BMI in childhood and adolescence is associated with impaired reproductive function-a population-based cohort study from birth to age 50 years

Peer reviewe

An optimal growth pattern during pregnancy and early childhood associates with better fertility in men

Peer reviewe

Maternal and infant prediction of the child BMI trajectories; studies across two generations of Northern Finland birth cohorts

Background/objective Children BMI is a longitudinal phenotype, developing through interplays between genetic and environmental factors. Whilst childhood obesity is escalating, we require a better understanding of its early origins and variation across generations to prevent it. Subjects/methods We designed a cross-cohort study including 12,040 Finnish children from the Northern Finland Birth Cohorts 1966 and 1986 (NFBC1966 and NFBC1986) born before or at the start of the obesity epidemic. We used group-based trajectory modelling to identify BMI trajectories from 2 to 20 years. We subsequently tested their associations with early determinants (mother and child) and the possible difference between generations, adjusted for relevant biological and socioeconomic confounders. Results We identified four BMI trajectories, ‘stable-low’ (34.8%), ‘normal’ (44.0%), ‘stable-high’ (17.5%) and ‘early-increase’ (3.7%). The ‘early-increase’ trajectory represented the highest risk for obesity. We analysed a dose-response association of maternal pre-pregnancy BMI and smoking with BMI trajectories. The directions of effect were consistent across generations and the effect sizes tended to increase from earlier generation to later. Respectively for NFBC1966 and NFBC1986, the adjusted risk ratios of being in the early-increase group were 1.08 (1.06–1.10) and 1.12 (1.09–1.15) per unit of pre-pregnancy BMI and 1.44 (1.05–1.96) and 1.48 (1.17–1.87) in offspring of smoking mothers compared to non-smokers. We observed similar relations with infant factors including birthweight for gestational age and peak weight velocity. In contrast, the age at adiposity peak in infancy was associated with the BMI trajectories in NFBC1966 but did not replicate in NFBC1986. Conclusions Exposures to adverse maternal predictors were associated with a higher risk obesity trajectory and were consistent across generations. However, we found a discordant association for the timing of adiposity peak over a 20-year period. This suggests the role of residual environmental factors, such as nutrition, and warrants additional research to understand the underlying gene–environment interplay

Maternal body weight and gestational diabetes differentially influence placental and pregnancy outcomes

Context: Maternal obesity and gestational diabetes mellitus (GDM) can both contribute to adverse neonatal outcomes. The extent to which this may be mediated by differences in placental metabolism and nutrient transport remains to be determined. Objective: Our objective was to examine whether raised maternal body mass index (BMI) and/or GDM contributed to a resetting of the expression of genes within the placenta that are involved in energy sensing, oxidative stress, inflammation, and metabolic pathways. Methods: Pregnant women from Spain were recruited as part of the “Study of Maternal Nutrition and Genetics on the Foetal Adiposity Programming” survey at the first antenatal visit (12–20 weeks of gestation) and stratified according to prepregnancy BMI and the incidence of GDM. At delivery, placenta and cord blood were sampled and newborn anthropometry measured. Results: Obese women with GDM had higher estimated fetal weight at 34 gestational weeks and a greater risk of preterm deliveries and cesarean section. Birth weight was unaffected by BMI or GDM; however, women who were obese with normal glucose tolerance had increased placental weight and higher plasma glucose and leptin at term. Gene expression for markers of placental energy sensing and oxidative stress, were primarily affected by maternal obesity as mTOR was reduced, whereas SIRT-1 and UCP2 were both upregulated. In placenta from obese women with GDM, gene expression for AMPK was also reduced, whereas the downstream regulator of mTOR, p70S6KB1 was raised. Conclusions: Placental gene expression is sensitive to both maternal obesity and GDM which both impact on energy sensing and could modulate the effect of either raised maternal BMI or GDM on birth weight

Effect of pre- and postnatal growth and post-weaning activity on glucose metabolism in the offspring

Maternal caloric restriction during late gestation reduces birth weight, but whether long-term adverse metabolic outcomes of intra-uterine growth retardation (IUGR) are dependent on either accelerated postnatal growth or exposure to an obesogenic environment after weaning is not established. We induced IUGR in twin-pregnant sheep using a 40% maternal caloric restriction commencing from 110 days of gestation until term (∼147 days), compared with mothers fed to 100% of requirements. Offspring were reared either as singletons to accelerate postnatal growth or as twins to achieve standard growth. To promote an adverse phenotype in young adulthood, after weaning, offspring were reared under a low-activity obesogenic environment with the exception of a subgroup of IUGR offspring, reared as twins, maintained in a standard activity environment. We assessed glucose tolerance together with leptin and cortisol responses to feeding in young adulthood when the hypothalamus was sampled for assessment of genes regulating appetite control, energy and endocrine sensitivity. Caloric restriction reduced maternal plasma glucose, raised non-esterified fatty acids, and changed the metabolomic profile, but had no effect on insulin, leptin, or cortisol. IUGR offspring whose postnatal growth was enhanced and were obese showed insulin and leptin resistance plus raised cortisol. This was accompanied by increased hypothalamic gene expression for energy and glucocorticoid sensitivity. These long-term adaptations were reduced but not normalized in IUGR offspring whose postnatal growth was not accelerated and remained lean in a standard post-weaning environment. IUGR results in an adverse metabolic phenotype, especially when postnatal growth is enhanced and offspring progress to juvenile-onset obesity

Common maternal and fetal genetic variants show expected polygenic effects on risk of small- or large-for-gestational-age (SGA or LGA), except in the smallest 3% of babies

This is the final version. Available on open access from the Public Library of Science via the DOI in this recordData Availability: We used both published summary results (i.e. taking results from published research papers and websites) and individual participant cohort data as follows: Journal published and website summary data were used for generating the genetic scores of birth weight, fasting glucose and systolic blood pressure. The references to those published data sources are provided in the main paper. We used individual participant data from ALSPAC, EFSOCH and NFBC cohorts. The data in ALSPAC are fully available, via managed systems, to any researchers. The managed system is a requirement of the study funders but access is not restricted on the basis of overlap with other applications to use the data or on the basis of peer review of the proposed science. Researchers have to pay for a dataset to be prepared for them. ALSPAC. The ALSPAC data management plan (http://www.bristol.ac.uk/alspac/researchers/data-access/documents/alspac-data-management-plan.pdf) describes in detail the policy regarding data sharing, which is through a system of managed open access. The steps below highlight how to apply for access to the data included in this paper and all other ALSPAC data. 1. Please read the ALSPAC access policy (PDF, 627kB) which describes the process of accessing the data and samples in detail, and outlines the costs associated with doing so. 2. You may also find it useful to browse the fully searchable ALSPAC research proposals database, which lists all research projects that have been approved since April 2011. 3. Please submit your research proposal for consideration by the ALSPAC Executive Committee. You will receive a response within 10 working days to advise you whether your proposal has been approved. If you have any questions about accessing data, please email [email protected]. EFSOCH. Requests for access to the original EFSOCH dataset should be made in writing in the first instance to the EFSOCH data team via the Exeter Clinical Research Facility [email protected]. NFBC: Data is available from the Northern Finland Birth Cohort (NFBC) for researchers who meet the criteria for accessing confidential data. Please, contact NFBC project center ([email protected]) and visit the cohort website (www.oulu.fi/nfbc) for more information.Babies born clinically Small- or Large-for-Gestational-Age (SGA or LGA; sex- and gestational age-adjusted birth weight (BW) 90th percentile, respectively), are at higher risks of complications. SGA and LGA include babies who have experienced environment-related growth-restriction or overgrowth, respectively, and babies who are heritably small or large. However, the relative proportions within each group are unclear. We assessed the extent to which common genetic variants underlying variation in birth weight influence the probability of being SGA or LGA. We calculated independent fetal and maternal genetic scores (GS) for BW in 11,951 babies and 5,182 mothers. These scores capture the direct fetal and indirect maternal (via intrauterine environment) genetic contributions to BW, respectively. We also calculated maternal fasting glucose (FG) and systolic blood pressure (SBP) GS. We tested associations between each GS and probability of SGA or LGA. For the BW GS, we used simulations to assess evidence of deviation from an expected polygenic model. Higher BW GS were strongly associated with lower odds of SGA and higher odds of LGA (ORfetal=0.75 (0.71,0.80) and 1.32 (1.26,1.39); ORmaternal=0.81 (0.75,0.88) and 1.17 (1.09,1.25), respectively per 1 decile higher GS). We found evidence that the smallest 3% of babies had a higher BW GS, on average, than expected from their observed birth weight (assuming an additive polygenic model: Pfetal=0.014, Pmaternal=0.062). Higher maternal SBP GS was associated with higher odds of SGA P=0.005 . We conclude that common genetic variants contribute to risk of SGA and LGA, but that additional factors become more important for risk of SGA in the smallest 3% of babies.Wellcome TrustRoyal SocietyNational Institute for Health Research (NIHR

NMR metabolomic modeling of age and lifespan: A multicohort analysis.

Metabolomic age models have been proposed for the study of biological aging, however, they have not been widely validated. We aimed to assess the performance of newly developed and existing nuclear magnetic resonance spectroscopy (NMR) metabolomic age models for prediction of chronological age (CA), mortality, and age-related disease. Ninety-eight metabolic variables were measured in blood from nine UK and Finnish cohort studies (N ≈31,000 individuals, age range 24-86 years). We used nonlinear and penalized regression to model CA and time to all-cause mortality. We examined associations of four new and two previously published metabolomic age models, with aging risk factors and phenotypes. Within the UK Biobank (N ≈102,000), we tested prediction of CA, incident disease (cardiovascular disease (CVD), type-2 diabetes mellitus, cancer, dementia, and chronic obstructive pulmonary disease), and all-cause mortality. Seven-fold cross-validated Pearson's r between metabolomic age models and CA ranged between 0.47 and 0.65 in the training cohort set (mean absolute error: 8-9 years). Metabolomic age models, adjusted for CA, were associated with C-reactive protein, and inversely associated with glomerular filtration rate. Positively associated risk factors included obesity, diabetes, smoking, and physical inactivity. In UK Biobank, correlations of metabolomic age with CA were modest (r = 0.29-0.33), yet all metabolomic model scores predicted mortality (hazard ratios of 1.01 to 1.06/metabolomic age year) and CVD, after adjustment for CA. While metabolomic age models were only moderately associated with CA in an independent population, they provided additional prediction of morbidity and mortality over CA itself, suggesting their wider applicability

Vitamin D levels in women with polycystic ovary syndrome: a population-based study

Background: Conflicting evidence supports a role for vitamin D in women with reproductive disorders such as polycystic ovary syndrome (PCOS) but studies on large, unselected populations have been lacking. Methods: We conducted a general population-based study from the prospective Northern Finland Birth Cohort 1966 (NFBC1966). Serum 25-hydroksyvitamin D (25(OH)D) levels were evaluated in women with self-reported PCOS (n = 280) versus non-symptomatic controls (n = 1573) at the age of 31 with wide range of endocrine and metabolic confounders. Results: The levels of 25(OH)D were similar among women with and without self-reported PCOS (50.35 vs. 48.30 nmol/L, p = 0.051). Women with self-reported PCOS presented with a higher body mass index (BMI), increased insulin resistance, and low-grade inflammation and testosterone levels compared to controls. The adjusted linear regression model showed a positive association between total 25(OH)D levels in self-reported PCOS (β = 2.46, 95% confidence interval (CI) 0.84 to 4.08, p = 0.003). The result remained after adjustment for BMI, testosterone, homeostatic model assessment of insulin resistance (HOMA-IR), and high-sensitivity C-reactive protein (hs-CRP) levels. Conclusion: In this population-based setting, PCOS was associated with higher vitamin D levels when adjusting for confounding factors, without distinct beneficial effects on metabolic derangements

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 offspring's 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

Polycystic ovary syndrome and leukocyte telomere length : cross-sectional and longitudinal changes

Objective Telomeres are DNA-protein complexes that protect chromosome ends from DNA damage and are surrogate biomarkers of cellular ageing. Current evidence, almost entirely from cross-sectional observations, supports negative associations between leukocyte telomere length (LTL) and adverse lifestyle factors and cardio-metabolic risk factors. Polycystic ovary syndrome (PCOS), the most common gynecological endocrine disorder, is associated with inflammation and oxidative stress, both factors associated with accelerated telomere attrition. We therefore hypothesized that LTL would be shorter and decrease more rapidly in women with PCOS in comparison to a control population. Design Population-based cohort study: women of Northern Finland Birth Cohort 1966, with clinical examinations at ages 31 and 46. The sample included self-reported PCOS (PCOS) (age 31:N=190; age 46:N=207) and referent women (age 31:N=1054; age 46:N=1324) with data on LTL. Methods The association between LTL and PCOS at ages 31 and 46 was analyzed by linear regression models adjusted for BMI, smoking, alcohol consumption and socioeconomic status at the corresponding age. Results Women with PCOS had similar mean LTL at ages 31 and 46 (P>0.4 for both). The mean LTL change between ages 31 and 46 did not differ between groups (P=0.19). However, we observed a significant LTL attrition between ages 31 and 46 in the reference population (P<0.001), but not in women with PCOS (P=0.96). Conclusions This finding may suggest a difference in LTL attrition rate in women with PCOS, an unexpected finding that might affect their risk of age-related disease. Further research is needed to clarify the underlying mechanisms