Kirsten R. Poore

Mismatched pre- and postnatal nutrition leads to cardiovascular dysfunction and altered renal function in adulthood

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.

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

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 weight pigs, plasma leptin concentrations were reduced in low birth weight females at 3 months and in low birth weight males at 12 months of age. This study demonstrates sex‐specific effects of low birth weight on postnatal growth and body fatness and on plasma leptin concentrations in pigs.

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

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‐month‐old 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.

The effect of birth weight on hypothalamo‐pituitary‐adrenal axis function in juvenile and adult pigs

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 µg (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.

The effect of maternal undernutrition in early gestation on gestation length and fetal and postnatal growth in sheep

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 < 0.05). In different-sex twin pairs, maternal undernutrition resulted in longer gestation compared with C (146.5 ± 0.6 versus 144.6 ± 0.6 d, p < 0.05). Increased weight gain by weaning (20.8 ± 0.8 versus 17.9 ± 0.8 kg, p < 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.

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 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.

Effects of pre- and periconceptional undernutrition on arterial function in adult female sheep are vascular bed dependent

The nutritional environment during development and even prior to conception may contribute to cardiovascular risk. In mature adult female sheep, we investigated the effect of preconceptional and periconceptional maternal nutritional restriction on the vascular reactivity of arteries from four vascular beds supplying the heart, thorax, kidney and hindlimb. Welsh Mountain ewes received 100% of nutrient requirements throughout gestation (control group, C, n= 18), or 50% of nutrient requirements for 30 days prior to conception (preconceptional group, PRE, n= 20) or for 15 days either side of conception (periconceptional group, PERI, n= 31) and 100% thereafter. In 3.5‐year‐old female offspring, the left anterior descending coronary (LAD), left internal thoracic (LITA), right renal and second and third order femoral arteries were dissected and their reactivity was assessed by organ bath or wire myography. Vasoconstrictor responses were greater in both LAD and LITA from PERI offspring compared with C (P < 0.01), while vasoconstriction was unaffected by maternal diet in arteries from the renal and femoral circulations (P= n.s.). Endothelium‐dependent and ‐independent vasodilatation was attenuated in third order femoral arteries of PRE and PERI groups compared with C (P < 0.05). Endothelium‐independent vasodilatation was attenuated in both the LAD and renal arteries in the PERI group compared with C (P < 0.05). These data show that moderate maternal undernutrition either prior to or around conception affects vascular function of adult offspring. The effect depends on the timing of the insult, but also on the vascular bed studied and vessel hierarchy in the vascular tree.

Developmental origins of the metabolic syndrome: body clocks and stress responses

The prevalence of the metabolic syndrome, which represents a spectrum of metabolic and cardiovascular disorders, continues to increase at an alarming rate in contemporary society. Inadequate responses of an individual to environmental challenges such as unbalanced diet or lack of physical exercise during their life course has been recognised to increase risk of this pathological condition. Recent evidence suggests that this may involve alterations in the settings of the circadian clock system, which consists of oscillating molecular pacemakers found not only in the hypothalamic region of the brain but also in most peripheral tissues, and of the hypothalamic-pituitary-adrenal (HPA) axis which regulates stress responses. These two systems are now known to interact to produce an integrated response to environmental challenges. In this review, we highlight the importance of environmental cues during early development in establishing the homeostatic set-points of the circadian clock and HPA stress systems. These effects can operate within the normal range and are not in themselves pathological, but can nevertheless affect an individuals response to environmental challenges in adult life and thus their risk of the metabolic syndrome.

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

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 (T3), 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 T3 infusion (8–12 μg (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.

Raised dietary n‐6 polyunsaturated fatty acid intake increases 2‐series prostaglandin production during labour in the ewe

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 < 0.05). A steep increase in EMG activity occurred 18–38 h after the start of Dex infusion. Twice basal EMG activity (defined as established labour) occurred on average 7 h earlier in the LA‐supplemented ewes (P < 0.05). The basal concentrations of maternal and fetal PGFM and fetal PGE2 were approximately doubled in LA‐supplemented ewes before the start of Dex infusion (P < 0.01). The rise in fetal PGE2 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.