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Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about the translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; furthermore, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine.

Mir483is a conserved and highly expressed microRNA in placental mammals, embedded within the Igf2gene. Its expression is dysregulated in a number of human diseases, including metabolic disorders and certain cancers. Here, we investigate the developmental regulation and function of Mir483 in vivo. We find that Mir483expression is dependent on Igf2transcription and the regulation of the Igf2/H19imprinting control region. Transgenic Mir483overexpression in uterocauses fetal, but not placental, growth restriction through insulin-like growth factor 1 (IGF1) and IGF2 and also causes cardiovascular defects leading to fetal death. Overexpression of Mir483post-natally results in growth stunting through IGF1 repression, increased hepatic lipid production, and excessive adiposity. IGF1 infusion rescues the post-natal growth restriction. Our findings provide insights into the function of Mir483as a growth suppressor and metabolic regulator and suggest that it evolved within the INS-IGF2-H19transcriptional region to limit excessive tissue growth through repression of IGF signaling.

Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.

The agouti viable yellow (Avy) allele is an insertional mutation in the mouse genome caused by a variably methylated intracisternal A particle (VM-IAP) retrotransposon. Avyexpressivity is sensitive to a range of early-life chemical exposures and nutritional interventions, suggesting that environmental perturbations can have long-lasting effects on the methylome. However, the extent to which VM-IAP elements are environmentally labile with phenotypic implications is unknown. Using a recently identified repertoire of VM-IAPs, we assessed the epigenetic effects of different environmental contexts. A longitudinal aging analysis indicated that VM-IAPs are stable across the murine lifespan, with only small increases in DNA methylation detected for a subset of loci. No significant effects were observed after maternal exposure to the endocrine disruptor bisphenol A, an obesogenic diet or methyl donor supplementation. A genetic mouse model of abnormal folate metabolism exhibited shifted VM-IAP methylation levels and altered VM-IAP-associated gene expression, yet these effects are likely largely driven by differential targeting by polymorphic KRAB zinc finger proteins. We conclude that epigenetic variability at retrotransposons is not predictive of environmental susceptibility.

Background/Objectives: Successful pregnancy requires the de novo creation of low-resistance utero-placental and feto-placental circulations and incomplete remodeling of this vasculature can lead to maternal or fetal compromise. Maternal BMI and fetal sex are known to influence vascular compliance and placental development, but it is unknown if these are independent or synergistic effects. Here we aim to investigate the impact of maternal obesity, fetal sex, and any interaction thereof on maternal cardiovascular adaptation to pregnancy, by assessing the physiological drop of uterine artery doppler pulsatility (UtA-PI) and umbilical artery doppler pulsatility index (UA-PI) over gestation. Subjects/Methods: Nulliparous women with a singleton pregnancy participating in a prospective cohort study (n= 4212) underwent serial UtA-PI and UA-PI measurements at 20-, 28- and 36-weeks gestation. Linear mixed regression models were employed to investigate the influence of maternal BMI, fetal sex and interactions thereof on the magnitude of change in UtA-PI and UA-PI. Results: Throughout gestation, UtA-PI was higher for male fetuses and UA-PI was higher for female fetuses. The physiological drop of UtA-PI was significantly smaller in overweight (change −24.3% [95%CI −22.3, −26.2]) and obese women (change −21.3% [−18.3, −24.3]), compared to normal-weight women (change −25.7% [−24.3, −27.0]) but did not differ by fetal sex. The physiological drop in UA-PI was greater for female than male fetuses (–32.5% [−31.5, −33.5] vs. −30.7% [−29.8, −31.7]) but did not differ by maternal BMI. No interactions between maternal BMI and fetal sex were found. Conclusions: Maternal cardiovascular adaptation to pregnancy is independently associated with maternal BMI and fetal sex. Our results imply sexual dimorphism in both maternal cardiovascular adaptation and feto-placental resistance.

Background: Though it is well established that neonatal nutrition plays a major role in lifelong offspring health, the mechanisms underpinning this have not been well defined. Early postnatal accelerated growth resulting from maternal nutritional status is associated with increased appetite and body weight. Likewise, slow growth correlates with decreased appetite and body weight. Food consumption and food-seeking behaviour are directly modulated by central serotonergic (5-hydroxytryptamine, 5-HT) pathways. This study examined the effect of a rat maternal postnatal low protein (PLP) diet on 5-HT receptor mediated food intake in offspring. Methods: Microarray analyses, in situ hybridization or laser capture microdissection of the ARC followed by RT-PCR were used to identify genes up- or down-regulated in the arcuate nucleus of the hypothalamus (ARC) of 3-month-old male PLP rats. Third ventricle cannulation was used to identify altered sensitivity to serotonin receptor agonists and antagonists with respect to food intake. Results: Male PLP offspring consumed less food and had lower growth rates up to 3 months of age compared with Control offspring from dams fed a normal diet. In total, 97 genes were upregulated including the 5-HT5Areceptor (5-HT5AR) and 149 downregulated genes in PLP rats compared with Controls. The former obesity medication fenfluramine and the 5-HT receptor agonist 5-Carboxamidotryptamine (5-CT) significantly suppressed food intake in both groups, but the PLP offspring were more sensitive to d-fenfluramine and 5-CT compared with Controls. The effect of 5-CT was antagonized by the 5-HT5AR antagonist SB699551. 5-CT also reduced NPY-induced hyperphagia in both Control and PLP rats but was more effective in PLP offspring. Conclusions: Postnatal low protein programming of growth in rats enhances the central effects of serotonin on appetite by increasing hypothalamic 5-HT5AR expression and sensitivity. These findings provide insight into the possible mechanisms through which a maternal low protein diet during lactation programs reduced growth and appetite in offspring.

Background: In utero exposure to obesity is consistently associated with increased risk of metabolic disease, obesity and cardiovascular dysfunction in later life despite the divergence of birth weight outcomes. The placenta plays a critical role in offspring development and long-term health, as it mediates the crosstalk between the maternal and fetal environments. However, its phenotypic and molecular modifications in the context of maternal obesity associated with fetal growth restriction (FGR) remain poorly understood. Methods: Using a mouse model of maternal diet-induced obesity, we investigated changes in the placental transcriptome through RNA sequencing (RNA-seq) and Ingenuity Pathway Analysis (IPA) at embryonic day (E) 19. The most differentially expressed genes (FDR < 0.05) were validated by Quantitative real-time PCR (qPCR) in male and female placentae at E19. The expression of these targets and related genes was also determined by qPCR at E13 to examine whether the observed alterations had an earlier onset at mid-gestation. Structural analyses were performed using immunofluorescent staining against Ki67 and CD31 to investigate phenotypic outcomes at both timepoints. Results: RNA-seq and IPA analyses revealed differential expression of transcripts and pathway interactions related to placental vascular development and tissue morphology in obese placentae at term, including downregulation of Muc15, Cnn1, and Acta2. Pdgfb, which is implicated in labyrinthine layer development, was downregulated in obese placentae at E13. This was consistent with the morphological evidence of reduced labyrinth zone (LZ) size, as well as lower fetal weight at both timepoints irrespective of offspring sex. Conclusions: Maternal obesity results in abnormal placental LZ development and impaired vascularization, which may mediate the observed FGR through reduced transfer of nutrients across the placenta.

Obesity during pregnancy has a long-term effect on the health of the offspring including risk of developing the metabolic syndrome. Using a mouse model of maternal diet-induced obesity, we employed a genome-wide approach to investigate the microRNA (miRNA) and miRNA transcription profile in adipose tissue to understand mechanisms through which this occurs. Male offspring of diet-induced obese mothers, fed a control diet from weaning, showed no differences in body weight or adiposity at 8 weeks of age. However, offspring from the obese dams had up-regulated cytokine (Tnfα; P< .05) and chemokine (Ccl2and Ccl7; P< .05) signaling in their adipose tissue. This was accompanied by reduced expression of miR-706, which we showed can directly regulate translation of the inflammatory proteins IL-33 (41% up-regulated; P< .05) and calcium/calmodulin-dependent protein kinase 1D (30% up-regulated; P< .01). We conclude that exposure to obesity during development primes an inflammatory environment in adipose tissue that is independent of offspring adiposity. Programming of adipose tissue miRNAs that regulate expression of inflammatory signaling molecules may be a contributing mechanism.

‘Developmental programming’, which occurs as a consequence of suboptimal in utero and early environments, can be associated with metabolic dysfunction in later life, including an increased incidence of cardiovascular disease and type 2 diabetes, and predisposition of older men to sarcopenia. However, the molecular mechanisms underpinning these associations are poorly understood. Many conditions associated with developmental programming are also known to be associated with the aging process. We therefore utilized our well-established rat model of low birth weight and accelerated postnatal catch-up growth (termed ‘recuperated’) in this study to establish the effects of suboptimal maternal nutrition on age-associated factors in skeletal muscle. We demonstrated accelerated telomere shortening (a robust marker of cellular aging) as evidenced by a reduced frequency of long telomeres (48.5-8.6 kb) and an increased frequency of short telomeres (4.2-1.3 kb) in vastus lateralis muscle from aged recuperated offspring compared to controls. This was associated with increased protein expression of the DNA-damage-repair marker 8-oxoguanine-glycosylase (OGG1) in recuperated offspring. Recuperated animals also demonstrated an oxidative stress phenotype, with decreased citrate synthase activity, increased electron-transport-complex activities of complex I, complex II-III and complex IV (all markers of functional mitochondria), and increased xanthine oxidase (XO), p67phox and nuclear-factor kappa-light-chain-enhancer of activated B-cells (NF-κB). Recuperated offspring also demonstrated increased antioxidant defense capacity, with increased protein expression of manganese superoxide dismutase (MnSOD), copper-zinc superoxide dismutase (CuZnSOD), catalase and heme oxygenase-1 (HO1), all of which are known targets of NF-κB and can be upregulated as a consequence of oxidative stress. Recuperated offspring also had a pro-inflammatory phenotype, as evidenced by increased tumor necrosis factor-α (TNFα) and interleukin-1β (IL1β) protein levels. Taken together, we demonstrate, for the first time to our knowledge, an accelerated aging phenotype in skeletal muscle in the context of developmental programming. These findings may pave the way for suitable interventions in at-risk populations.

Although obesity is a global epidemic, the physiological mechanisms involved are not well understood. Recent advances reveal that susceptibility to obesity can be programmed by maternal and neonatal nutrition. Specifically, a maternal low-protein diet during pregnancy causes decreased intrauterine growth, rapid postnatal catch-up growth and an increased risk for diet-induced obesity. Given that the synthesis of the neurotransmitter 5-hydroxytryptamine (5-HT) is nutritionally regulated and 5-HT is a trophic factor, we hypothesised that maternal diet influences fetal 5-HT exposure, which then influences development of the central appetite network and the subsequent efficacy of 5-HT to control energy balance in later life. Consistent with our hypothesis, pregnant rats fed a low-protein diet exhibited elevated serum levels of 5-HT, which was also evident in the placenta and fetal brains at embryonic day 16.5. This increase was associated with reduced levels of 5-HT2CR, the primary 5-HT receptor influencing appetite, in the fetal, neonatal and adult hypothalamus. As expected, a reduction of 5-HT2CR was associated with impaired sensitivity to 5-HT-mediated appetite suppression in adulthood. 5-HT primarily achieves effects on appetite by 5-HT2CR stimulation of pro-opiomelanocortin (POMC) peptides within the arcuate nucleus of the hypothalamus (ARC). We show that 5-HT2ARs are also anatomically positioned to influence the activity of ARC POMC neurons and that mRNA encoding 5-HT2AR is increased in the hypothalamus of in utero growth-restricted offspring that underwent rapid postnatal catch-up growth. Furthermore, these animals at 3 months of age are more sensitive to appetite suppression induced by 5-HT2AR agonists. These findings not only reveal a 5-HT-mediated mechanism underlying the programming of susceptibility to obesity, but also provide a promising means to correct it, by treatment with a 5-HT2AR agonist.

Low birth weight and rapid postnatal growth increases the risk of developing insulin resistance and type 2 diabetes in later life. However, underlying mechanisms and potential intervention strategies are poorly defined. Here we demonstrate that male Wistar rats exposed to a low-protein diet in utero that had a low birth weight but then underwent postnatal catch-up growth (recuperated offspring) had reductions in the insulin signaling proteins p110-β (13% ± 6% of controls [P< .001]) and insulin receptor substrate-1 (39% ± 10% of controls [P< .05]) in adipose tissue. These changes were not accompanied by any change in expression of the corresponding mRNAs, suggesting posttranscriptional regulation. Recuperated animals displayed evidence of a proinflammatory phenotype of their adipose tissue with increased IL-6 (139% ± 8% [P< .05]) and IL1-β (154% ± 16% [P< .05]) that may contribute to the insulin signaling protein dysregulation. Postweaning dietary supplementation of recuperated animals with coenzyme Q (CoQ10) (1 mg/kg of body weight per day) prevented the programmed reduction in insulin receptor substrate-1 and p110-β and the programmed increased in IL-6. These findings suggest that postweaning CoQ10supplementation has antiinflammatory properties and can prevent programmed changes in insulin-signaling protein expression. We conclude that CoQ10supplementation represents an attractive intervention strategy to prevent the development of insulin resistance that results from suboptimal in utero nutrition.

Although aging is ubiquitous across organisms, the rate at which it occurs varies considerably between species and individuals. The initial links between oxidative stress and rates of cellular aging were postulated over 50 years ago by Harman, who published a theory connecting free radical damage with the aging process in 19561. Since then a wide body of literature has accumulated demonstrating the links between oxidative damage to various cellular components and cellular senescence2. Oxidative stress is known to contribute to the aetiology of a wide variety of pathological processes including metabolic, cardiovascular and neoplastic diseases, all of which can shorten lifespan. Macromolecules such as proteins, lipids and particularly DNA can be irreversibly damaged by oxidative stress, leading to a decline in cellular function and apoptosis. This leads to aging, initially at a cellular level, then of the tissues and organs, culminating in whole organism pathology and eventually death. This article explores the various processes by which cells accrue oxidative damage and how such long-term damage leads to senescence. In particular, we focus on how the early-life environment influences the accumulation of oxidative stress over the entire life-course of an individual and how this may accelerate the normal aging process.

The environment experienced during critical windows of development can ‘programme’ long-term health and risk of metabolic diseases such as type 2 diabetes in the offspring. The purpose of this review is to discuss potential epigenetic mechanisms involved in the developmental programming of type 2 diabetes by early nutrition.

Individuals with a low birth weight are at increased risk of developing type 2 diabetes; however, the underlying molecular mechanisms are not known. We have shown previously that low birth weight is associated with changes in insulin signaling protein expression in muscle. The current aim was to determine if low birth weight is associated with changes in insulin signaling proteins in adipose tissue. A total of 17 males aged 22 years were recruited from the Danish Medical Birth Registry. Nine had low birth weights (bottom 10th percentile), and eight bad a normal birth weight (50th to 90th percentile). Adipose biopsies were taken from the abdomen using a Bergstrom needle, and protein expression was determined by Western blotting. There were no differences in expression of the insulin receptor, protein kinase C [zeta], glycogen synthase kinase (GSK)-3[alpha], or GSK3[beta] between the two groups. However, there were reductions in expression of GLUT4 (52 [+ or -] 10.9% reduction, P < 0.01), p85[alpha] regulatory subunit of phosphatidylinositol (PI) 3-kinase (45 [+ or -] 9% reduction, P < 0.01), and the p110[beta] subunit of PI 3-kinase (48 [+ or -] 17% reduction, P = 0.06). These findings suggest that low birth weight is associated with reduced expression of important insulin signaling proteins in adipose tissue that may contribute to an increased risk of type 2 diabetes., Susan E. Ozanne, (1) Katie J. Tingey, (1) Louise Grunnet, (2) Heidi Storgaard, (2) Christine Jensen, (2) Allan Vaag (2) From the (1) Department of Clinical Biochemistry, University of Cambridge, [...]

Developmental programming of non-communicable diseases is now an established paradigm. With respect to hypertension and chronic kidney disease, adverse events experienced in utero can affect development of the fetal kidney and reduce final nephron number. Low birthweight and prematurity are the most consistent clinical surrogates for a low nephron number and are associated with increased risk of hypertension, proteinuria, and kidney disease in later life. Rapid weight gain in childhood or adolescence further compounds these risks. Low birthweight, prematurity, and rapid childhood weight gain should alert clinicians to an individual's lifelong risk of hypertension and kidney disease, prompting education to minimise additional risk factors and ensuring follow-up. Birthweight and prematurity are affected substantially by maternal nutrition and health during pregnancy. Optimisation of maternal health and early childhood nutrition could, therefore, attenuate this programming cycle and reduce the global burden of hypertension and kidney disease in the future.

The nutritional environment in which the mammalian fetus or infant develop is recognized as influencing the risk of chronic diseases, such as type 2 diabetes and hypertension, in a phenomenon that has become known as developmental programming. The late onset of such diseases in response to earlier transient experiences has led to the suggestion that developmental programming may have an epigenetic component, because epigenetic marks such as DNA methylation or histone tail modifications could provide a persistent memory of earlier nutritional states. One class of genes that has been considered a potential target or mediator of programming events is imprinted genes, because these genes critically depend upon epigenetic modifications for correct expression and because many imprinted genes have roles in controlling fetal growth as well as neonatal and adult metabolism. In this study, we have used an established model of developmental programming—isocaloric protein restriction to female mice during gestation or lactation—to examine whether there are effects on expression and DNA methylation of imprinted genes in the offspring. We find that although expression of some imprinted genes in liver of offspring is robustly and sustainably changed, methylation of the differentially methylated regions (DMRs) that control their monoallelic expression remains largely unaltered. We conclude that deregulation of imprinting through a general effect on DMR methylation is unlikely to be a common factor in developmental programming.

Type 2 diabetes, which has dramatically increased during the last decade normally results from a combination of pancreatic beta cell dysfunction and insulin resistance. One of the most recent risk factors identified for type 2 diabetes is a sub-optimal fetal and neonatal environment. Numerous human epidemiological studies worldwide have highlighted that a disturbed nutritional environment of the fetus, either poor or too abundant will compromise the health of the offspring by increasing the susceptibility to insulin resistance, to glucose intolerance and to diabetes in later life. In addition to adverse intrauterine events, the detrimental role of catch-up growth and of the mismatch between the prenatal and the postnatal metabolic environment in such pathology is now clear. To understand the mechanisms that are responsible for such programming and to be able to design prevention strategies, a number of animal models have been created. This manuscript reviews the data from several rodent models in which maternal or neonatal diet has been altered. These include models of maternal under-nutrition and over-nutrition as well as gestational diabetes. In general, abnormal beta cell mass and beta cell dysfunction are present at birth and insulin resistance, glucose intolerance and diabetes appear in adult offspring. Obesity, pregnancy and ageing exaggerate the phenotype and there is some evidence to suggest that the phenotype can be transmitted to a second generation independently of any further environmental modification. Possible underlying mechanisms are discussed and evidence for potential early intervention strategies are reported.

Epigenetic mechanisms alter gene expression without changing the nucleotide sequence; nevertheless, they can transmit through generations of cells. This article discusses how the fetal environment might affect the epigenotype of the fetus and how this might affect subsequent development of diseases, such as diabetes, later in life and perhaps in subsequent generations.

It is well documented that females live longer than males and more renal damage occurs in males. However, the underlying mechanisms are not fully understood. The aim of this study was to define aging effects on albuminuria and kidney telomere length from male and female rats and to determine mechanisms, which may explain any observed differences. Cellular senescence is known to play a major role in nephropathology, and as such, a range of senescence markers were compared in male and female renal tissue. Oxidative stress has been shown to accelerate telomere shortening and elicit cellular growth arrest. Thus major antioxidants, MnSOD, glutathione peroxidase I, and glutathione reductase, were also evaluated. Urinary albumin excretion increased with age in both sexes, but the increase was greater in males than females. In the cortex and medulla of both male and female rats, age-related telomere shortening occurred, the effect being more pronounced in males than in females. The cortical region had more short telomeres than the medulla in both genders. p53 And p21 expression over time significantly increased in males, but not in females. MnSOD expression was elevated in female vs. male cortex. Gxp1 and glutathione reductase levels were increased in the older female cortex compared with males. Our findings indicate that a reduction in oxidative damage protection may be responsible for accelerated telomere shortening over time, resulting in increased cellular senescence, loss of renal function, and death in male rats.

Type 2 diabetes, obesity and the metabolic syndrome are rapidly escalating in progressively younger individuals, leading to increased mortality, morbidity and healthcare costs. Research into preventing as well as treating these conditions is of the utmost importance. The link between low birth weight and the subsequent increased risk of developing Type 2 diabetes and obesity, as well as other features of the metabolic syndrome such as hypertension, is well established. This review discusses the evidence from both epidemiological studies and animal models supporting this link, as well as potential mechanisms. More recently, increasing focus has been on the detrimental effect of rapid postnatal growth after poor fetal growth. Improving prenatal nutrition and maintaining a steady and appropriate growth rate in early life could dramatically decrease the rates of Type 2 diabetes, obesity and other metabolic complications. Individuals who are at high risk because of their fetal and prenatal growth could, if informed, be able to make improved life choices. A combination of improved fetal and early-life nutrition and appropriate risk management for high-risk individuals could reduce the huge clinical burden of these conditions. This review will focus on the evidence suggesting a link between fetal and early-life growth and the risk of developing Type 2 diabetes, obesity and other factors of the metabolic syndrome in adult life. This evidence exists from a wide range of epidemiological studies as well as from a variety of animal models. Interventions both during pregnancy and early life as well as informed life choices in those at risk could dramatically reduce the huge clinical burden of obesity and its comorbidities.

There is increasing concern about the rapidly rising incidence of obesity worldwide and its impact both on mortality, morbidity and the cost of healthcare. In the last 15 years, a large volume of research has linked low birth weight to many adult diseases in humans, such as Type II diabetes, cardiovascular disease, hypertension and the metabolic syndrome. Obesity is a causal factor in all these conditions. There are epidemiological studies linking low birth weight to increased adiposity, but the timing of the insult during gestation seems crucial, as reducing maternal nutrition in late gestation and during lactation causes a reduction in later obesity. Recent studies in animal models have provided clues towards mechanisms of altered appetite regulation following alterations in fetal and neonatal growth. The outcome of these and future studies could prove clinically crucial, particularly in the debate over the benefits of breast feeding, which provides a lower plane of nutrition compared with formula feeding.

Poor early growth is associated with Type II diabetes, hypertension and other features of the metabolic syndrome in adulthood. It has been suggested that this results from the development of a thrifty phenotype by a malnourished fetus. Such a phenotype would predispose the offspring to the development of obesity if born into conditions of over-nutrition. The present study aimed to determine if early nutrition affected subsequent development of obesity. Mice were established as follows: (a) controls (offspring of control dams), (b) recuperated (offspring of dams fed a low-protein diet during pregnancy, but nursed by control dams) and (c) postnatal low-protein (offspring of control dams nursed by low-protein-fed dams). Mice were weaned on to standard laboratory chow or a cafeteria diet. Recuperated offspring, although smaller at birth (P<0.01), caught up and exceeded the weight of control offspring by 7 days of age (P<0.001). Postnatal low-protein offspring were smaller than controls by 7 days of age (P<0.001). Recuperated animals gained more weight than controls when given free access to a highly palatable diet (P<0.01). Postnatal low-protein animals showed no additional weight gain when given a highly palatable diet compared with chow-fed litter-mates. These results suggest that the early environment has long-term consequences for weight gain. These programmed responses are powerful enough to block excess weight gain from a highly palatable diet and, thus, have major implications for the drug-free regulation of food intake and obesity.

There is substantial and long-standing literature linking the level of general nutrition to longevity. Reducing nutrition below the amount needed to sustain maximum growth increases longevity in a wide range of organisms. Oxidative damage has been shown to be a major feature of the aging process. Telomere shortening is now well established as a key process regulating cell senescence in vitro.There is some evidence that the same process may be important for aging in vivo.Very recently it has been found that oxidative damage accelerates telomere shortening. It is therefore possible for us to propose as an outline hypothesis that the level of nutrition determines oxidative damage which in turn determines telomere shortening and cell senescence and that this pathway is important in determining aging and longevity in vivo.We also propose that telomeres in addition to their well-recognized role in “counting” cell divisions are also, through their GGG sequence, important monitors of oxidative damage over the life span of a cell. This may explain the evolutionary conservations of this triplet in the repeat telomere sequence unit.

1. Recent studies have revealed a link between fetal and early post-natal growth retardation and the development of features of the insulin resistance syndrome in later life. Obesity is also a strong risk factor for this syndrome. The aim of this study was to assess whether maternal and early protein restriction, which causes growth retardation, and obesity are risk factors that are independent for the development of certain features of the insulin resistance syndrome, especially hypertension. 2. Pregnant Sprague—Dawley rats were given either 20% or 8% protein isocaloric diets throughout pregnancy and lactation. Female offspring were weaned onto the same diets as their mothers and they remained on these diets until 70 days of age. Half the rats were then given standard laboratory chow, whilst the remainder were fed a highly palatable cafeteria-style diet. Rats were maintained on these diets for the remainder of the study. 3. Rats given the 8% protein diet remained physically lighter than comparable animals fed the 20% protein diet throughout the study. In contrast, cafeteria-fed rats showed excessive weight gain. At 1 year of age the rats had their systolic blood pressures and fasting lipids measured, as well as undergoing an intraperitoneal glucose-tolerance test. 4. Cafeteria-fed rats had worse glucose tolerances than controls and hypertriacylglycerolaemia. The early 8% protein rats had significantly increased blood pressures, as did the cafeteria-fed rats. These increases were additive, suggesting that early protein restriction, and later obesity, are indeed independent risk factors for the development of hypertension.

Quantitative reverse transcriptase PCR (RT-PCR) is a sensitive method for the measurement of mRNA copy number. However, the methodology has gained a reputation for poor reproducibility, leading to concern over the validity of much of the data generated using this technique. We have developed two variants of quantitative competitive RT-PCR using a synthesized RNA as an internal standard to measure precisely the relative levels of α-, β- and γ-fibrinogen mRNAs in the four lobes of the rat liver. In the first of these variants we altered only the amount of total RNA in the RT-PCR reaction, keeping the amount of internal standard RNA and the number of PCR cycles constant. In the second variant only the number of PCR cycles was altered, and the amounts of total RNA and standard RNA were kept constant. Both variants of RT-PCR allowed calculation of the number of mRNA copies, which did not differ significantly between the two techniques. Of the two variants, the second gave better reproducibility, and the intra-assay coefficient of variation for this technique was 14% (n = 20). Using these two variants we have shown that there are different numbers of fibrinogen mRNAs in the four liver lobes for each of the three genes (α-fibrinogen F = 14.64, P = 0.0003; β-fibrinogen F = 3.74, P = 0.04; γ-fibrinogen F = 3.75, P = 0.04). In conclusion, by using two variants of quantitative competitive RT-PCR we have shown that this technique can be used to give reproducible results, and the low intra-assay coefficient of variation suggests that quantitative RT-PCR should be the technique of choice for accurate measurement of mRNA copy number.

Studies published in 2014 have helped in our understanding of the epigenetic mechanisms by which suboptimal nutritional exposures during in uterodevelopment are transmitted to subsequent generations through the maternal and the paternal germlines. Advances include identification of common genetic loci that are vulnerable to the effects of in uteroundernutrition and overnutrition, as well as those that are epigenetically modified tissue-wide.

Maternal undernutrition around the time of conception is associated with an increased risk of insulin resistance in adulthood. We determined the effect of maternal undernutrition in the periconceptional period (PCUN, i.e., 60 days prior to 6 days after conception) and the preimplantation period (PIUN, i.e., 0–6 days after conception) on mRNA expression and protein abundance of key insulin-signaling molecules as well as the global microRNA expression in quadriceps muscle of singleton and twin fetal sheep in late gestation. In singleton fetuses, exposure to PCUN resulted in lower protein abundance of PIK3CB (P< 0.01), PRKCZ (P< 0.05), and pPRKCZ (Thr410) (P< 0.05) in skeletal muscle compared to controls. In PIUN singletons, there was a higher protein abundance of IRS1 (P< 0.05), PDPK1 (P< 0.05), and SLC2A4 (P< 0.05) compared to controls. In twins, PCUN resulted in higher protein abundance of IRS1 (P< 0.05), AKT2 (P< 0.05), PDPK1 (P< 0.05), and PRKCZ (P< 0.001), while PIUN also resulted in higher protein abundance of IRS1 (P< 0.05), PRKCZ (P< 0.001), and SLC2A4 (P< 0.05) in fetal muscle compared to controls. There were specific patterns of the types and direction of changes in the expression of 22 microRNAs in skeletal muscle after exposure to PCUN or PIUN and clear differences in these patterns between singleton and twin pregnancies. These findings provide evidence that maternal undernutrition around the time of conception induces changes in the expression of microRNAs, which may play a role in altering the abundance of the key insulin-signaling molecules in skeletal muscle and in the association between PCUN undernutrition and insulin resistance in adult life.

Reviews the state of knowledge about children's windows of vulnerability to developmental toxicants. Use of the information to improve risk assessment and public health; Structure and functions of cardiovascular system; Relation of structural defects of endocrine glands to environmental exposures.