Melanie A. Hyatt

Nutritional programming of the metabolic syndrome

The primary markers of the metabolic syndrome are central obesity, insulin resistance and hypertension. In this review, we consider the effect of changes in maternal nutrition during critical windows in fetal development on an individuals subsequent predisposition to the metabolic syndrome. The fetal origins of obesity, cardiovascular disease and insulin resistance have been investigated in a wide range of epidemiological and animal studies; these investigations highlight adaptations made by the nutritionally manipulated fetus that aim to maintain energy homeostasis to ensure survival. One consequence of such developmental plasticity may be a long term re-setting of cellular energy homeostasis, most probably via epigenetic modification of genes involved in a number of key regulatory pathways. For example, reduced maternal–fetal nutrition during early gestation to midgestation affects adipose tissue development and adiposity of the fetus by setting an increased number of adipocyte precursor cells. Importantly, clinically relevant adaptations to nutritional challenges in utero may only manifest as primary components of the metabolic syndrome if followed by a period of accelerated growth early in the postnatal period and/or if offspring become obese.

Gestational Age, Birth Weight, and Risk of Respiratory Hospital Admission in Childhood

OBJECTIVE: To investigate the risk of emergency respiratory hospital admission during childhood associated with gestational age at birth and growth restriction in utero. METHODS: The study included a total population electronic birth cohort with anonymized record-linkage of multiple health and administrative data sets. Participants were 318 613 children born in Wales, United Kingdom, between May 1, 1998, and December 31, 2008. The main outcome measure was emergency respiratory hospital admissions. RESULTS: The rate of admission in the first year of life ranged from 41.5 per 100 child-years for infants born before 33 weeks’ gestation to 9.8 per 100 child-years for infants born at 40 to 42 weeks’ gestation. The risk of any emergency respiratory admission up to age 5 years increased as gestational age decreased to <40 weeks. Even at 39 weeks’ gestation, there was an increased risk of emergency hospital admissions for respiratory conditions compared with infants born at 40 to 42 weeks (adjusted hazard ratio 1.10; 95% confidence interval 1.08–1.13). Small for gestational age (<10th centile for gestation and gender-specific birth weight) was independently associated with an increased risk of any emergency respiratory admission to hospital (adjusted hazard ratio 1.07; 95% confidence interval 1.04–1.10). CONCLUSIONS: The risk of emergency respiratory admission up to age 5 years decreased with each successive week in gestation up to 40 to 42 weeks. Although the magnitude of increased risk associated with moderate and late preterm births is small, the number of infants affected is large and therefore presents a significant impact on health care services.

Suboptimal maternal nutrition, during early fetal liver development, promotes lipid accumulation in the liver of obese offspring.

Maternal nutrition during the period of early organ development can modulate the offsprings ability to metabolise excess fat as young adults when exposed to an obesogenic environment. This study examined the hypothesis that exposing offspring to nutrient restriction coincident with early hepatogenesis would result in endocrine and metabolic adaptations that subsequently lead to increased ectopic lipid accumulation within the liver. Pregnant sheep were fed either 50 or 100% of total metabolisable energy requirements from 30 to 80 days gestation and 100% thereafter. At weaning, offspring were made obese, and at ∼1 year of age livers were sampled. Lipid infiltration and molecular indices of gluconeogenesis, lipid metabolism and mitochondrial function were measured. Although hepatic triglyceride accumulation was not affected by obesity per se, it was nearly doubled in obese offspring born to nutrient-restricted mothers. This adaptation was accompanied by elevated gene expression for peroxisome proliferator-activated receptor γ (PPARG) and its co-activator PGC1α, which may be indicative of changes in the rate of hepatic fatty acid oxidation. In contrast, maternal diet had no influence on the stimulatory effect of obesity on gene expression for a range of proteins involved in glucose metabolism and energy balance including glucokinase, glucocorticoid receptors and uncoupling protein 2. Similarly, although gene expressions for the insulin and IGF1 receptors were suppressed by obesity they were not influenced by the prenatal nutritional environment. In conclusion, excess hepatic lipid accumulation with juvenile obesity is promoted by suboptimal nutrition coincident with early development of the fetal liver.

Early developmental influences on hepatic organogenesis

The liver is the largest of the bodys organs, with the greatest number of functions, playing a central role in coordinating metabolic homeostasis, nutrient processing and detoxification. The fetal liver forms during early gestation in response to a sequential array of distinct biological events, regulated by intrinsically programmed mechanisms and extracellular signals which instruct hepatic cells to either proliferate, differentiate or undergo apoptosis. A vast number of genes are involved in the initiation and control of liver development, many of which are sensitive to nutritional and hormonal regulation in utero. Moreover, liver mass is influenced by the gestational environment. Therefore, during periods of hepatic cell proliferation and differentiation, the developing fetal liver is sensitive to damage from both internal and external sources including teratogens, infection and nutritional deficiencies. For example, fetuses exposed to decreased materno-fetal nutrition during late gestation have a reduced liver mass, and/or perturbed liver function, which includes increased plasma LDL cholesterol and fibrinogen concentrations. These occur in conjunction with other risk factors present in the early stages of cardiovascular disease i.e. decreased glucose tolerance and insulin insensitivity in later life. Taken together, these findings suggest that liver mass, and later function, are essentially set in utero during fetal development - a process that is ultimately regulated by the intrauterine environment.

Nutritional manipulation between early to mid-gestation: effects on uncoupling protein-2, glucocorticoid sensitivity, IGF-I receptor and cell proliferation but not apoptosis in the ovine placenta.

In sheep, modest maternal nutrient restriction (NR) over the period of rapid placental growth restricts placentome growth and results in offspring in which glucocorticoid action is enhanced. Therefore, this study investigated the placental effects of early to mid-gestational NR on glucocorticoid receptor (GR), 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2), uncoupling protein-2 (UCP2), and IGF type-I receptor (IGF-IR) mRNA abundance together with cell proliferation and apoptosis as determined histologically, and the mitochondrial proteins voltage-dependent anion channel and cytochrome c that are involved in apoptosis. Placenta was sampled at 80 and 140 days gestation (dGA; term ~147 dGA). NR was imposed between 28 and 80 days gestation when control and nutrient-restricted groups consumed 150 or 60% respectively of their total metabolizable energy requirements. All mothers were then fed to requirements up to term. Total fetal placentome weights were decreased by NR at 80 dGA but were heavier at 140 dGA following 60 days of nutritional rehabilitation. GR and UCP2 mRNA abundance increased whilst 11betaHSD2 mRNA decreased with gestational age. NR persistently up-regulated GR and UCP2 mRNA abundance. 11betaHSD2 mRNA was reduced by NR at 80 dGA but increased near to term. IGF-IRmRNA abundance was only decreased at 80 dGA. Placental apoptosis and mitochondrial protein abundance were unaffected by NR, whereas cell proliferation was markedly reduced. In conclusion, placental UCP2 and local glucocorticoid action are affected by the gestational nutritional status and may result in the offspring showing enhanced glucocorticoid sensitivity, thereby predisposing them to disease in later life.

Ontogeny and nutritional manipulation of the hepatic prolactin–growth hormone–insulin-like growth factor axis in the ovine fetus and in neonate and juvenile sheep

The somatotrophic axis is the main endocrine system regulating postnatal growth; however, prenatal growth is independent of growth hormone (GH). Fetal development relies on the coordinated actions of a range of hormones, including insulin-like growth factors (IGF), and prolactin (PRL), in the control of differentiation, growth and maturation. In the sheep the abundance peaks for liver IGF-II and PRL receptors occur during late gestation while that for IGF-I receptor occurs at birth. All receptors, with the exception of GH receptor subsequently decrease by age 6 months. It has been proposed that maternal undernutrition during gestation regulates the maturation of the fetal hypothalmic-pituitary-adrenal axis and endocrine sensitivity. Critically, the timing of the nutritional insult may affect the magnitude of reprogramming. Maternal malnutrition during early to mid-gestation (3.2-3.8 MJ/d (60% total metabolisable energy requirements) v. 8.7-9.9 MJ/d (150% total metabolisable energy requirements) between 28 and 80 d of gestation) had no effect on body or liver weight. Nutrient-restricted (NR) fetuses sampled at 80 d (mid-gestation) showed up-regulation of hepatic PRL receptor, but following refeeding the normal gestational rise in PRL and GH receptors did not occur. Hepatic IGF-II receptor was down regulated in NR fetuses at both mid- and late gestation. Conversely, 6-month-old offspring showed no difference in the abundance of either GH receptor or PRL receptor, while IGF-II mRNA was increased. Offspring of ewes malnourished during late gestation (9.1 MJ/d (60% total metabolisable energy requirements) v. 12.7 MJ/d (100% total metabolisable energy requirements) from 110 d of gestation to term) showed reduced abundance of hepatic GH and PRL receptor mRNA. In conclusion, maternal undernutrition during the various stages of gestation reprogrammed the PRL-GH-IGF axis. Nutritional regulation of cytokine receptors may contribute to altered liver function following the onset of GH-dependent growth, which may be important in regulating endocrine adaptations during subsequent periods of nutritional deprivation.

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

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

Do Children Who Move Home and School Frequently Have Poorer Educational Outcomes in Their Early Years at School? An Anonymised Cohort Study

Frequent mobility has been linked to poorer educational attainment. We investigated the association between moving home and moving school frequently and the early childhood formal educational achievement. We carried out a cohort analysis of 121,422 children with anonymised linked records. Our exposure measures were: 1) the number of residential moves registered with a health care provider, and 2) number of school moves. Our outcome was the formal educational assessment at age 6–7. Binary regression modeling was used to examine residential moves within the three time periods: 0 – <1 year; 1 – <4 years and 4 – <6 years. School moves were examined from age 4 to age 6. We adjusted for demographics, residential moves at different times, school moves and birth related variables. Children who moved home frequently were more likely not to achieve in formal assessments compared with children not moving. Adjusted odds ratios were significant for 3 or more moves within the time period 1 –<4 years and for any number of residential moves within the time period 4–<6 years. There was a dose response relationship, with increased odds ratios with increased frequency of residential moves (2 or more moves at 4–<6 years, adjusted odds ratio 1.16 (1.03, 1.29). The most marked effect was seen with frequent school moves where 2 or more moves resulted in an adjusted odds ratio of 2.33 (1.82, 2.98). This is the first study to examine the relationship between residential and school moves in early childhood and the effect on educational attainment. Children experiencing frequent mobility may be disadvantaged and should be closely monitored. Additional educational support services should be afforded to children, particularly those who frequently change school, in order to help them achieve the expected educational standards.

Effects of maternal cold exposure and nutrient restriction on the ghrelin receptor, the GH-IGF axis, and metabolic regulation in the postnatal ovine liver

Maternal cold exposure of pregnant sheep promotes fetal growth, whereas nutrient restriction (NR) can reverse this effect. The present study was designed to establish whether cold exposure induced by winter shearing of the mother at 70 days gestation (term=147 days), with or without NR (induced by a 50% reduction in maternal food intake from 110 days gestation), has specific effects on mRNA abundance of hepatic genes related to growth and liver energy metabolism that could regulate postnatal body and liver growth. Measurements of hepatic gene expression for the GH secretagog receptor-1a (GHSR-1A), peroxisome proliferator-activated receptor (PPAR)alpha, phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase activity together with glycogen content were made in the livers of offspring at 1 and 30 days of age. Maternal NR reduced liver mass at day 1, whereas offspring of cold-exposed mothers had larger livers at day 30 irrespective of maternal diet. Cold exposure resulted in the up-regulation of GHSR-1A mRNA abundance and reduced glucose-6-phosphatase activity at 1, but not 30 days of age, whereas IGF-II mRNA was decreased at 1 and 30 days. PPARalpha mRNA abundance was enhanced, while PEPCK was reduced in 30-day old offspring of cold-exposed mothers. NR caused reductions in IGF-I mRNA and, at 1-day postnatal age, down-regulated GHR, while, at 30 days, reduced GHSR-1A gene expression and hepatic glycogen content. In conclusion, we have shown that maternal cold exposure and NR have different effects on the hepatic GH-IGF and metabolic axis that may contribute to changes in liver growth over the first month of life.

Maternal dexamethasone administration and the maturation of perirenal adipose tissue of the neonatal sheep

Maternal dexamethasone administration promotes fetal maturation such that thermoregulation is improved following premature delivery and is thus comparable with a full term birth. In the present study we determined the impact of dexamethasone on both the mothers’ metabolic status together with adipose tissue function in the newborn. Glucocorticoid action, adipokine gene expression and mitochondrial protein abundance were measured in perirenal adipose tissue of neonatal sheep that were born into either a warm (30oC) or cool (15oC) ambient temperature at 140 days of gestation (dGA; term ~147 dGA), either two days after maternal dexamethasone administration, or at 146 dGA for controls. Dexamethasone administration resulted in a reduction in maternal food intake in conjunction with raised plasma cortisol and free triiodothyronine. In offspring of dexamethasone administered mothers, plasma cortisol was lower and non-esterified fatty acids (NEFA) higher than controls. Glucocorticoid receptor (GR), 11β-hydroxysteroid dehydrogenase (11β-HSD1), interleukin-6 and uncoupling protein (UCP)1 and 2 mRNA together with voltage dependent anion channel, cytochrome c protein and UCP1 abundance were all increased by dexamethasone administration and being born into a cool ambient temperature. Gene expression of tumor necrosis factor α, adiponectin and peroxisome proliferator-activated receptor transcription factor γ were unaffected by dexamethasone. The abundance of mRNA for the GR, 11β-HSD1, UCP1 and 2 mRNA together with each protein were positively correlated to plasma NEFA and negatively correlated to plasma cortisol. In conclusion, despite reduced maternal food intake dexamethasone promotes maturation of glucocorticoid action and mitochondrial protein abundance in the newborn, an adaptation dependent on delivery temperature.