Kirsten Poore - Academia.edu (original) (raw)

Papers by Kirsten Poore

Research paper thumbnail of The effects of birth weight and postnatal growth patterns on fat depth and plasma leptin concentrations in juvenile and adult pigs

The Journal of physiology, 2004

Low birth weight is associated with altered adipose tissue deposition and regulation of leptin pr... more Low birth weight is associated with altered adipose tissue deposition and regulation of leptin production. This study determined the effects of naturally occurring variations in birth weight in pigs on postnatal growth patterns, body fat depth and plasma leptin and other hormone concentrations. Low (< 1.47 kg) and high (> 1.53 kg) birth weight piglets were studied at 3 months (juvenile; n= 47) and 12 months of age (young adult; n= 17). At each age, arterial and venous catheters were inserted under general anaesthesia. Plasma leptin, cortisol, glucose, insulin and catecholamine concentrations were determined in basal blood samples. Body fat depth was measured by ultrasound at 12 months of age. Overall, adult fat depth was greater in low compared to high birth weight pigs and increased fat depth was associated with thinness at birth and poor early growth rates. These effects were strongest in females. Fat depth was related to current weight only in males. Compared to high birth ...

Research paper thumbnail of Ontogeny of pulmonary and renal angiotensin-converting enzyme in pigs

Molecular and cellular endocrinology, Jan 20, 2001

The present study investigated the ontogeny of pulmonary and renal angiotensin-converting enzyme ... more The present study investigated the ontogeny of pulmonary and renal angiotensin-converting enzyme (ACE) in foetal and postnatal pigs, and examined the effect of cortisol on tissue ACE in utero. Data were compared with those in sheep at similar ages. Under anaesthesia, tissues and umbilical blood were collected from pig foetuses between 81-115 days of gestation (term, 115+/-2 days). Twelve foetuses delivered at 97+/-2 days were infused with saline or cortisol (3-6 mgkg(-1)day(-1)) using osmotic mini-pumps implanted 6 days previously. Tissues were collected from newborn piglets, and from pigs at 2-4 weeks, 10-12 weeks and 10-12 months of age. Unlike in sheep, gestational age and exogenous cortisol had no effect on pulmonary or renal ACE in pigs. After birth, pulmonary ACE decreased to a nadir at 2-4 weeks and remained low thereafter. Renal ACE increased between 10-12 weeks and 10-12 months. Postnatal changes in tissue ACE may have consequences for cardiovascular, pulmonary and renal fu...

Research paper thumbnail of Angiotensin II infusion in vivo does not modulate cortisol secretion in the late-gestation ovine fetus

The American journal of physiology, 1998

Maturation of the fetal adrenal gland is critical for the onset of ovine parturition. It has long... more Maturation of the fetal adrenal gland is critical for the onset of ovine parturition. It has long been proposed that the fetal adrenal gland may be under inhibitory influences during late gestation. In vitro evidence has suggested that angiotensin II may be such an inhibitory factor and may help to prevent a premature increase in cortisol concentrations. The aim of this study was to test the effect of angiotensin II infusion in vivo on basal cortisol concentrations and fetal adrenal responsiveness to an ACTH-(1-24) challenge. Fetuses received a continuous infusion of either angiotensin II (100 ng . min-1 . kg-1; n = 7) or saline (2 ml/h; n = 4), which commenced at 140 days of gestation (GA) and continued for a total of 50 h. Adrenal responsiveness to the administration of ACTH-(1-24) (5 microg/kg) was determined during angiotensin II or saline infusions at both 2 and 48 h after infusion onset. Angiotensin II had no significant effect on adrenal responsiveness after acute (2 h) or ch...

Research paper thumbnail of The effect of birth weight on hypothalamo-pituitary-adrenal axis function in juvenile and adult pigs

The Journal of Physiology, 2003

Programming of the hypothalamo-pituitary-adrenal (HPA) axis during prenatal and early postnatal l... more Programming of the hypothalamo-pituitary-adrenal (HPA) axis during prenatal and early postnatal life may explain, in part, the association between low birth weight (BW) and the increased incidence of cardiovascular and metabolic disease in later life. This study examined the effect of natural variations in BW on HPA axis function in juvenile and adult pigs. Low (< 1.47 kg) and high (> 1.53 kg) BW pure-bred Large White piglets from 15 litters were studied at 3 (n = 47) and 12 (n = 17) months of age. At each age, HPA axis function was tested by hypoglycaemic challenge (I.V. insulin; 0.5 IU (kg body weight) _1 ) and ACTH challenge (I.V. Synacthen, 2 mg (kg body weight) _1 ). At 3 months of age, adrenal size, the ratio of adrenal cortical to medullary area and stimulated cortisol concentrations were elevated in pigs that were of low BW and that remained small after birth. At 12 months of age, thinness at birth was associated with elevated adrenal responsiveness to insulin-induced hypoglycaemia. These results are consistent with the hypothesis that impaired fetal and early postnatal growth are associated with altered HPA axis function in later life.

Research paper thumbnail of Developmental regulation of hepatic and renal gluconeogenic enzymes by thyroid hormones in fetal sheep during late gestation

The Journal of Physiology, 2003

Tissue glucose-6-phosphatase (G6P) and phosphoenolpyruvate carboxykinase (PEPCK) activities were ... more Tissue glucose-6-phosphatase (G6P) and phosphoenolpyruvate carboxykinase (PEPCK) activities were investigated in sheep fetuses after experimental manipulation of thyroid hormone status. Increments in hepatic and renal G6P and PEPCK activities seen between 127-130 and 140-145 days of gestation (term, 145 ± 2 days) were abolished when the normal prepartum rise in plasma triiodothyronine (T 3 ), but not cortisol, was prevented by fetal thyroidectomy (TX). At 127-130 days, hepatic and renal G6P, and renal PEPCK, activities were similar in intact and TX fetuses; however, hepatic PEPCK was increased by TX. At 140-145 days, tissue G6P and PEPCK activities in TX fetuses were lower than in intact fetuses. In immature fetuses infused with cortisol (2-3 mg (kg body wt) _1 day _1 ) for five days, hepatic and renal enzyme activities were increased to those seen in mature fetuses near term. After five days of T 3 infusion (8-12 mg (kg body wt) _1 day _1 ), G6P and PEPCK activities in the liver and kidney were greater than in saline-infused fetuses, but only renal G6P and PEPCK increased to the level seen close to term. Therefore, in fetal sheep, thyroid hormones are important for the prepartum rises in G6P and PEPCK activities in the liver and kidney and may mediate, in part, the maturational effects of cortisol.

Research paper thumbnail of The effects of birth weight on basal cardiovascular function in pigs at 3 months of age

The Journal of Physiology, 2002

In man, epidemiological studies have shown that low birth weight (BW) is associated with an incre... more In man, epidemiological studies have shown that low birth weight (BW) is associated with an increased risk of cardiovascular disease in later life. In this study, the long-term consequences of variations in natural BW on basal cardiovascular function were investigated in pigs at 3 months of postnatal age. Low (< 1.41 kg; n = 20) and high (> 1.52 kg; n = 20) BW Large White piglets were selected from a total of 12 litters for study at 3 months of age. Basal mean arterial pressure (MAP) and heart rate (HR) were recorded for ~30 min using standard recording equipment and basal arterial blood samples were taken for hormone analyses. Concentrations of angiotensin-converting enzyme (ACE) were also measured in kidney, lung and plasma. Basal MAP, but not HR, in 3-monthold pigs was significantly inversely related to BW and positively related to the ratio of head length to BW. Postnatal growth rate of low BW pigs was slower than that of high BW pigs such that low BW piglets remained significantly smaller at 3 months of age. There were no differences in basal plasma adrenaline or cortisol concentrations between low and high BW pigs. However, basal plasma noradrenaline concentrations were significantly elevated in low BW compared to high BW pigs. Renal and pulmonary ACE levels were significantly reduced in low BW compared to high BW pigs. These data show that basal MAP in 3-month-old pigs is negatively associated with BW and positively correlated to disproportionate size at birth. This effect was associated with an increase in basal plasma noradrenaline concentrations.

Research paper thumbnail of Adrenal Responsiveness and the Timing of Parturition in Hypothalamo-Pituitary Disconnected Ovine Foetuses With and Without Constant Adrenocorticotrophin Infusion

Journal of Neuroendocrinology, 2001

Ovine parturition results from an increase in foetal cortisol secretion in late gestation which i... more Ovine parturition results from an increase in foetal cortisol secretion in late gestation which is dependant on an intact hypothalamo-pituitary connection. The cortisol surge and parturition fails in hypothalamo-pituitary disconnected (HPD) foetuses but, paradoxically, immunoreactive (ir)-ACTH concentrations and secretory dynamics appear normal. This study compares the occurrence and timing of labour, basal ir-ACTH and cortisol concentrations and adrenal responsiveness in HPD foetuses (HPD/ACTH) receiving constant ACTH infusion (43 ng/h/kg) from surgery (114±1 days gestational age (GA)) with those of saline-infused HPD or intact foetuses (HPD/SAL and INT/SAL). HPD/ACTH foetuses initiated labour at 147±2 days GA, which was not significantly different from INT/SAL foetuses (149±1 day GA). HPD/SAL foetuses were killed electively at 146±3 days GA with no signs of labour. Foetal ir-ACTH concentrations in all groups were indistinguishable, but only HPD/ACTH and INT/SAL foetuses had a significant cortisol surge. Adrenal responsiveness to ACTH

Research paper thumbnail of Do Not Turn to the Hypothalamus for Feedback on Stress If You Are Growth Restricted

Endocrinology, 2013

Submission Deadline: January 30, 2013 12:00PM (noon) ET www.endo-society.org/endo2013

Research paper thumbnail of The effect of birth weight on glucose tolerance in pigs at 3 and 12 months of age

Diabetologia, 2002

Aims/hypothesis. The aim of this study was to examine the effect of birth weight on glucose toler... more Aims/hypothesis. The aim of this study was to examine the effect of birth weight on glucose tolerance in juvenile and adult pigs. Methods. Low (<1.47 kg) and high (>1.53 kg) birth weight piglets from 15 litters were studied at 3 (n=47) and 12 (n=17) months of age. At each age, selected pigs were tranquilised and catheters were inserted into the dorsal aorta and caudal vena cava under general anaesthesia. After recovery, glucose (0.5 g/kg; i.v.) was administered and regular arterial blood samples were taken for 2 h for plasma glucose and insulin measurements. Hepatic gluconeogenic enzyme activities were measured at post mortem. Results. At 12, but not at 3 months of age, the area under the glucose and insulin curves after glucose administration were greater (p<0.05) in low rather than in high birth weight pigs. The glucose area at 12 months was negatively correlated with body weight and BMI at birth. Disproportionate shape at birth was associated with reduced hepatic gluconeogenic enzyme concentrations and low birth weight pigs had reduced basal glucose concentrations at 12 months of age. Conclusion/interpretation. This study has shown an association between low birth weight and thinness at birth and glucose intolerance at 12 months of postnatal age, but not at 3 months. This effect was not due to insulin deficiency or increased hepatic gluconeogenic enzyme activity. [Diabetologia (2002[Diabetologia ( ) 45:1247[Diabetologia ( -1254

Research paper thumbnail of Insulin sensitivity in juvenile and adult Large White pigs of low and high birthweight

Diabetologia, 2004

Aims/hypothesis. We have previously demonstrated poor glucose tolerance in adult pigs of naturall... more Aims/hypothesis. We have previously demonstrated poor glucose tolerance in adult pigs of naturally occurring low birthweight. The aim of this study was to examine sensitivity to insulin in juvenile (3-monthold) and adult (12-month-old) pigs of low and high birthweight. Methods. Low (<1.47 kg) and high (>1.53 kg) birthweight piglets from 15 litters were studied at 3 (n=47) and 12 (n=17) months of age. At each age the selected pigs were tranquilised and catheters were inserted into the dorsal aorta and caudal vena cava under general anaesthesia. After recovery, insulin sensitivity was measured as the glucose decrement (mmol·l −1 ·min −1 ) during the first 10 min after an intravenous insulin bolus (0.5 IU/kg). Data (means ± SEM) were analysed by the Student's t test, ANOVA and linear regression.

Research paper thumbnail of The role of the pituitary gland and ACTH in the regulation of mRNAs encoding proteins essential for adrenal steroidogenesis in the late-gestation ovine fetus

Journal of Endocrinology - J ENDOCRINOL, 2001

To further understand the relative roles of the pituitary gland and ACTH in the regulation of mRN... more To further understand the relative roles of the pituitary gland and ACTH in the regulation of mRNAs encoding proteins that are essential for adrenal development, we investigated the effects of, first, an ACTH infusion and labour in intact fetuses and, secondly, the effect of an ACTH infusion to fetuses with and without a pituitary gland, on the relative abundance of the mRNA encoding for the ACTH receptor (MC2R), steroidogenic factor 1 (SF-1), cholesterol side-chain cleavage enzyme (P450scc), 3-hydroxysteroid dehydrogenase (3HSD) and 17- hydroxylase (P450C17) in the fetal adrenal gland. ACTH1-24 infusion (14·7 pmol/kg per h) to intact fetuses was without effect on the abundance of mRNA encoding MC2R and SF-1, irrespective of whether the infusion was given for 18 (115-132 days of gestation) or 32 days (115 days to term (147 days of gestation)). Hypophysec- tomy (HX) did not alter the expression of MC2R mRNA; however, the abundance of SF-1 mRNA fell by approxi- mately 50% following th...

Research paper thumbnail of The role of the pituitary gland and ACTH in the regulation of mRNAs encoding proteins essential for adrenal steroidogenesis in the late-gestation ovine fetus

Journal of Endocrinology

To further understand the relative roles of the pituitary gland and ACTH in the regulation of mRN... more To further understand the relative roles of the pituitary gland and ACTH in the regulation of mRNAs encoding proteins that are essential for adrenal development, we investigated the effects of, first, an ACTH infusion and labour in intact fetuses and, secondly, the effect of an ACTH infusion to fetuses with and without a pituitary gland, on the relative abundance of the mRNA encoding for the ACTH receptor (MC2R), steroidogenic factor 1 (SF-1), cholesterol side-chain cleavage enzyme (P450(scc)), 3beta-hydroxysteroid dehydrogenase (3betaHSD) and 17alpha-hydroxylase (P450(C17)) in the fetal adrenal gland. ACTH(1-24) infusion (14.7 pmol/kg per h) to intact fetuses was without effect on the abundance of mRNA encoding MC2R and SF-1, irrespective of whether the infusion was given for 18 (115-132 days of gestation) or 32 days (115 days to term (147 days of gestation)). Hypophysectomy (HX) did not alter the expression of MC2R mRNA; however, the abundance of SF-1 mRNA fell by approximately 50...

Research paper thumbnail of Glutamate cycling may drive organic anion transport on the basal membrane of human placental syncytiotrophoblast

The Journal of physiology, Jan 17, 2015

The organic anion transporter OAT4 (SLC22A11) and organic anion transporting polypeptide OATP2B1 ... more The organic anion transporter OAT4 (SLC22A11) and organic anion transporting polypeptide OATP2B1 (SLCO2B1) are expressed in the basal membrane of the placental syncytiotrophoblast. These transporters mediate exchange whereby uptake of one organic anion is coupled to efflux of a counter-ion. In placenta, these exchangers mediate placental uptake of substrates for oestrogen synthesis as well as clearing waste products and xenobiotics from the fetal circulation. However, the identity of the counter-ion driving this transport in the placenta, and in other tissues, is unclear. While glutamate is not a known OAT4 or OATP2B1 substrate, we propose that its high intracellular concentration has the potential to drive accumulation of substrates from the fetal circulation. In the isolated perfused placenta, glutamate exchange was observed between the placenta and the fetal circulation. This exchange could not be explained by known glutamate exchangers. However, glutamate efflux was trans-stimul...

Research paper thumbnail of The role of the placenta in the developmental origins of health and disease-Implications for practice

The placenta is actively involved in transporting nutrients to the fetus, it has both direct and ... more The placenta is actively involved in transporting nutrients to the fetus, it has both direct and indirect effects on fetal cardiovascular function and has endocrine influences on the mother and fetus. As such, a properly functioning placenta is crucial for normal fetal development and plays a central role in mediating effects of the maternal environment on the fetus. An altered external environment or abnormal placental function can induce developmental changes in the fetus and may have important consequences for the risk of cardiovascular and metabolic disease in adult life.

Research paper thumbnail of 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

The Journal of physiology, Jan 15, 2010

The early-life environment affects risk of later metabolic disease, including glucose intolerance... more 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 c...

Research paper thumbnail of Raised dietary n-6 polyunsaturated fatty acid intake increases 2-series prostaglandin production during labour in the ewe

The Journal of Physiology, 2005

Preterm labour is the major cause of perinatal morbidity and mortality in humans. The incidence i... more Preterm labour is the major cause of perinatal morbidity and mortality in humans. The incidence is around 10% and the causes are often unknown. Consumption of dietary n-6 polyunsaturated fatty acids (PUFAs) in western societies is increasing. These are metabolized to arachidonic acid, the precursor for 2-series prostaglandins (PGs), major signalling molecules during labour. This study investigated the effect of dietary supplementation with linoleic acid (LA, 18 : 2, n-6) on parturition. Ewes were fed a control or LA-supplemented diet from 100 days gestation. Labour was induced using a standardized glucocorticoid challenge (dexamethasone, Dex) to the fetus, starting on day 139. Electromyographic (EMG) activity and fetal and maternal circulating PG concentrations were monitored. One third of LA-fed ewes delivered early (pre-Dex) although basal uterine EMG activity preceding Dex was higher in control ewes (P < 0. . The basal concentrations of maternal and fetal PGFM and fetal PGE 2 were approximately doubled in LA-supplemented ewes before the start of Dex infusion (P < 0.01). The rise in fetal PGE 2 and maternal oestradiol concentrations post-Dex occurred earlier in the LA-supplemented ewes. All PG measurements remained significantly higher in the LA-supplemented ewes during labour onset. This study suggests that consumption of a high LA diet in late pregnancy can enhance placental PG production and may thus increase the risk of preterm labour.

Research paper thumbnail of Early-life undernutrition induces sex-specific effects on the sympatho-adrenal response to stress in sheep

Proceedings of the Nutrition Society, 2008

ABSTRACT Early life undernutrition induces sex-specific effects on the sympathoadrenal response t... more ABSTRACT Early life undernutrition induces sex-specific effects on the sympathoadrenal response to stress in sheep. By J.P. BOULLIN, K.R. POORE, J.K. CLEAL, J.P. NEWMAN, D. NOAKES†, M.A. HANSON and L.R. GREEN, Institute of Developmental Sciences, Developmental Origins of Health and Disease Division, University of Southampton, MP 887 Southampton General Hospital, Tremona Road, Southampton SO16 5YD; †Department of Veterinary Reproduction, Royal Veterinary College, Hawkshead Lane, North Mymms, AT9 7TA. Altered adrenocortical and sympathoadrenal activity may mediate the link between the early life environment and cardiovascular and metabolic abnormalities in later life (1). We have demonstrated previously that nutrition in early postnatal life has long-term effects on adult pituitary and adrenocortical responsiveness to stress (2). The aim of this study was to determine the long-term effects of early pre- and postnatal life nutrient restriction on adult sympathoadrenal function in sheep. Ewes received either 100% (C, n = 39) or 50% nutritional requirements (U, n = 41) from 1-31 days gestation and 100% thereafter. Male and female offspring were then fed either ad libitum (CC, n = 22; UC, n = 19) or to reduce body weight to 85% of target from 12-25 weeks postnatal age (CU, n = 17; UU, n = 22) and ad libitum thereafter. At age 2.5 years, catheters were inserted into the carotid artery and jugular vein under general anaesthesia. Basal arterial blood pressure was derived from the mean of recordings taken on 3 separate days under control conditions. Sympathoadrenal responses to a stress test were assessed by transporting the sheep in their carts from their normal holding room to a different empty room followed by 30 min isolation (transport and isolation (TI) test). Plasma adrenaline and noradrenaline concentrations were measured prior to (-15 and -1 min) and during (10, 20 and 30 min) the test by radioimmunoassay (2 CAT RIA, Labor Diagnostica Nord). Heart rate responses to the TI test were measured by an implanted loop recorder (REVEAL). Data were analysed by ANOVA. There were no significant differences between sex or group in basal heart rate or blood pressure. The adrenaline output (as given by area under curve, AUC) during the TI test was significantly (P &amp;lt; 0.05) enhanced in female (Figure), but not male, sheep that were exposed to postnatal undernutrition, regardless of the prenatal nutrient environment. There was no difference between sex or group in heart rate response during the TI test. The sex-specific effects of the postnatal nutrient environment on adrenomedullary output in response to stress follow a similar pattern to our previous observations on pituitary-adrenocortical responsiveness in these animals (2). This suggests a generalised effect of postnatal undernutrition at the level of the adrenal. The absence of an accompanying increase in heart rate could reflect a down regulation in cardiac β-adrenergic pathways or altered parasympathetic tone. 1. Phillips DI, Jones A, Goulden PA. (2006) Birth weight, stress, and the metabolic syndrome in adult life. Ann N Y Acad Sci. 1083:28-36. 2. Poore KR, Cleal JK, Newman JP, Boullin J, Noakes D, Hanson MA and Green LR (2006) Hypothalamo-pituitary-adrenal axis responsiveness in adult sheep following early life nutrient restriction. 4th International Congress on DOHaD, Utrecht, The Netherlands. Early Human Devel 82(8): 537 (F-15). Supported by the British Heart Foundation and Wessex Medical Research.

Research paper thumbnail of Mismatched pre- and postnatal nutrition leads to cardiovascular dysfunction and altered renal function in adulthood

Proceedings of the National Academy of Sciences, 2007

The early life environment has long-term implications for the risk of developing cardiovascular (... more The early life environment has long-term implications for the risk of developing cardiovascular (CV) disease in adulthood. Fetal responses to changes in maternal nutrition may be of immediate benefit to the fetus, but the long-term effects of these adaptations may prove detrimental if nutrition in postnatal life does not match that predicted by the fetus on the basis of its prenatal environment. We tested this predictive adaptive response hypothesis with respect to CV function in sheep. We observed that a mismatch between pre-and postnatal nutrient environments induced an altered CV function in adult male sheep that was not seen when environments were similar. Sheep that received postnatal undernutrition alone had altered growth, CV function, and basal hypothalamo-pituitary-adrenal axis activity in adulthood. Prenatal undernutrition induced greater weight gain by weaning compared with the prenatal control diet, which may provide a reserve in the face of a predicted poor diet in later life. In an adequate postnatal nutrient environment (i.e., relatively mismatched), these offspring exhibited cardiac hypertrophy and altered CV function in adulthood. These data support the concept that adult CV function can be determined by developmental responses to intrauterine nutrition made in expectation of the postnatal nutritional environment, and that if these predictions are not met, the adult may be maladapted and at greater risk of CV disease. Our findings have substantial implications for devising strategies to reduce the impact of a mismatch in nutrition levels in humans undergoing rapid socio-economic transitions in both developing and developed societies.

Research paper thumbnail of Differential Pathways to Adult Metabolic Dysfunction following Poor Nutrition at Two Critical Developmental Periods in Sheep

PLoS ONE, 2014

Epidemiological and experimental studies suggest early nutrition has long-term effects on suscept... more Epidemiological and experimental studies suggest early nutrition has long-term effects on susceptibility to obesity, cardiovascular and metabolic diseases. Small and large animal models confirm the influence of different windows of sensitivity, from fetal to early postnatal life, on offspring phenotype. We showed previously that undernutrition in sheep either during the first month of gestation or immediately after weaning induces differential, sex-specific changes in adult metabolic and cardiovascular systems. The current study aims to determine metabolic and molecular changes that underlie differences in lipid and glucose metabolism induced by undernutrition during specific developmental periods in male and female sheep. Ewes received 100% (C) or 50% nutritional requirements (U) from 1-31 days gestation, and 100% thereafter. From weaning (12 weeks) to 25 weeks, offspring were then fed either ad libitum (CC, UC) or were undernourished (CU, UU) to reduce body weight to 85% of their individual target. From 25 weeks, all offspring were fed ad libitum. A cohort of late gestation fetuses were studied after receiving either 40% nutritional requirements (1-31 days gestation) or 50% nutritional requirements (104-127 days gestation). Post-weaning undernutrition increased in vivo insulin sensitivity, insulin receptor and glucose transporter 4 expression in muscle, and lowered hepatic methylation at the delta-like homolog 1/maternally expressed gene 3 imprinted cluster in adult females, but not males. Early gestational undernutrition induced lower hepatic expression of gluconeogenic factors in fetuses and reduced in vivo adipose tissue insulin sensitivity in adulthood. In males, undernutrition in early gestation increased adipose tissue lipid handling mechanisms (lipoprotein lipase, glucocorticoid receptor expression) and hepatic methylation within the imprinted control region of insulin-like growth factor 2 receptor in adulthood. Therefore, undernutrition during development induces changes in mechanisms of lipid and glucose metabolism which differ between tissues and sexes dependent on the period of nutritional restriction. Such changes may increase later life obesity and dyslipidaemia risk.

Research paper thumbnail of The Effect of Maternal Undernutrition in Early Gestation on Gestation Length and Fetal and Postnatal Growth in Sheep

Pediatric Research, 2007

In utero undernutrition in humans may result in cardiovascular (CV), metabolic, and growth adapta... more In utero undernutrition in humans may result in cardiovascular (CV), metabolic, and growth adaptations. In sheep, maternal nutrient restriction during pregnancy, without effects on fetal or birth weight, results in altered CV control in the offspring. Adjustment of gestation length after undernutrition could be a strategy to enhance postnatal health/survival. The aim of this study was to determine in sheep the effect of a 50% reduction in maternal nutrient intake [undernutrition group (U) versus 100%, control group (C)] during 1-31 d of gestation (dGA) on gestation length and offspring size. By 28 dGA, U ewes had gained less weight than C, and twin-bearing ewes had gained less weight than singleton-bearing ewes regardless of group (p Ͻ 0.05). In different-sex twin pairs, maternal undernutrition resulted in longer gestation compared with C (146.5 Ϯ 0.6 versus 144.6 Ϯ 0.6 d, p Ͻ 0.05). Increased weight gain by weaning (20.8 Ϯ 0.8 versus 17.9 Ϯ 0.8 kg, p Ͻ 0.05) was observed in U male twins. These findings suggest that the strategy (i.e. growth rate or length of time in utero) adopted by the fetus to enhance immediate survival depends on offspring number and sex. This is likely to reflect the degree of constraint imposed on the fetus.

Research paper thumbnail of The effects of birth weight and postnatal growth patterns on fat depth and plasma leptin concentrations in juvenile and adult pigs

The Journal of physiology, 2004

Low birth weight is associated with altered adipose tissue deposition and regulation of leptin pr... more Low birth weight is associated with altered adipose tissue deposition and regulation of leptin production. This study determined the effects of naturally occurring variations in birth weight in pigs on postnatal growth patterns, body fat depth and plasma leptin and other hormone concentrations. Low (< 1.47 kg) and high (> 1.53 kg) birth weight piglets were studied at 3 months (juvenile; n= 47) and 12 months of age (young adult; n= 17). At each age, arterial and venous catheters were inserted under general anaesthesia. Plasma leptin, cortisol, glucose, insulin and catecholamine concentrations were determined in basal blood samples. Body fat depth was measured by ultrasound at 12 months of age. Overall, adult fat depth was greater in low compared to high birth weight pigs and increased fat depth was associated with thinness at birth and poor early growth rates. These effects were strongest in females. Fat depth was related to current weight only in males. Compared to high birth ...

Research paper thumbnail of Ontogeny of pulmonary and renal angiotensin-converting enzyme in pigs

Molecular and cellular endocrinology, Jan 20, 2001

The present study investigated the ontogeny of pulmonary and renal angiotensin-converting enzyme ... more The present study investigated the ontogeny of pulmonary and renal angiotensin-converting enzyme (ACE) in foetal and postnatal pigs, and examined the effect of cortisol on tissue ACE in utero. Data were compared with those in sheep at similar ages. Under anaesthesia, tissues and umbilical blood were collected from pig foetuses between 81-115 days of gestation (term, 115+/-2 days). Twelve foetuses delivered at 97+/-2 days were infused with saline or cortisol (3-6 mgkg(-1)day(-1)) using osmotic mini-pumps implanted 6 days previously. Tissues were collected from newborn piglets, and from pigs at 2-4 weeks, 10-12 weeks and 10-12 months of age. Unlike in sheep, gestational age and exogenous cortisol had no effect on pulmonary or renal ACE in pigs. After birth, pulmonary ACE decreased to a nadir at 2-4 weeks and remained low thereafter. Renal ACE increased between 10-12 weeks and 10-12 months. Postnatal changes in tissue ACE may have consequences for cardiovascular, pulmonary and renal fu...

Research paper thumbnail of Angiotensin II infusion in vivo does not modulate cortisol secretion in the late-gestation ovine fetus

The American journal of physiology, 1998

Maturation of the fetal adrenal gland is critical for the onset of ovine parturition. It has long... more Maturation of the fetal adrenal gland is critical for the onset of ovine parturition. It has long been proposed that the fetal adrenal gland may be under inhibitory influences during late gestation. In vitro evidence has suggested that angiotensin II may be such an inhibitory factor and may help to prevent a premature increase in cortisol concentrations. The aim of this study was to test the effect of angiotensin II infusion in vivo on basal cortisol concentrations and fetal adrenal responsiveness to an ACTH-(1-24) challenge. Fetuses received a continuous infusion of either angiotensin II (100 ng . min-1 . kg-1; n = 7) or saline (2 ml/h; n = 4), which commenced at 140 days of gestation (GA) and continued for a total of 50 h. Adrenal responsiveness to the administration of ACTH-(1-24) (5 microg/kg) was determined during angiotensin II or saline infusions at both 2 and 48 h after infusion onset. Angiotensin II had no significant effect on adrenal responsiveness after acute (2 h) or ch...

Research paper thumbnail of The effect of birth weight on hypothalamo-pituitary-adrenal axis function in juvenile and adult pigs

The Journal of Physiology, 2003

Programming of the hypothalamo-pituitary-adrenal (HPA) axis during prenatal and early postnatal l... more Programming of the hypothalamo-pituitary-adrenal (HPA) axis during prenatal and early postnatal life may explain, in part, the association between low birth weight (BW) and the increased incidence of cardiovascular and metabolic disease in later life. This study examined the effect of natural variations in BW on HPA axis function in juvenile and adult pigs. Low (< 1.47 kg) and high (> 1.53 kg) BW pure-bred Large White piglets from 15 litters were studied at 3 (n = 47) and 12 (n = 17) months of age. At each age, HPA axis function was tested by hypoglycaemic challenge (I.V. insulin; 0.5 IU (kg body weight) _1 ) and ACTH challenge (I.V. Synacthen, 2 mg (kg body weight) _1 ). At 3 months of age, adrenal size, the ratio of adrenal cortical to medullary area and stimulated cortisol concentrations were elevated in pigs that were of low BW and that remained small after birth. At 12 months of age, thinness at birth was associated with elevated adrenal responsiveness to insulin-induced hypoglycaemia. These results are consistent with the hypothesis that impaired fetal and early postnatal growth are associated with altered HPA axis function in later life.

Research paper thumbnail of Developmental regulation of hepatic and renal gluconeogenic enzymes by thyroid hormones in fetal sheep during late gestation

The Journal of Physiology, 2003

Tissue glucose-6-phosphatase (G6P) and phosphoenolpyruvate carboxykinase (PEPCK) activities were ... more Tissue glucose-6-phosphatase (G6P) and phosphoenolpyruvate carboxykinase (PEPCK) activities were investigated in sheep fetuses after experimental manipulation of thyroid hormone status. Increments in hepatic and renal G6P and PEPCK activities seen between 127-130 and 140-145 days of gestation (term, 145 ± 2 days) were abolished when the normal prepartum rise in plasma triiodothyronine (T 3 ), but not cortisol, was prevented by fetal thyroidectomy (TX). At 127-130 days, hepatic and renal G6P, and renal PEPCK, activities were similar in intact and TX fetuses; however, hepatic PEPCK was increased by TX. At 140-145 days, tissue G6P and PEPCK activities in TX fetuses were lower than in intact fetuses. In immature fetuses infused with cortisol (2-3 mg (kg body wt) _1 day _1 ) for five days, hepatic and renal enzyme activities were increased to those seen in mature fetuses near term. After five days of T 3 infusion (8-12 mg (kg body wt) _1 day _1 ), G6P and PEPCK activities in the liver and kidney were greater than in saline-infused fetuses, but only renal G6P and PEPCK increased to the level seen close to term. Therefore, in fetal sheep, thyroid hormones are important for the prepartum rises in G6P and PEPCK activities in the liver and kidney and may mediate, in part, the maturational effects of cortisol.

Research paper thumbnail of The effects of birth weight on basal cardiovascular function in pigs at 3 months of age

The Journal of Physiology, 2002

In man, epidemiological studies have shown that low birth weight (BW) is associated with an incre... more In man, epidemiological studies have shown that low birth weight (BW) is associated with an increased risk of cardiovascular disease in later life. In this study, the long-term consequences of variations in natural BW on basal cardiovascular function were investigated in pigs at 3 months of postnatal age. Low (< 1.41 kg; n = 20) and high (> 1.52 kg; n = 20) BW Large White piglets were selected from a total of 12 litters for study at 3 months of age. Basal mean arterial pressure (MAP) and heart rate (HR) were recorded for ~30 min using standard recording equipment and basal arterial blood samples were taken for hormone analyses. Concentrations of angiotensin-converting enzyme (ACE) were also measured in kidney, lung and plasma. Basal MAP, but not HR, in 3-monthold pigs was significantly inversely related to BW and positively related to the ratio of head length to BW. Postnatal growth rate of low BW pigs was slower than that of high BW pigs such that low BW piglets remained significantly smaller at 3 months of age. There were no differences in basal plasma adrenaline or cortisol concentrations between low and high BW pigs. However, basal plasma noradrenaline concentrations were significantly elevated in low BW compared to high BW pigs. Renal and pulmonary ACE levels were significantly reduced in low BW compared to high BW pigs. These data show that basal MAP in 3-month-old pigs is negatively associated with BW and positively correlated to disproportionate size at birth. This effect was associated with an increase in basal plasma noradrenaline concentrations.

Research paper thumbnail of Adrenal Responsiveness and the Timing of Parturition in Hypothalamo-Pituitary Disconnected Ovine Foetuses With and Without Constant Adrenocorticotrophin Infusion

Journal of Neuroendocrinology, 2001

Ovine parturition results from an increase in foetal cortisol secretion in late gestation which i... more Ovine parturition results from an increase in foetal cortisol secretion in late gestation which is dependant on an intact hypothalamo-pituitary connection. The cortisol surge and parturition fails in hypothalamo-pituitary disconnected (HPD) foetuses but, paradoxically, immunoreactive (ir)-ACTH concentrations and secretory dynamics appear normal. This study compares the occurrence and timing of labour, basal ir-ACTH and cortisol concentrations and adrenal responsiveness in HPD foetuses (HPD/ACTH) receiving constant ACTH infusion (43 ng/h/kg) from surgery (114±1 days gestational age (GA)) with those of saline-infused HPD or intact foetuses (HPD/SAL and INT/SAL). HPD/ACTH foetuses initiated labour at 147±2 days GA, which was not significantly different from INT/SAL foetuses (149±1 day GA). HPD/SAL foetuses were killed electively at 146±3 days GA with no signs of labour. Foetal ir-ACTH concentrations in all groups were indistinguishable, but only HPD/ACTH and INT/SAL foetuses had a significant cortisol surge. Adrenal responsiveness to ACTH

Research paper thumbnail of Do Not Turn to the Hypothalamus for Feedback on Stress If You Are Growth Restricted

Endocrinology, 2013

Submission Deadline: January 30, 2013 12:00PM (noon) ET www.endo-society.org/endo2013

Research paper thumbnail of The effect of birth weight on glucose tolerance in pigs at 3 and 12 months of age

Diabetologia, 2002

Aims/hypothesis. The aim of this study was to examine the effect of birth weight on glucose toler... more Aims/hypothesis. The aim of this study was to examine the effect of birth weight on glucose tolerance in juvenile and adult pigs. Methods. Low (<1.47 kg) and high (>1.53 kg) birth weight piglets from 15 litters were studied at 3 (n=47) and 12 (n=17) months of age. At each age, selected pigs were tranquilised and catheters were inserted into the dorsal aorta and caudal vena cava under general anaesthesia. After recovery, glucose (0.5 g/kg; i.v.) was administered and regular arterial blood samples were taken for 2 h for plasma glucose and insulin measurements. Hepatic gluconeogenic enzyme activities were measured at post mortem. Results. At 12, but not at 3 months of age, the area under the glucose and insulin curves after glucose administration were greater (p<0.05) in low rather than in high birth weight pigs. The glucose area at 12 months was negatively correlated with body weight and BMI at birth. Disproportionate shape at birth was associated with reduced hepatic gluconeogenic enzyme concentrations and low birth weight pigs had reduced basal glucose concentrations at 12 months of age. Conclusion/interpretation. This study has shown an association between low birth weight and thinness at birth and glucose intolerance at 12 months of postnatal age, but not at 3 months. This effect was not due to insulin deficiency or increased hepatic gluconeogenic enzyme activity. [Diabetologia (2002[Diabetologia ( ) 45:1247[Diabetologia ( -1254

Research paper thumbnail of Insulin sensitivity in juvenile and adult Large White pigs of low and high birthweight

Diabetologia, 2004

Aims/hypothesis. We have previously demonstrated poor glucose tolerance in adult pigs of naturall... more Aims/hypothesis. We have previously demonstrated poor glucose tolerance in adult pigs of naturally occurring low birthweight. The aim of this study was to examine sensitivity to insulin in juvenile (3-monthold) and adult (12-month-old) pigs of low and high birthweight. Methods. Low (<1.47 kg) and high (>1.53 kg) birthweight piglets from 15 litters were studied at 3 (n=47) and 12 (n=17) months of age. At each age the selected pigs were tranquilised and catheters were inserted into the dorsal aorta and caudal vena cava under general anaesthesia. After recovery, insulin sensitivity was measured as the glucose decrement (mmol·l −1 ·min −1 ) during the first 10 min after an intravenous insulin bolus (0.5 IU/kg). Data (means ± SEM) were analysed by the Student's t test, ANOVA and linear regression.

Research paper thumbnail of The role of the pituitary gland and ACTH in the regulation of mRNAs encoding proteins essential for adrenal steroidogenesis in the late-gestation ovine fetus

Journal of Endocrinology - J ENDOCRINOL, 2001

To further understand the relative roles of the pituitary gland and ACTH in the regulation of mRN... more To further understand the relative roles of the pituitary gland and ACTH in the regulation of mRNAs encoding proteins that are essential for adrenal development, we investigated the effects of, first, an ACTH infusion and labour in intact fetuses and, secondly, the effect of an ACTH infusion to fetuses with and without a pituitary gland, on the relative abundance of the mRNA encoding for the ACTH receptor (MC2R), steroidogenic factor 1 (SF-1), cholesterol side-chain cleavage enzyme (P450scc), 3-hydroxysteroid dehydrogenase (3HSD) and 17- hydroxylase (P450C17) in the fetal adrenal gland. ACTH1-24 infusion (14·7 pmol/kg per h) to intact fetuses was without effect on the abundance of mRNA encoding MC2R and SF-1, irrespective of whether the infusion was given for 18 (115-132 days of gestation) or 32 days (115 days to term (147 days of gestation)). Hypophysec- tomy (HX) did not alter the expression of MC2R mRNA; however, the abundance of SF-1 mRNA fell by approxi- mately 50% following th...

Research paper thumbnail of The role of the pituitary gland and ACTH in the regulation of mRNAs encoding proteins essential for adrenal steroidogenesis in the late-gestation ovine fetus

Journal of Endocrinology

To further understand the relative roles of the pituitary gland and ACTH in the regulation of mRN... more To further understand the relative roles of the pituitary gland and ACTH in the regulation of mRNAs encoding proteins that are essential for adrenal development, we investigated the effects of, first, an ACTH infusion and labour in intact fetuses and, secondly, the effect of an ACTH infusion to fetuses with and without a pituitary gland, on the relative abundance of the mRNA encoding for the ACTH receptor (MC2R), steroidogenic factor 1 (SF-1), cholesterol side-chain cleavage enzyme (P450(scc)), 3beta-hydroxysteroid dehydrogenase (3betaHSD) and 17alpha-hydroxylase (P450(C17)) in the fetal adrenal gland. ACTH(1-24) infusion (14.7 pmol/kg per h) to intact fetuses was without effect on the abundance of mRNA encoding MC2R and SF-1, irrespective of whether the infusion was given for 18 (115-132 days of gestation) or 32 days (115 days to term (147 days of gestation)). Hypophysectomy (HX) did not alter the expression of MC2R mRNA; however, the abundance of SF-1 mRNA fell by approximately 50...

Research paper thumbnail of Glutamate cycling may drive organic anion transport on the basal membrane of human placental syncytiotrophoblast

The Journal of physiology, Jan 17, 2015

The organic anion transporter OAT4 (SLC22A11) and organic anion transporting polypeptide OATP2B1 ... more The organic anion transporter OAT4 (SLC22A11) and organic anion transporting polypeptide OATP2B1 (SLCO2B1) are expressed in the basal membrane of the placental syncytiotrophoblast. These transporters mediate exchange whereby uptake of one organic anion is coupled to efflux of a counter-ion. In placenta, these exchangers mediate placental uptake of substrates for oestrogen synthesis as well as clearing waste products and xenobiotics from the fetal circulation. However, the identity of the counter-ion driving this transport in the placenta, and in other tissues, is unclear. While glutamate is not a known OAT4 or OATP2B1 substrate, we propose that its high intracellular concentration has the potential to drive accumulation of substrates from the fetal circulation. In the isolated perfused placenta, glutamate exchange was observed between the placenta and the fetal circulation. This exchange could not be explained by known glutamate exchangers. However, glutamate efflux was trans-stimul...

Research paper thumbnail of The role of the placenta in the developmental origins of health and disease-Implications for practice

The placenta is actively involved in transporting nutrients to the fetus, it has both direct and ... more The placenta is actively involved in transporting nutrients to the fetus, it has both direct and indirect effects on fetal cardiovascular function and has endocrine influences on the mother and fetus. As such, a properly functioning placenta is crucial for normal fetal development and plays a central role in mediating effects of the maternal environment on the fetus. An altered external environment or abnormal placental function can induce developmental changes in the fetus and may have important consequences for the risk of cardiovascular and metabolic disease in adult life.

Research paper thumbnail of 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

The Journal of physiology, Jan 15, 2010

The early-life environment affects risk of later metabolic disease, including glucose intolerance... more 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 c...

Research paper thumbnail of Raised dietary n-6 polyunsaturated fatty acid intake increases 2-series prostaglandin production during labour in the ewe

The Journal of Physiology, 2005

Preterm labour is the major cause of perinatal morbidity and mortality in humans. The incidence i... more Preterm labour is the major cause of perinatal morbidity and mortality in humans. The incidence is around 10% and the causes are often unknown. Consumption of dietary n-6 polyunsaturated fatty acids (PUFAs) in western societies is increasing. These are metabolized to arachidonic acid, the precursor for 2-series prostaglandins (PGs), major signalling molecules during labour. This study investigated the effect of dietary supplementation with linoleic acid (LA, 18 : 2, n-6) on parturition. Ewes were fed a control or LA-supplemented diet from 100 days gestation. Labour was induced using a standardized glucocorticoid challenge (dexamethasone, Dex) to the fetus, starting on day 139. Electromyographic (EMG) activity and fetal and maternal circulating PG concentrations were monitored. One third of LA-fed ewes delivered early (pre-Dex) although basal uterine EMG activity preceding Dex was higher in control ewes (P < 0. . The basal concentrations of maternal and fetal PGFM and fetal PGE 2 were approximately doubled in LA-supplemented ewes before the start of Dex infusion (P < 0.01). The rise in fetal PGE 2 and maternal oestradiol concentrations post-Dex occurred earlier in the LA-supplemented ewes. All PG measurements remained significantly higher in the LA-supplemented ewes during labour onset. This study suggests that consumption of a high LA diet in late pregnancy can enhance placental PG production and may thus increase the risk of preterm labour.

Research paper thumbnail of Early-life undernutrition induces sex-specific effects on the sympatho-adrenal response to stress in sheep

Proceedings of the Nutrition Society, 2008

ABSTRACT Early life undernutrition induces sex-specific effects on the sympathoadrenal response t... more ABSTRACT Early life undernutrition induces sex-specific effects on the sympathoadrenal response to stress in sheep. By J.P. BOULLIN, K.R. POORE, J.K. CLEAL, J.P. NEWMAN, D. NOAKES†, M.A. HANSON and L.R. GREEN, Institute of Developmental Sciences, Developmental Origins of Health and Disease Division, University of Southampton, MP 887 Southampton General Hospital, Tremona Road, Southampton SO16 5YD; †Department of Veterinary Reproduction, Royal Veterinary College, Hawkshead Lane, North Mymms, AT9 7TA. Altered adrenocortical and sympathoadrenal activity may mediate the link between the early life environment and cardiovascular and metabolic abnormalities in later life (1). We have demonstrated previously that nutrition in early postnatal life has long-term effects on adult pituitary and adrenocortical responsiveness to stress (2). The aim of this study was to determine the long-term effects of early pre- and postnatal life nutrient restriction on adult sympathoadrenal function in sheep. Ewes received either 100% (C, n = 39) or 50% nutritional requirements (U, n = 41) from 1-31 days gestation and 100% thereafter. Male and female offspring were then fed either ad libitum (CC, n = 22; UC, n = 19) or to reduce body weight to 85% of target from 12-25 weeks postnatal age (CU, n = 17; UU, n = 22) and ad libitum thereafter. At age 2.5 years, catheters were inserted into the carotid artery and jugular vein under general anaesthesia. Basal arterial blood pressure was derived from the mean of recordings taken on 3 separate days under control conditions. Sympathoadrenal responses to a stress test were assessed by transporting the sheep in their carts from their normal holding room to a different empty room followed by 30 min isolation (transport and isolation (TI) test). Plasma adrenaline and noradrenaline concentrations were measured prior to (-15 and -1 min) and during (10, 20 and 30 min) the test by radioimmunoassay (2 CAT RIA, Labor Diagnostica Nord). Heart rate responses to the TI test were measured by an implanted loop recorder (REVEAL). Data were analysed by ANOVA. There were no significant differences between sex or group in basal heart rate or blood pressure. The adrenaline output (as given by area under curve, AUC) during the TI test was significantly (P &amp;lt; 0.05) enhanced in female (Figure), but not male, sheep that were exposed to postnatal undernutrition, regardless of the prenatal nutrient environment. There was no difference between sex or group in heart rate response during the TI test. The sex-specific effects of the postnatal nutrient environment on adrenomedullary output in response to stress follow a similar pattern to our previous observations on pituitary-adrenocortical responsiveness in these animals (2). This suggests a generalised effect of postnatal undernutrition at the level of the adrenal. The absence of an accompanying increase in heart rate could reflect a down regulation in cardiac β-adrenergic pathways or altered parasympathetic tone. 1. Phillips DI, Jones A, Goulden PA. (2006) Birth weight, stress, and the metabolic syndrome in adult life. Ann N Y Acad Sci. 1083:28-36. 2. Poore KR, Cleal JK, Newman JP, Boullin J, Noakes D, Hanson MA and Green LR (2006) Hypothalamo-pituitary-adrenal axis responsiveness in adult sheep following early life nutrient restriction. 4th International Congress on DOHaD, Utrecht, The Netherlands. Early Human Devel 82(8): 537 (F-15). Supported by the British Heart Foundation and Wessex Medical Research.

Research paper thumbnail of Mismatched pre- and postnatal nutrition leads to cardiovascular dysfunction and altered renal function in adulthood

Proceedings of the National Academy of Sciences, 2007

The early life environment has long-term implications for the risk of developing cardiovascular (... more The early life environment has long-term implications for the risk of developing cardiovascular (CV) disease in adulthood. Fetal responses to changes in maternal nutrition may be of immediate benefit to the fetus, but the long-term effects of these adaptations may prove detrimental if nutrition in postnatal life does not match that predicted by the fetus on the basis of its prenatal environment. We tested this predictive adaptive response hypothesis with respect to CV function in sheep. We observed that a mismatch between pre-and postnatal nutrient environments induced an altered CV function in adult male sheep that was not seen when environments were similar. Sheep that received postnatal undernutrition alone had altered growth, CV function, and basal hypothalamo-pituitary-adrenal axis activity in adulthood. Prenatal undernutrition induced greater weight gain by weaning compared with the prenatal control diet, which may provide a reserve in the face of a predicted poor diet in later life. In an adequate postnatal nutrient environment (i.e., relatively mismatched), these offspring exhibited cardiac hypertrophy and altered CV function in adulthood. These data support the concept that adult CV function can be determined by developmental responses to intrauterine nutrition made in expectation of the postnatal nutritional environment, and that if these predictions are not met, the adult may be maladapted and at greater risk of CV disease. Our findings have substantial implications for devising strategies to reduce the impact of a mismatch in nutrition levels in humans undergoing rapid socio-economic transitions in both developing and developed societies.

Research paper thumbnail of Differential Pathways to Adult Metabolic Dysfunction following Poor Nutrition at Two Critical Developmental Periods in Sheep

PLoS ONE, 2014

Epidemiological and experimental studies suggest early nutrition has long-term effects on suscept... more Epidemiological and experimental studies suggest early nutrition has long-term effects on susceptibility to obesity, cardiovascular and metabolic diseases. Small and large animal models confirm the influence of different windows of sensitivity, from fetal to early postnatal life, on offspring phenotype. We showed previously that undernutrition in sheep either during the first month of gestation or immediately after weaning induces differential, sex-specific changes in adult metabolic and cardiovascular systems. The current study aims to determine metabolic and molecular changes that underlie differences in lipid and glucose metabolism induced by undernutrition during specific developmental periods in male and female sheep. Ewes received 100% (C) or 50% nutritional requirements (U) from 1-31 days gestation, and 100% thereafter. From weaning (12 weeks) to 25 weeks, offspring were then fed either ad libitum (CC, UC) or were undernourished (CU, UU) to reduce body weight to 85% of their individual target. From 25 weeks, all offspring were fed ad libitum. A cohort of late gestation fetuses were studied after receiving either 40% nutritional requirements (1-31 days gestation) or 50% nutritional requirements (104-127 days gestation). Post-weaning undernutrition increased in vivo insulin sensitivity, insulin receptor and glucose transporter 4 expression in muscle, and lowered hepatic methylation at the delta-like homolog 1/maternally expressed gene 3 imprinted cluster in adult females, but not males. Early gestational undernutrition induced lower hepatic expression of gluconeogenic factors in fetuses and reduced in vivo adipose tissue insulin sensitivity in adulthood. In males, undernutrition in early gestation increased adipose tissue lipid handling mechanisms (lipoprotein lipase, glucocorticoid receptor expression) and hepatic methylation within the imprinted control region of insulin-like growth factor 2 receptor in adulthood. Therefore, undernutrition during development induces changes in mechanisms of lipid and glucose metabolism which differ between tissues and sexes dependent on the period of nutritional restriction. Such changes may increase later life obesity and dyslipidaemia risk.

Research paper thumbnail of The Effect of Maternal Undernutrition in Early Gestation on Gestation Length and Fetal and Postnatal Growth in Sheep

Pediatric Research, 2007

In utero undernutrition in humans may result in cardiovascular (CV), metabolic, and growth adapta... more In utero undernutrition in humans may result in cardiovascular (CV), metabolic, and growth adaptations. In sheep, maternal nutrient restriction during pregnancy, without effects on fetal or birth weight, results in altered CV control in the offspring. Adjustment of gestation length after undernutrition could be a strategy to enhance postnatal health/survival. The aim of this study was to determine in sheep the effect of a 50% reduction in maternal nutrient intake [undernutrition group (U) versus 100%, control group (C)] during 1-31 d of gestation (dGA) on gestation length and offspring size. By 28 dGA, U ewes had gained less weight than C, and twin-bearing ewes had gained less weight than singleton-bearing ewes regardless of group (p Ͻ 0.05). In different-sex twin pairs, maternal undernutrition resulted in longer gestation compared with C (146.5 Ϯ 0.6 versus 144.6 Ϯ 0.6 d, p Ͻ 0.05). Increased weight gain by weaning (20.8 Ϯ 0.8 versus 17.9 Ϯ 0.8 kg, p Ͻ 0.05) was observed in U male twins. These findings suggest that the strategy (i.e. growth rate or length of time in utero) adopted by the fetus to enhance immediate survival depends on offspring number and sex. This is likely to reflect the degree of constraint imposed on the fetus.