differences between the groups in ACTH or cortisol responses to CRF/AVP administration in 1.5-year-old males (Fig. 2A and C, Table 2).

Figure 3
Plasma ACTH and cortisol concentrations prior to and following the i.v. administration of CRF (0.5 μg (kg body wt)−1) plus AVP (0.1 μg (kg body wt)−1) in male (A and C) and female (B and D) sheep at 2.5 years •, ...
Figure 2
Plasma ACTH and cortisol concentrations prior to and following the i.v. administration of CRF (0.5 μg (kg body wt)−1) plus AVP (0.1 μg (kg body wt)−1) in male (A and C) and female (B and D) sheep at 1.5 years •, ...

At 2.5 years, there were no effects of the nutritional regime in females on ACTH responses over time (Fig. 3B), Δ peak ACTH or ACTH AUC (Table 3) during the CRF/AVP challenge. However, cortisol responses over time (RM ANOVA) were significantly (P < 0.05) greater in prenatally undernourished compared to prenatal control females (Fig. 3D). There were also trends for increased Δ peak cortisol and cortisol AUC to ACTH AUC ratio (P < 0.06) in prenatally undernourished compared to prenatal control females (Table 3). In 2.5-year-old males, there were no differences between the groups for ACTH responses over time (Fig. 3A). There was a trend (P= 0.057) for a reduction in the cortisol responses with time in postnatally undernourished compared with postnatal control males (Fig. 3C).

At both postnatal ages, cortisol responses to CRF/AVP administration were higher (P < 0.05) in female compared to male sheep overall (see Figs 2 and and3,3, Tables 2 and and33).

Transport and isolation test at 2.5 years of age

ACTH and cortisol responses

The TI test at 2.5 years of age caused an increase (P < 0.001; RM ANOVA over time) in plasma ACTH and cortisol in all animals (Fig. 4). There were no significant effects of early gestation or post-weaning nutrition on ACTH or cortisol responses over time, Δ peak and AUC for ACTH, Δ peak cortisol or the ratio of cortisol AUC to ACTH AUC in males or females (Fig. 4, Tables 2 and and3).3). The apparent reduction in cortisol output during the TI test in males that were postnatally undernourished (Fig. 4C) failed to reach statistical significance. However, in male twins Δ peak cortisol tended (P= 0.071) to be reduced in postnatally undernourished animals (3.8 ± 0.8 ng ml−1) compared to postnatal control animals (6.1 ± 0.7 ng ml−1; see also Table 2). In females, there was a significant (P < 0.05) interaction between prenatal nutrition and postnatal nutrition for cortisol AUC: in the prenatal control groups there was an effect of postnatal nutrition (i.e. CU > CC, P < 0.05) and in the postnatal control groups there was an effect of postnatal nutrition (i.e. UC > CC, P < 0.01; Table 3).

Figure 4
Plasma ACTH and cortisol concentrations prior to and following the transport and isolation (TI) stress test in male (A, C and E) and female (B, D and F) sheep at 2.5 years •, prenatal control–postnatal control (CC); [filled triangle], prenatal ...

The cortisol response over time and cortisol Δ peak and AUC during the TI test were greater (P < 0.001) in females than in males (Fig. 4, Tables 2 and and3).3). In males, ACTH responses over time were greater (P < 0.05) and cortisol responses (over time and Δ peak) tended to be greater (P < 0.1) in twins compared to singletons (data not shown).

Catecholamine responses

The TI test at 2.5 years of age caused an increase (P < 0.001; RM ANOVA over time) in plasma adrenaline in all animals (Fig. 4). In females, the adrenaline response over time was enhanced (P < 0.05) in postnatally undernourished animals, regardless of the prenatal nutritional regime, when compared to those with control postnatal nutrition (Fig. 4F). In addition, adrenaline concentrations in females were increased (P < 0.005) in the postnatally undernourished group (Δ peak: CU, 290 ± 65 pg ml−1; UU, 188 ± 33 pg ml−1; AUC: CU, 4867 ± 1397 pg min ml−1; UU, 2980 ± 555 pg min ml−1) compared to postnatal control groups (Δ peak: CC, 116 ± 37 pg ml−1; UC 91 ± 10 pg ml−1; AUC: CC, 2052 ± 685 pg min ml−1; UC, 1349 ± 226 pg min ml−1). In male twins, adrenaline responses over time during the TI test were greater (P < 0.05) in prenatally undernourished groups, regardless of the postnatal nutrition, when compared to prenatal control groups (data not shown). This was reflected by increased (P < 0.05) Δ peak and AUC for adrenaline in prenatally undernourished male twins (Δ peak: 321.8 ± 38.8 pg ml−1; AUC: 5817.2 ± 891.9 pg min ml−1) when compared to twins that had control prenatal nutrition (Δ peak: 162.8 ± 33.2 pg ml−1; AUC: 2547.4 ± 515.9 pg min ml−1).

The TI test did not cause a consistent increase in plasma noradrenaline concentrations in all animals and there was no effect of time in the RM ANOVA (data not shown). No further data analysis (Δ peak or AUC) or statistical testing of the noradrenaline responses during the TI test was performed.

Relationships between ACTH, cortisol and catecholamine concentrations and body size and growth

Basal concentrations

Males. In male sheep as a whole, current corrected fat depth was positively related to basal ACTH concentrations (2.5 years: r=+0.50, P < 0.005), basal cortisol concentrations (1.5 years: r=+0.47, P < 0.005; 2.5 years: r=+0.57, P < 0.001) and the ratio of basal cortisol:ACTH (1.5 years: r=+ 0.20, P < 0.005). Higher basal ACTH and cortisol concentrations at 2.5 years was associated with faster growth rate (r=+0.56, P < 0.001 and r=+0.35, P < 0.05, respectively) and greater gain (Δ) in body fat depth (r=+0.52, P < 0.005 and r=+0.37, P < 0.05 (Fig. 6C), respectively) between 1.5 and 2.5 years.

Figure 6
Relationships between HPA axis activity and body fatness A and B, relationships between adrenocortical sensitivity calculated from CRF/AVP challenge at 1.5 years and corrected fat depth in male sheep (A) and body condition score (BCS) (B) in female sheep. ...

Females. In female sheep as a whole, birth weight was negatively associated with higher basal ACTH concentrations at 2.5 years (r=−0.36, P < 0.05). A faster growth rate from birth to 12 weeks and a higher body weight at 12 weeks were associated with increased basal adrenaline at 2.5 years (r=+0.40, P= 0.05 and r=+0.40, P < 0.05, respectively). Poor growth rate between 12 and 25 weeks and reduced weight at 25 weeks were associated with reduced basal noradrenaline concentrations at 2.5 years (r=+0.42 and r=+0.44, respectively, both P < 0.05). Growth between 25 and 35 weeks was negatively associated with the ratio of basal cortisol to ACTH at 2.5 years (r=−0.42, P < 0.05) and basal cortisol at 2.5 years was reduced in those of higher weight at 35 weeks (r=−0.37 P < 0.05). Basal ACTH concentrations were positively related to corrected fat depth at 1.5 years (r=+0.35, P < 0.05) and BCS at 2.5 years (r=+0.37, P < 0.05). Basal noradrenaline concentrations at 2.5 years were negatively associated with corrected fat depth at 1.5 and 2.5 years (r=−0.52, P < 0.01 and r=−0.59, P < 0.005, respectively). Gain in fatness (ΔBCS) between 1.5 and 2.5 years was positively related to elevated basal noradrenaline (r=+0.40, P < 0.05) and adrenaline (r=+0.69, P < 0.001; Fig. 6D) concentrations at 2.5 years.

Responses to CRF/AVP challenges and TI test

Males. In male sheep as a whole, birth weight was negatively associated with higher stimulated cortisol output during CRF/AVP challenge at 1.5 years (AUC: r=−0.33, Δ peak: r=−0.32; both P < 0.05) but positively related to cortisol AUC during CRF/AVP challenge at 2.5 years (r=+ 0.36, P < 0.05). Faster weight gain between birth and 12 weeks and greater weight at 12 weeks was associated with reduced stimulated cortisol output during the CRF/AVP challenge (Δ peak: r=−0.40, P < 0.05 and r=−0.41, P < 0.01, respectively) and TI test (Δ peak: r=−0.46 (Fig. 5A) and r=−0.50, respectively; AUC: r=−0.45 and r=−0.483, respectively; all P < 0.05) at 2.5 years. In contrast, low weight gain during the undernutrition challenge (12–25 weeks) was associated with reduced cortisol output during the CRF/AVP challenge (Δ peak: r=+0.39, P < 0.05; AUC: r=+0.55, P < 0.001) and TI test (Δ peak: r=+0.61, P < 0.005 (Fig. 5C); AUC: r=+0.54, P < 0.05) at 2.5 years. Accelerated growth rate after this time (35 weeks–1.5 years) was associated with reduced ACTH output (Δ peak: r=−0.47, AUC: r=−0.50; both P < 0.05) and cortisol output (Δ peak: r=−0.59, P < 0.01 (Fig. 5E); AUC: r=−0.52, P < 0.05) output during the TI test at 2.5 years. ACTH output was also reduced in those with a greater weight at 1.5 years (Δ peak: r=−0.48, AUC: r=−0.47; both P < 0.05).

Figure 5
Relationships between Δ peak cortisol response to TI test in male sheep and Δ peak adrenaline response to TI test in female sheep at 2.5 years to growth rates from birth to 12 weeks (A and B), 12 to 25 weeks (C and D) and 35 weeks to 1.5 ...

Current corrected fat depth was positively related to cortisol AUC (1.5 years: r=+ 0.33, 2.5 years: r=+0.40; both P < 0.05) and cortisol:ACTH AUC during the CRF/AVP challenge (1.5 years: r=+0.19, P < 0.001; Fig. 6A). Gain (Δ) in body fat depth between 1.5 and 2.5 years of age was positively associated with elevated ACTH AUC during the CRF/AVP challenge at 2.5 years (r=+0.36, P < 0.05). Adrenaline output during the TI test at 2.5 years was positively associated with higher BCS at 1.5 years (Δ peak: r=+0.40, AUC: r=+0.44, both P < 0.05) and at 2.5 years (AUC: r=+0.36, P= 0.056).

Females. In female sheep as a whole, a faster growth rate from birth to 12 weeks and a higher body weight at 12 weeks were associated with increased Δ peak adrenaline concentrations during the TI test at 2.5 years (r=+0.46 (Fig. 5B) and r=+0.46, respectively, both P < 0.05). Poor growth between 12 and 25 weeks was associated with reduced stimulated ACTH output (AUC: r=+0.56, P < 0.001; Δ peak: r=+0.51, P < 0.01), reduced cortisol output (AUC: r=+0.36, P < 0.05) and increased adrenocortical sensitivity (cortisol to ACTH AUC ratio: r=−0.44, P < 0.01) during the CRF/AVP challenge at 1.5 years and increased Δ peak adrenaline output (r=−0.47, P < 0.05; Fig. 5D) during the TI test at 2.5 years. Faster growth between 25 and 35 weeks was associated with a reduced stimulated ACTH output at 1.5 years (Δ peak: r=−0.33, P < 0.05). Faster growth between 35 weeks and 1.5 years was associated with an enhanced cortisol output during the CRF/AVP challenge at 2.5 years (Δ peak: r=+0.48, P < 0.005). BCS was positively related to adrenocortical sensitivity (r=+0.35, P < 0.05; Fig. 6B) but negatively related to stimulated ACTH output during the CRF/AVP challenge at 1.5 years (Δ peak: r=−0.33, P < 0.05; AUC: r=−0.39, P < 0.05).

Relationships between HPA axis/sympathoadrenal activity and glucose tolerance

Indices of glucose tolerance in this cohort have been reported previously (Poore et al. 2007). In males, there were negative associations between basal glucose concentrations and basal HPA axis activity at 1.5 years (ACTH: r=−0.69, P < 0.001; cortisol: r=−0.51, P < 0.001) and 2.5 years (ACTH: r=−0.52, P < 0.005; cortisol: r=−0.37, P < 0.05). In 1.5-year-old females, improved glucose tolerance (lower glucose AUC during glucose tolerance test) was associated with lower ACTH AUC (r=+0.41, P < 0.05) and lower cortisol AUC (r=+0.44, P < 0.01) during the CRF/AVP challenge. At 2.5 years, lower glucose AUC in females tended to be associated with reduced basal adrenocortical sensitivity (r=+0.32, P= 0.081) and heightened adrenomedullary output during the TI test (adrenaline AUC: r=−0.41, P= 0.057). Cortisol output in females at 2.5 years was positively related to basal glucose concentrations (CRF/AVP challenge; Δ peak: r=+0.47, P < 0.05) but negatively related to basal insulin concentrations (TI test; Δ peak: r=−0.46, AUC: r=−0.47, both P < 0.05). Basal ACTH in females was positively associated with insulin AUC during the glucose tolerance test at 2.5 years (r=+0.39, P < 0.05).

Pituitary and adrenal gland weights at 2.5 years of age

There were no significant effects of early gestation or post-weaning nutrition on pituitary or total adrenal weights (corrected for body weight) (Table 2). Adrenal weight in females was significantly (P < 0.005) greater than in males (Table 2). Adrenal weights at 2.5 years were positively correlated to concurrent adrenocortical output in males (basal cortisol: r=+0.45; cortisol AUC during CRF/AVP challenge: r=+0.54; cortisol:ACTH AUC during CRF/AVP challenge: r=+0.71; cortisol AUC during TI test: r=+0.60; all P < 0.005) and females (basal cortisol: r=+0.54, P < 0.005; cortisol AUC during CRF/AVP challenge: r=+0.70, P < 0.005; cortisol AUC during TI test: r=+0.57, P < 0.01) but were not related to basal or stimulated noradrenaline and adrenaline concentrations.

Increasing pituitary weight was associated with reduced basal ACTH concentrations at 2.5 years (r=−0.46, P < 0.005) in males only. Stimulated ACTH responses were not significantly related to pituitary weight in females or males. In males, pituitary weight was reduced with increasing BCS (r=−0.39, P < 0.05), fat depth (r=−0.33, P < 0.05), Δ fat depth (r=−0.44, P < 0.01) and growth rate (r=−0.62, P < 0.001) between 1.5 and 2.5 years.

Discussion

This study shows for the first time that nutrition in the post-weaning period has long-lasting effects on HPA axis and sympathoadrenal function in sheep in a sex- and age-specific manner. In females, we found that post-weaning undernutrition, a challenge little studied compared to other well-characterised models (Meaney et al. 1993; Plotsky & Meaney, 1993; Weaver et al. 2000; Young, 2000), was associated with reduced pituitary but maintained cortisol output in response to CRF/AVP administration at 1.5 years of age. This study is one of a few, however, to examine postnatal reductions in nutrition, with their effects on postnatal growth trajectories, in relation to later HPA and sympathoadrenal activity. In adult rats challenged by neonatal handling, there is a similar reduction in pituitary stress response and altered negative feedback sensitivity of the HPA axis, due to changes in density and epigenetic status of hippocampal GR (Meaney et al. 1989; Weaver et al. 2004). Epigenetic modification of GR also occurs in response to changes in early life diet (Lillycrop et al. 2005; Burdge et al. 2009). In sheep, hippocampal GR expression is increased around 12 weeks of age (Sloboda et al. 2008), and therefore nutrient restriction around this time may affect normal hippocampal development, with similar disruption of the HPA feedback regulation. Alternatively, lower ACTH output during CRF/AVP challenge in postnatally undernourished females may be due to reduced pituitary sensitivity brought about by changes in receptor density, ACTH production from proopiomelanocortin or the proportion of corticotrophe subtypes. In contrast to handled rats, however, cortisol output in postnatally undernourished female sheep was not concomitantly reduced, suggesting an enhanced adrenocortical responsiveness to the prevailing ACTH concentrations in these groups. Further studies are required to determine whether this is due to increases in steroidogenic enzymes and/or the ACTH receptor density in the cortex, which have both been shown to be affected by nutritional/stressful stimuli (Ross et al. 2000; Edwards et al. 2002).

As well as comparing sheep according to their pre- and postnatal exposure to undernutrition, we examined relationships between HPA/sympathoadrenal function and postnatal growth trajectories prior to and following the post-weaning period in male and female sheep across all nutritional groups. As expected, there were direct relationships in 1.5-year-old females between slow growth from 12 to 25 weeks of age and reduced ACTH output and enhanced adrenocortical sensitivity following CRF/AVP administration. We reported previously that sheep exposed to a post-weaning nutrient restriction show accelerated growth in the months following the challenge, returning body weight to within the normal range by 1.5 years (Poore et al. 2007). Such a faster growth rate was also related to reduced ACTH output at 1.5 years in this study. Although increased adrenocortical sensitivity in the 1.5-year-old groups exposed to post-weaning undernutrition was no longer observed when studied 1 year later, a faster growth rate from 35 weeks to 1.5 years was also related to increased CRF/AVP-induced cortisol output in 2.5-year-old females, suggesting a persistent influence of growth trajectories in earlier life on adrenocortical function in mature adult females.

The transport and isolation stress test, performed only at 2.5 years, raised ACTH, cortisol and adrenaline concentrations. Although our findings do not allow speculation about long-term effects of early nutrition on central versus peripheral aspects of the HPA axis, the pattern of results obtained from the CRF/AVP and TI challenges were similar within each sex. Stress-induced cortisol output was increased in postnatally undernourished females, at least in those with control prenatal nutrition, further suggesting that the effects of post-weaning nutrition on adrenocortical function may persist into mature adulthood. Sympathoadrenal function in response to the stress test, however, was clearly affected by early life nutrition, with increased adrenaline output in postnatally undernourished females. This was again directly associated with slower growth from 12 to 25 weeks of age. No such effects were observed for noradrenaline output following stress, but a high degree of variation between animals and high variability in the noradrenaline assay may have masked any effects. Possible mechanisms linking the early life environment and sympathoadrenal function include persistent effects on sympathetic nerve activity and degree of innervation (Phillips & Barker, 1997; Ruijtenbeek et al. 2000), activity of catecholamine biosynthetic pathways (Adams et al. 1998) or development of adrenal chromaffin tissue (Molendi-Coste et al. 2006). Adrenocortical responses to challenge were related to total adrenal size but catecholamine responses were not. However, we recognise this is a poor indicator of adrenal function and have no information about the relative ratio of adrenal cortex to medulla, which may be affected by growth patterns (Poore & Fowden, 2003). Persistently elevated adrenocortical cortisol output may up-regulate the activity of medullary phenylethanolamine N-methyltransferase (PNMT) (Kvetnansky et al. 1995), contributing to increased stress-induced adrenaline output in postnatally undernourished females.

We observed no overall group effects of pre- or postnatal undernutrition on pituitary or adrenal function in young adult males, in contrast to females. However, adrenocortical, but not adrenomedullary, output during stress in mature adult males was affected by post-weaning growth patterns, the same critical period identified in females. Poor growth from 12 to 25 weeks was related to lower CRF/AVP- and stress-induced cortisol output at 2.5 years and there was a small reduction in CRF/AVP-induced cortisol secretion in males postnatally undernourished. Accelerated growth into adulthood was associated with reduced stress-induced ACTH as well as cortisol output. Thus, in males, as in females, a pattern of poor growth post-weaning followed by catch-up into adulthood may be associated with reduced stimulated ACTH output. A corresponding increase in adrenocortical sensitivity was not observed in postnatally undernourished males as it was in females and cortisol responses were correspondingly reduced. Therefore, while poor postnatal growth in females heightened adrenocortical responsiveness at 1.5 years and adrenomedullary responsiveness at 2.5 years, the effect in males appeared to be reduced adrenocortical output and only at 2.5 years. These findings are in common with other studies showing sexual dimorphism in HPA axis activity following early life challenges (McCormick et al. 1995; Meaney et al. 1996; Matthews, 2002; Jones et al. 2006) and in general greater HPA axis activity in our female compared to male cohort is similar to that reported in sheep (Canny et al. 1999; Gardner et al. 2006) and other species (Rivier, 1999; Poore & Fowden, 2003). Different responses to nutritional challenges in postnatal life may reflect different strategies employed by males and females to optimise later reproductive fitness (Godfrey et al. 2010).

The effects of post-weaning nutrition on HPA axis activity in males and females were unaffected by previous exposure to early gestation (1–31 days) undernutrition, suggesting no interaction between the pre- and postnatal environments (Smythe et al. 1994; Maccari et al. 1995; Cleal et al. 2007a). However, there was a sex- and age-dependent effect of undernutrition in early gestation in its own right, consistent with previous reports in animals that this period affects HPA axis activity in later fetal (Hawkins et al. 1999; Bloomfield et al. 2004) and postnatal life (Hoet & Hanson, 1999; Gardner et al. 2006), albeit in different ways depending on the undernutrition challenge employed. In our study, cortisol concentrations, both basal and following CRF/AVP, were increased in maternally undernourished sheep, but only in 2.5-year-old females. The long-term effects of prenatal stress in rats (Weinstock et al. 1992; Weinstock et al. 1998) are usually also more marked in female offspring and may be induced by increased fetal exposure to glucocorticoids. We (Cleal et al. 2007b) and others (Bloomfield et al. 2004; Jaquiery et al. 2006) actually find reduced basal cortisol levels in ewes during early gestation undernutrition. However, it remains possible that fetal glucocorticoid exposure may be inappropriate during early gestation via effects of undernutrition on factors that influence glucocorticoid activity in placental and fetal tissues such as 11β-hydroxysteroid dehydrogenase or GR expression (Langley-Evans et al. 1996b; Baserga et al. 2005) and/or by longer-term effects on placental growth and function (Fowden et al. 2008).

Recently, lower birth weight has been associated with greater basal adrenocortical activity in girls but greater adrenocortical responses to stress in boys (Jones et al. 2006). We also found in our sheep cohort that lower birth weight was related to basal HPA axis activity in females (higher ACTH concentrations) and to stimulated output in male (higher cortisol responses at 1.5 years but lower responses at 2.5 years). Early gestation undernutrition did not affect birth weight but was associated with faster growth in the first 12 postnatal weeks and increased weight at 12 weeks in males (Cleal et al. 2007b). Accelerated, or ‘catch-up’ growth following low birth weight in human and animal studies is associated with later disease risk (Cianfarani et al. 1999; Eriksson et al. 1999; Poore & Fowden, 2004) and we show here that faster growth after birth (0–12 weeks) is associated with elevated adrenomedullary output in females and reduced adrenocortical output in mature males. These results suggest that the immediate postpartum period in sheep is also a critical developmental window for later adrenal function, in a sex-dependent manner. Postnatal release from the relative growth restraint induced by undernutrition in early gestation, particularly in faster growing males (Pedersen, 1980), may have long-term consequences on later endocrine homeostasis.

Although our sheep cohort contained both singleton and twin offspring, this did not influence the main findings. However, twin sheep have lower basal cortisol concentrations and blunted adrenocortical responses to ACTH or hypoxaemia in late gestation and a delayed prepartum ACTH and cortisol surge (Edwards & McMillen, 2002; Gardner et al. 2004), a strategy that may delay parturition to ensure adequate fetal maturation and viability (Edwards & McMillen, 2002; Gardner et al. 2004). Periconceptional undernutrition in sheep increases adrenal output during late gestation in twins but not singletons (Edwards & McMillen, 2002) and we found that, in adult males, early gestation undernutrition increased stress-induced adrenaline secretion only in twins, suggesting a persistent effect on adrenal function of early gestation undernutrition and the relatively lower maternal nutrition available to twins.

Changes in HPA axis may underlie the effects of the early life environment on adult glucose tolerance (Phillips et al. 1998) and play a role in obesity (Seckl et al. 2004; Pivonello et al. 2005). In our model, growth patterns in the critical developmental window post-weaning affect both HPA axis activity (current study) and glucose handing (Poore et al. 2007) in females. However, increased adrenocortical output would be expected to reduce glucose tolerance (Anagnostis et al. 2009), the opposite of what is observed in postnatally undernourished females at both 1.5 and 2.5 years (Poore et al. 2007). Nevertheless, the effects of the early life environment on both HPA axis and glucose homeostasis can change in an age-dependent manner (Hoet & Hanson, 1999; Petry et al. 2001; Poore & Fowden, 2004). Thus, heightened adrenal capacity for cortisol secretion induced by slower growth trajectories in early life may predispose to a subsequent deterioration in glucose tolerance if it persists into older age, particularly if also challenged by other stressful stimuli (Bjorntorp, 2001). In addition, persistently increased stress-induced sympathoadrenal activity in postnatally undernourished females may have long-term negative effects on metabolic homeostasis due to sustained activation of adrenergic receptors in organs that regulate glucose metabolism (Julius & Gudbrandsson, 1992). Glucose metabolism is unaffected by post-weaning undernutrition in males (Poore et al. 2007) and it is unknown whether reduced adrenocortical output would affect this finding in the longer term.

Poor early growth in female sheep may predispose to obesity due to a persistent increase in glucose handling/insulin sensitivity (Poore et al. 2007). Enhanced insulin sensitivity has been observed in growth-restricted lambs following placental restriction (De Blasio et al. 2007), as well as in low birth weight human infants (Mericq et al. 2005), and aids the return to normal body weight. While this may have an adaptive advantage in terms of reproductive fitness (Godfrey et al. 2010), persistently increased insulin sensitivity may become detrimental to body fat control and thus glucose homeostasis in later life. Altered HPA function may also influence body composition. By 2.5 years, BCS or subcutaneous fat depth over the spine is not different between the four nutritional groups (Poore et al. 2007), although more subtle differences in body fat distribution may not be apparent using these simple measures. However, we show here that early growth trajectories influence adult HPA and sympathoadrenal function, themselves related to our measures of fatness. In both males and females, heightened adrenocortical responsiveness was associated with greater fatness and basal adrenal output was greatest in those that gained more fat from young to mature adult life, consistent with the effect of excess cortisol on obesity and components of the metabolic syndrome (Pivonello et al. 2005). Lower basal catecholamine output (noradrenaline) associated with poor postnatal growth in females may also predispose to obesity (Tataranni et al. 1997; Webber & Macdonald, 2000). Across all females, however, those which had the highest change in body condition had higher catecholamine concentrations, a trend observed in human obese subjects (van Baak, 2001). Persistently elevated adrenomedullary responsiveness in postnatally undernourished females may be also associated with changes in body fat distribution towards the abdomen, as shown in rats that were handled in the neonatal period (Young, 2000).

In conclusion, this study has shown that the post-weaning period in sheep is a critical developmental window in terms of adult HPA and sympathoadrenal function, as we have shown for glucose tolerance (Poore et al. 2007). These effects are sex- and age-specific. Poor postnatal growth increases output from the adrenal cortex and medulla in females but reduces adrenocortical responses in males. In both males and females, adult body composition was also associated with activity of the adrenal cortex and medulla. Changes observed in both HPA and sympathoadrenal function suggest a potential for early life growth and nutrition to have profound effects on cardiovascular function. Such findings may thus help to identify individuals at risk of metabolic and cardiovascular disorders.

Acknowledgments

This work and M.A.H. were supported by The British Heart Foundation. J.P.B. was supported by Hope (Wessex Medical Research). We are grateful to staff at the Biological Services Unit, Royal Veterinary College and the Biological Research Facility, University of Southampton for the care of all animals. We thank the laboratory of Dr P. Woods for performing the noradrenaline and adrenaline assays and Professor J. M. Morgan for support of J.P.B.

Glossary

Abbreviations

ACTH
adrenocorticotropic hormone
AUC
area under the curve
AVP
arginine vasopressin
BCS
body condition score
CRF
corticotropin-releasing factor
GR
glucocorticoid receptor
HPA
hypothalamo-pituitary-adrenal
TI
transport and isolation

Author contributions

This work was carried out at the Department of Veterinary Reproduction, Royal Veterinary College and Institute of Developmental Sciences, University of Southampton, UK. Conception and design of experiments was performed by K.R.P., J.P.B., M.A.H. and L.R.G. Collection of the data was performed by K.R.P., J.P.B., J.K.C., J.P.N., D.E.N. and L.R.G. Analysis and interpretation of data, and drafting and revising the manuscript were performed by K.R.P., M.A.H. and L.R.G. All authors approved the final version of the manuscript.

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