Differential pathways to adult metabolic dysfunction following poor nutrition at two critical developmental periods in sheep

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

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

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-stimulated by an OAT4 and OATP2B1 substrate (bromosulphothalein). Exchange of glutamate for bromosulphothalein was only observed when glutamate reuptake was inhibited (by addition of aspartate). To determine if OAT4 and/or OATP2B1 mediate glutamate exchange, uptake and efflux of glutamate were investigated in Xenopus laevis oocytes. Our data demonstrate that in Xenopus oocytes expressing either OAT4 or OATP2B1 efflux of intracellular [14C]glutamate could be stimulated by conditions including extracellular glutamate (OAT4), estrone-sulphate and bromosulphothalein (both OAT4 and OATP2B1) or pravastatin (OATP2B1). Cycling of glutamate across the placenta involving efflux via OAT4 and OATP2B1 and subsequent reuptake will drive placental uptake of organic anions from the fetal circulation.<br/

Virtual Avebury: Exploring sense of place in a virtual archaeology simulation

This paper describes and discusses creating and evaluating a virtual reality simulation of Avebury Stone Circle and Henge complex as it might have appeared and sounded circa 2300 BCE. Avebury is a Neolithic heritage site in the UK which is part of the Stonehenge, Avebury and Associated Sites UNESCO World Heritage Site. The overall aim of the project was to better understand the sense of place and presence that visitors can experience in virtual simulations of heritage sites. We investigated how virtual spaces might become experienced as places by visitors through their exploration, active participation, sensory stimulation and communication with other visitors in the simulation. More than 1200 members of the public experienced the simulation, both at Avebury itself and at three public exhibitions. The specific objectives of the project were to explore if and how the believability of a simulation was associated with feeling a sense of place in the virtual landscape, and if some personal characteristics, viz. age, disability, sex, immersive tendency, familiarity with IT and frequency of playing computer games, were associated with levels of enjoyment in, and learning from, the simulation. We analysed the data from a detailed questionnaire completed by 388 of the 702 visitors to Avebury from June to September 2018 who experienced the simulation, supported by observational data from all participants at all events. We found that believability was associated with a sense of place in the simulation, i.e. that the more believable the simulation appeared, the greater the sense of place experienced by the participants. We also found that personal characteristics had very little influence upon visitor reactions to the simulation, suggesting that such simulations might have wide appeal for heritage and museum visitors, regardless of age, gender or familiarity with technology

Reduced fetal vitamin D status by maternal undernutrition during discrete gestational windows in sheep

Placental transport of vitamin D and other nutrients (e.g. amino acids, fats and glucose) to the fetus is sensitive to maternal and fetal nutritional cues. We studied the effect of maternal calorific restriction on fetal vitamin D status and the placental expression of genes for nutrient transport (aromatic T-type amino acid transporter-1 [TAT-1]; triglyceride hydrolase / lipoprotein uptake facilitator lipoprotein lipase [LPL]) and vitamin D homeostasis (CYP27B1; vitamin D receptor [VDR]), and their association with markers of fetal cardiovascular function and skeletal muscle growth. Pregnant sheep received 100% total metabolizable energy (ME) requirements (control), 40% total ME requirements peri-implantation (PI40, 1–31 days of gestation [dGA]) or 50% total ME requirements in late gestation (L, 104–127 dGA). Fetal, but not maternal, plasma 25-hydroxy-vitamin D (25OHD) concentration was lower in PI40 and L maternal undernutrition groups (p<0.01) compared with the control group at 0.86 gestation. PI40 group placental CYP27B1 mRNA levels were increased (p<0.05) compared with the control group. Across all groups, higher fetal plasma 25OHD concentration was associated with higher skeletal muscle myofibre and capillary density (p<0.05). In the placenta, higher VDR mRNA levels were associated with higher TAT-1 (p<0.05) and LPL (p<0.01) mRNA levels. In the PI40 maternal undernutrition group only, reduced fetal plasma 25OHD concentration may be mediated in part by altered placental CYP27B1. The association between placental mRNA levels of VDR and nutrient transport genes suggests a way in which the placenta may integrate nutritional cues in the face of maternal dietary challenges and alter fetal physiology

Effort-reward imbalance at work and risk of type 2 diabetes in a national sample of 50,552 workers in Denmark : A prospective study linking survey and register data

Objective: To examine the prospective relation between effort-reward imbalance at work and risk of type 2 diabetes. Methods: We included 50,552 individuals from a national survey of the working population in Denmark, aged 30-64 years and diabetes-free at baseline. Effort-reward imbalance was defined, in accordance with the literature, as a mismatch between high efforts at work (e.g. high work pace, time pressure), and low rewards received in return (e.g. low recognition, job insecurity) and assessed as a continuous and a categorical variable. Incident type 2 diabetes was identified in national health registers. Using Cox regression we calculated hazard ratios (HR) and 95% confidence intervals (95% CI) for estimating the association between effort-reward imbalance at baseline and risk of onset of type 2 diabetes during follow-up, adjusted for sex, age, socioeconomic status, cohabitation, children at home, migration background, survey year and sample method. Results: During 136,239 person-years of follow-up (mean = 2.7 years) we identified 347 type 2 diabetes cases (25.5 cases per 10,000 person-years). For each one standard deviation increase of the effort-reward imbalance score at baseline, the fully adjusted risk of type 2 diabetes during follow-up increased by 9% (HR: 1.09, 95% CI: 0.98-1.21). When we used effort-reward imbalance as a dichotomous variable, exposure to effort-reward imbalance was associated with an increased risk of type 2 diabetes with a HR of 1.27 (95% CI: 1.02-1.58). Conclusion The results of this nationwide study of the Danish workforce suggest that effort-reward imbalance at work may be a risk factor for type 2 diabetes.Peer reviewe

The age of Stonehenge

Stonehenge is the icon of British prehistory, and continues to inspire ingenious investigations and interpretations. A current campaign of research, being waged by probably the strongest archaeological team ever assembled, is focused not just on the monument, but on its landscape, its hinterland and the monuments within it. The campaign is still in progress, but the story so far is well worth reporting. Revisiting records of 100 years ago the authors demonstrate that the ambiguous dating of the trilithons, the grand centrepiece of Stonehenge, was based on samples taken from the wrong context, and can now be settled at 2600-2400 cal BC. This means that the trilithons are contemporary with Durrington Walls, near neighbour and Britain's largest henge monument. These two monuments, different but complementary, now predate the earliest Beaker burials in Britain – including the famous Amesbury Archer and Boscombe Bowmen, but may already have been receiving Beaker pottery. All this contributes to a new vision of massive monumental development in a period of high European intellectual mobility…

Placental uptake and metabolism of 25(OH)vitamin D determine its activity within the fetoplacental unit

Pregnancy 25-hydroxyvitamin D [25(OH)D] concentrations are associated with maternal and fetal health outcomes. Using physiological human placental perfusion and villous explants, we investigate the role of the placenta in regulating the relationships between maternal 25(OH)D and fetal physiology. We demonstrate active placental uptake of 25(OH)D3 by endocytosis, placental metabolism of 25(OH)D3 into 24,25-dihydroxyvitamin D3 and active 1,25-dihydroxyvitamin D [1,25(OH)2D3], with subsequent release of these metabolites into both the maternal and fetal circulations. Active placental transport of 25(OH)D3 and synthesis of 1,25(OH)2D3 demonstrate that fetal supply is dependent on placental function rather than simply the availability of maternal 25(OH)D3. We demonstrate that 25(OH)D3 exposure induces rapid effects on the placental transcriptome and proteome. These map to multiple pathways central to placental function and thereby fetal development, independent of vitamin D transfer. Our data suggest that the underlying epigenetic landscape helps dictate the transcriptional response to vitamin D treatment. This is the first quantitative study demonstrating vitamin D transfer and metabolism by the human placenta, with widespread effects on the placenta itself. These data demonstrate a complex interplay between vitamin D and the placenta and will inform future interventions using vitamin D to support fetal development and maternal adaptations to pregnancy.</jats:p

Trajectory of vitamin D status during pregnancy in relation to neonatal birth size and fetal survival: a prospective cohort study

Background: We investigated the associations between vitamin D status in early and late pregnancy with neonatal small for gestational age (SGA), low birth weight (LBW) and preterm delivery. Furthermore, associations between vitamin D status and pregnancy loss were studied. Methods: Serum 25-hydroxyvitamin D (25OHD) was sampled in gestational week ≤ 16 (trimester 1 (T1), N = 2046) and > 31 (trimester 3 (T3), N = 1816) and analysed using liquid chromatography tandem mass spectrometry. Pregnant women were recruited at antenatal clinics in south-west Sweden at latitude 57–58°N. Gestational and neonatal data were retrieved from medical records. Multiple gestations and terminated pregnancies were excluded from the analyses. SGA was defined as weight and/or length at birth < 2 SD of the population mean and LBW as < 2500 g. Preterm delivery was defined as delivery < 37 + 0 gestational weeks and pregnancy loss as spontaneous abortion or intrauterine fetal death. Associations between neonatal outcomes and 25OHD at T1, T3 and change in 25OHD (T3-T1) were studied using logistic regression. Results: T1 25OHD was negatively associated with pregnancy loss and 1 nmol/L increase in 25OHD was associated with 1% lower odds of pregnancy loss (OR 0.99, p = 0.046). T3 25OHD ≥ 100 nmol/L (equal to 40 ng/ml) was associated with lower odds of SGA (OR 0.3, p = 0.031) and LBW (OR 0.2, p = 0.046), compared to vitamin D deficiency (25OHD < 30 nmol/L, or 12 ng/ml). Women with a ≥ 30 nmol/L increment in 25OHD from T1 to T3 had the lowest odds of SGA, LBW and preterm delivery. Conclusions: Vitamin D deficiency in late pregnancy was associated with higher odds of SGA and LBW. Lower 25OHD in early pregnancy was only associated with pregnancy loss. Vitamin D status trajectory from early to late pregnancy was inversely associated with SGA, LBW and preterm delivery with the lowest odds among women with the highest increment in 25OHD. Thus, both higher vitamin D status in late pregnancy and gestational vitamin D status trajectory can be suspected to play a role in healthy pregnancy