GDF15 linked to maternal risk of nausea and vomiting during pregnancy.

GDF15, a hormone acting on the brainstem, has been implicated in the nausea and vomiting of pregnancy, including its most severe form, hyperemesis gravidarum (HG), but a full mechanistic understanding is lacking1-4. Here we report that fetal production of GDF15 and maternal sensitivity to it both contribute substantially to the risk of HG. We confirmed that higher GDF15 levels in maternal blood are associated with vomiting in pregnancy and HG. Using mass spectrometry to detect a naturally labelled GDF15 variant, we demonstrate that the vast majority of GDF15 in the maternal plasma is derived from the feto-placental unit. By studying carriers of rare and common genetic variants, we found that low levels of GDF15 in the non-pregnant state increase the risk of developing HG. Conversely, women with ß-thalassaemia, a condition in which GDF15 levels are chronically high5, report very low levels of nausea and vomiting of pregnancy. In mice, the acute food intake response to a bolus of GDF15 is influenced bi-directionally by prior levels of circulating GDF15 in a manner suggesting that this system is susceptible to desensitization. Our findings support a putative causal role for fetally derived GDF15 in the nausea and vomiting of human pregnancy, with maternal sensitivity, at least partly determined by prepregnancy exposure to the hormone, being a major influence on its severity. They also suggest mechanism-based approaches to the treatment and prevention of HG.

MC3R links nutritional state to childhood growth and the timing of puberty.

The state of somatic energy stores in metazoans is communicated to the brain, which regulates key aspects of behaviour, growth, nutrient partitioning and development1. The central melanocortin system acts through melanocortin 4 receptor (MC4R) to control appetite, food intake and energy expenditure2. Here we present evidence that MC3R regulates the timing of sexual maturation, the rate of linear growth and the accrual of lean mass, which are all energy-sensitive processes. We found that humans who carry loss-of-function mutations in MC3R, including a rare homozygote individual, have a later onset of puberty. Consistent with previous findings in mice, they also had reduced linear growth, lean mass and circulating levels of IGF1. Mice lacking Mc3r had delayed sexual maturation and an insensitivity of reproductive cycle length to nutritional perturbation. The expression of Mc3r is enriched in hypothalamic neurons that control reproduction and growth, and expression increases during postnatal development in a manner that is consistent with a role in the regulation of sexual maturation. These findings suggest a bifurcating model of nutrient sensing by the central melanocortin pathway with signalling through MC4R controlling the acquisition and retention of calories, whereas signalling through MC3R primarily regulates the disposition of calories into growth, lean mass and the timing of sexual maturation.

Changes over time in latent patterns of childhood-to-adulthood BMI development in Great Britain: evidence from three cohorts born in 1946, 1958, and 1970.

BACKGROUND: Most studies on secular trends in body mass index (BMI) are cross-sectional and the few longitudinal studies have typically only investigated changes over time in mean BMI trajectories. We aimed to describe how the evolution of the obesity epidemic in Great Britain reflects shifts in the proportion of the population demonstrating different latent patterns of childhood-to-adulthood BMI development. METHODS: We used pooled serial BMI data from 25,655 participants in three British cohorts: the 1946 National Survey of Health and Development (NSHD), 1958 National Child Development Study (NCDS), and 1970 British Cohort Study (BCS). Sex-specific growth mixture models captured latent patterns of BMI development between 11 and 42 years. The classes were characterised in terms of their birth cohort composition. RESULTS: The best models had four classes, broadly similar for both sexes. The 'lowest' class (57% of males; 47% of females) represents the normal weight sub-population, the 'middle' class (16%; 15%) represents the sub-population who likely develop overweight in early/mid-adulthood, and the 'highest' class (6%; 9%) represents those who likely develop obesity in early/mid-adulthood. The remaining class (21%; 29%) reflects a sub-population with rapidly 'increasing' BMI between 11 and 42 years. Both sexes in the 1958 NCDS had greater odds of being in the 'highest' class compared to their peers in the 1946 NSHD but did not have greater odds of being in the 'increasing' class. Conversely, males and females in the 1970 BCS had 2.78 (2.15, 3.60) and 1.87 (1.53, 2.28), respectively, times higher odds of being in the 'increasing' class. CONCLUSIONS: Our results suggest that the obesity epidemic in Great Britain reflects not only an upward shift in BMI trajectories but also a more recent increase in the number of individuals demonstrating more rapid weight gain, from normal weight to overweight, across the second, third, and fourth decades of life.

Maternal serum concentrations of bisphenol A and propyl paraben in early pregnancy are associated with male infant genital development.

STUDY QUESTION: Are maternal serum phthalate metabolite, phenol and paraben concentrations measured at 10-17 weeks of gestation associated with male infant genital developmental outcomes, specifically cryptorchidism, anogenital distance (AGD), penile length and testicular descent distance, at birth and postnatally? SUMMARY ANSWER: Maternal serum bisphenol A (BPA) concentration at 10-17 weeks of gestation was positively associated with congenital or postnatally acquired cryptorchidism, and n-propyl paraben (n-PrP) concentration was associated with shorter AGD from birth to 24 months of age. WHAT IS KNOWN ALREADY: Male reproductive disorders are increasing in prevalence, which may reflect environmental influences on foetal testicular development. Animal studies have implicated phthalates, BPA and parabens, to which humans are ubiquitously exposed. However, epidemiological studies have generated conflicting results and have often been limited by small sample size and/or measurement of chemical exposures outside the most relevant developmental window. STUDY DESIGN, SIZE, DURATION: Case-control study of cryptorchidism nested within a prospective cohort study (Cambridge Baby Growth Study), with recruitment of pregnant women at 10-17 postmenstrual weeks of gestation from a single UK maternity unit between 2001 and 2009 and 24 months of infant follow-up. Of 2229 recruited women, 1640 continued with the infancy study after delivery, of whom 330 mothers of 334 male infants (30 with congenital cryptorchidism, 25 with postnatally acquired cryptorchidism and 279 unmatched controls) were included in the present analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: Maternal blood was collected at enrolment, and serum levels of 16 phthalate metabolites, 9 phenols (including BPA) and 6 parabens were measured using liquid chromatography/tandem mass spectrometry. Logistic regression was used to model the association of cryptorchidism with serum chemical concentrations, adjusting for putative confounders. Additionally, offspring AGD, penile length and testicular descent distance were assessed at 0, 3, 12, 18 and 24 months of age, and age-specific Z scores were calculated. Associations between serum chemical levels and these outcomes were tested using linear mixed models. MAIN RESULTS AND THE ROLE OF CHANCE: Maternal serum BPA concentration was associated with offspring all-type cryptorchidism both when considered as a continuous exposure (adjusted odds ratio per log10 µg/l: 2.90, 95% CI 1.31-6.43, P = 0.009) and as quartiles (phet = 0.002). Detection of n-PrP in maternal serum was associated with shorter AGD (by 0.242 standard deviations, 95% CI 0.051-0.433, P = 0.01) from birth to 24 months of age; this reduction was independent of body size and other putative confounders. We did not find any consistent associations with offspring outcomes for the other phenols, parabens, and phthalate metabolites measured. LIMITATIONS, REASONS FOR CAUTION: We cannot discount confounding by other demographic factors or endocrine-disrupting chemicals. There may have been misclassification of chemical exposure due to use of single serum measurements. The cohort was not fully representative of pregnant women in the UK, particularly in terms of smoking prevalence and maternal ethnicity. WIDER IMPLICATIONS OF THE FINDINGS: Our observational findings support experimental evidence that intrauterine exposure to BPA and n-PrP during early gestation may adversely affect male reproductive development. More evidence is required before specific public health recommendations can be made. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by a European Union Framework V programme, the World Cancer Research Fund International, the Medical Research Council (UK), Newlife the Charity for Disabled Children, the Mothercare Group Foundation, Mead Johnson Nutrition and the National Institute for Health Research Cambridge Comprehensive Biomedical Research Centre. Visiting Fellowship (J.M.): Regional Programme 'Jiménez de la Espada' for Research Mobility, Cooperation and Internationalization, Seneca Foundation-Science and Technology Agency for the Region of Murcia (No. 20136/EE/17). K.O. is supported by the Medical Research Council (UK) (Unit Programme number: MC_UU_12015/2). The authors declare no conflict of interest.

A review on colorimetric methods for determination of organophosphate pesticides using gold and silver nanoparticles.

This review (with 99 refs.) summarizes the progress that has been made in colorimetric (i.e. spectrophotometric) determination of organophosphate pesticides (OPPs) using gold and silver nanoparticles (NPs). Following an introduction into the field, a first large section covers the types and functions of organophosphate pesticides. Methods for colorimetric (spectrophotometric) measurements including RGB techniques are discussed next. A further section covers the characteristic features of gold and silver-based NPs. Syntheses and modifications of metal NPs are covered in section 5. This is followed by overviews on enzyme inhibition-based assays, aptamer-based assays and chemical (non-enzymatic) assays, and a discussion of specific features of colorimetric assays. Several Tables are presented that give an overview on the wealth of methods and materials. A concluding section addresses current challenges and discusses potential future trends and opportunities. Graphical abstractSchematic representation of organophosphate pesticide determinations based on aggregation of nanoparticles (particular silver or gold nanoparticles). This leads to a color change which can be determined visually and monitored by a red shift in the absorption spectrum.

Voice break in boys-temporal relations with other pubertal milestones and likely causal effects of BMI.

STUDY QUESTION: How is timing of voice break related to other male pubertal milestones as well as to BMI? SUMMARY ANSWER: We provide a comprehensive temporal analysis of male pubertal milestones, including reproductive hormone dynamics, confirm voice break as a late milestone of male puberty and report a likely causal relationship between higher BMI and earlier age at voice break in men. WHAT IS KNOWN ALREADY: Voice break represents a late pubertal milestone and recalled age at voice break is frequently used in epidemiological studies as a measure of puberty. In contrast, clinical studies use mainly testicular enlargement and/or genital tanner stage as the marker of pubertal onset. However, neither correlation of pubertal milestones nor reproductive hormone dynamics have been assessed in detail previously. Further, although BMI and puberty timing are known to be closely linked, cause and effect between these traits are not known. STUDY DESIGN, SIZE, DURATION: The study included a population-based mixed cross-sectional and longitudinal cohort (2006-2014, COPENHAGEN Puberty Study) of 730 healthy Danish boys. Data for 55 871 male research participants from the 23andMe study were obtained, including genome-wide single nucleotide polymorphism data and age at voice break. PARTICIPANTS/MATERIALS, SETTING, METHODS: We performed a detailed evaluation of pubertal milestones and reproductive hormone levels (study population 1). A Mendelian randomization (MR) approach was used to determine the likely causal link between BMI and timing of voice break (study population 2). MAIN RESULTS AND THE ROLE OF CHANCE: Voice break occurred at mean age 13.6 (95% CI: 13.5-13.8) years. At voice break, mean (95% CI) testosterone levels, LH levels and bi-testicular volume were 10.9 (10.0-11.7) nmol/L, 2.4 (2.2-2.5) IU/L and 24 (23-25) mL, respectively. Voice break correlated moderately strongly with timing of male pubertal milestones, including testicular enlargement, gonadarche, pubarche, sweat odor, axillary hair growth and testosterone above limit of detection (r2 range: 0.43-0.61). Timing of all milestones was negatively associated with age-specific BMI (all P ≤ 0.001). MR analyses inferred likely causal effects of higher BMI on earlier voice break in males (-0.35 years/approximate SD, P < 0.001). LIMITATIONS, REASONS FOR CAUTION: Participation rate of the population-based cohort was 25%. Further, boys that were followed longitudinally were examined approximately every 6 months limiting the time resolution of pubertal milestones. Using adult BMI as exposure instead of prepubertal BMI in the MR analysis and the known inaccuracies of the testosterone immunoassay at low testosterone levels may be further limitations. WIDER IMPLICATIONS OF THE FINDINGS: We provide valuable normative data on the temporal relation of male pubertal milestones. Further, the likely causal relationship between BMI and puberty timing highlights the importance of preventing obesity in childhood. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by Danish Agency for Science, Technology and Innovation (09-067 180); Danish Ministry of the Environment, CeHoS (MST-621-00 065); Capital Region of Denmark (R129-A3966); Ministry of Higher Education and Science (DFF-1331-00 113); Innovation Fund Denmark (InnovationsFonden, 14-2013-4); The International Center for Research and Research Training in Endocrine Disrupting Effects of Male Reproduction and Child Health. B.H., F.R.D., J.R.B.P. and K.K.O. are supported by the Medical Research Council (MC_UU_12015/2). The 23andMe study is supported by the National Human Genome Research Institute of the National Institutes of Health (R44HG006981). Members of the 23andMe Research Team are employees of 23andMe, Inc. and hold stock or stock options in 23andMe. TRIAL REGISTRATION NUMBER: NCT01411527.

Adolescent parenthood associated with adverse socio-economic outcomes at age 30 years in women and men of the Pelotas, Brazil: 1982 Birth Cohort Study.

OBJECTIVE: To investigate the potential long-term effects of adolescent parenthood on completed education and income. DESIGN: Population-based birth cohort study. SETTING: All live births in 1982, whose mothers lived in the urban area of Pelotas, southern Brazil. SAMPLE: A total of 3701 participants: 1914 women and 1787 men at age 30 years. METHODS: Questionnaires were completed by the mothers in the early phases of this study, and by the cohort members in adolescence and adulthood. Linear regression models and G-computation were used in the analyses. MAIN OUTCOME MEASURES: Educational attainment and income at age 30 years. RESULTS: In women, adolescent parenthood was associated with lower attained education compared with women without adolescent maternity: by -2.8 years [95% confidence interval (CI) -3.2 to -2.3] if their first birth was at age 16-19, and by -4.4 years (-5.5 to -3.3) at age 11-15. These effects were greater among women who had three or more children. Women with adolescent parenthood also had 49 or 33% lower income at age 30 if their first child was born when aged 16-19 or 11-15, respectively. In men, the adverse effect of adolescent parenthood on education appeared to be mediated by a higher number of children and there was no effect of adolescent paternity on income at age 30 years. CONCLUSION: These findings suggest lasting socio-economic disadvantages of adolescent parenthood, with larger effects being apparent in women than in men. TWEETABLE ABSTRACT: Adolescent parenthood has an adverse effect on educational attainment later in life, and on household income among women.

Associations between maternal physical activity in early and late pregnancy and offspring birth size: remote federated individual level meta-analysis from eight cohort studies.

OBJECTIVE: Evidence on the impact of leisure time physical activity (LTPA) in pregnancy on birth size is inconsistent. We aimed to examine the association between LTPA during early and late pregnancy and newborn anthropometric outcomes. DESIGN: Individual level meta-analysis, which reduces heterogeneity across studies. SETTING: A consortium of eight population-based studies (seven European and one US) comprising 72 694 participants. METHODS: Generalised linear models with consistent inclusion of confounders (gestational age, sex, parity, maternal age, education, ethnicity, BMI, smoking, and alcohol intake) were used to test associations between self-reported LTPA at either early (8-18 weeks gestation) or late pregnancy (30+ weeks) and the outcomes. Results were pooled using random effects meta-analyses. MAIN OUTCOME MEASURES: Birth weight, large-for-gestational age (LGA), macrosomia, small-for-gestational age (SGA), % body fat, and ponderal index at birth. RESULTS: Late, but not early, gestation maternal moderate to vigorous physical activity (MVPA), vigorous activity, and LTPA energy expenditure were modestly inversely associated with BW, LGA, macrosomia, and ponderal index, without heterogeneity (all: I2  = 0%). For each extra hour/week of MVPA, RR for LGA and macrosomia were 0.97 (95% CI: 0.96, 0.98) and 0.96 (95% CI: 0.94, 0.98), respectively. Associations were only modestly reduced after additional adjustments for maternal BMI and gestational diabetes. No measure of LTPA was associated with risk for SGA. CONCLUSIONS: Physical activity in late, but not early, pregnancy is consistently associated with modestly lower risk of LGA and macrosomia, but not SGA. TWEETABLE ABSTRACT: In an individual participant meta-analysis, late pregnancy moderate to vigorous physical activity modestly reduced birth size outcomes.

Associations between body mass index-related genetic variants and adult body composition: The Fenland cohort study.

BACKGROUND/OBJECTIVE: Body mass index (BMI) is a surrogate measure of adiposity but does not distinguish fat from lean or bone mass. The genetic determinants of BMI are thought to predominantly influence adiposity but this has not been confirmed. Here we characterise the association between BMI-related genetic variants and body composition in adults. SUBJECTS/METHODS: Among 9667 adults aged 29-64 years from the Fenland study, a genetic risk score for BMI (BMI-GRS) was calculated for each individual as the weighted sum of BMI-increasing alleles across 96 reported BMI-related variants. Associations between the BMI-GRS and body composition, estimated by dual-energy X-ray absorptiometry (DXA) scans, were examined using age-adjusted linear regression models, separately by sex. RESULTS: The BMI-GRS was positively associated with all fat, lean and bone variables. Across body regions, associations of the greatest magnitude were observed for adiposity variables, for example, for each s.d. increase in BMI-GRS predicted BMI, we observed a 0.90 s.d. (95% confidence interval (CI): 0.71, 1.09) increase in total fat mass for men (P=3.75 × 10-21) and a 0.96 s.d. (95% CI: 0.77, 1.16) increase for women (P=6.12 × 10-22). Associations of intermediate magnitude were observed with lean variables, for example, total lean mass: men: 0.68 s.d. (95% CI: 0.49, 0.86; P=1.91 × 10-12); women: 0.85 s.d. (95% CI: 0.65, 1.04; P=2.66 × 10-17) and of a lower magnitude with bone variables, for example, total bone mass: men: 0.39 s.d. (95% CI: 0.20, 0.58; P=5.69 × 10-5); women: 0.45 s.d. (95% CI: 0.26, 0.65; P=3.96 × 106). Nominally significant associations with BMI were observed for 28 single-nucleotide polymorphisms. All 28 were positively associated with fat mass and 13 showed adipose-specific effects. CONCLUSIONS: In adults, genetic susceptibility to elevated BMI influences adiposity more than lean or bone mass. This mirrors the association between BMI and body composition. The BMI-GRS can be used to model the effects of measured BMI and adiposity on health and other outcomes.

Body shape and size in 6-year old children: assessment by three-dimensional photonic scanning.

BACKGROUND: Body shape and size are typically described using measures such as body mass index (BMI) and waist circumference, which predict disease risks in adults. However, this approach may underestimate the true variability in childhood body shape and size. OBJECTIVE: To use a comprehensive three-dimensional photonic scan approach to describe variation in childhood body shape and size. SUBJECTS/METHODS: At age 6 years, 3350 children from the population-based 2004 Pelotas birth cohort study were assessed by three-dimensional photonic scanner, traditional anthropometry and dual X-ray absorptiometry. Principal component analysis (PCA) was performed on height and 24 photonic scan variables (circumferences, lengths/widths, volumes and surface areas). RESULTS: PCA identified four independent components of children's body shape and size, which we termed: Corpulence, Central:peripheral ratio, Height and arm lengths, and Shoulder diameter. Corpulence showed strong correlations with traditional anthropometric and body composition measures (r>0.90 with weight, BMI, waist circumference and fat mass; r>0.70 with height, lean mass and bone mass); in contrast, the other three components showed weak or moderate correlations with those measures (all r<0.45). There was no sex difference in Corpulence, but boys had higher Central:peripheral ratio, Height and arm lengths and Shoulder diameter values than girls. Furthermore, children with low birth weight had lower Corpulence and Height and arm lengths but higher Central:peripheral ratio and Shoulder diameter than other children. Children from high socio-economic position (SEP) families had higher Corpulence and Height and arm lengths than other children. Finally, white children had higher Corpulence and Central:peripheral ratio than mixed or black children. CONCLUSIONS: Comprehensive assessment by three-dimensional photonic scanning identified components of childhood body shape and size not captured by traditional anthropometry or body composition measures. Differences in these novel components by sex, birth weight, SEP and skin colour may indicate their potential relevance to disease risks.

Associations of birth weight, linear growth and relative weight gain throughout life with abdominal fat depots in adulthood: the 1982 Pelotas (Brazil) birth cohort study.

BACKGROUND: Several studies have reported on associations of size at birth and early growth with general and central obesity; however, few have examined the potential effects of birth weight and postnatal growth on separate abdominal fat compartments. We investigated the effects of size at birth, linear growth and relative weight gain from birth to adulthood on visceral (VFT) and subcutaneous abdominal (SAFT) fat thicknesses at age 30 years. METHODS: A total of 2663 participants from the 1982 Pelotas (Brazil) birth cohort study had complete information on ultrasound measures of abdominal fat at age 30 years, and anthropometric measurements for at least five visits (0/2/4/23/30 years). We estimated weight and height Z-score changes, conditional relative weight gain and conditional height at several ages. RESULTS: In both men and women, VFT and SAFT showed positive associations with conditional relative weight gain during all age periods beyond 2 years and birth, respectively (all P⩽0.01). Women born with intrauterine growth restriction (IUGR) had greater VFT than other women (difference=0.15 s.d., 95% CI: 0.01-0.29), and they showed a stronger positive influence of infant weight gain 0-2 years on VFT (IUGR: ß=0.17 s.d., 95% CI: 0.05-0.29; non-IUGR: ß=0.01 s.d., 95% CI: -0.04 to 0.06; Pinteraction=0.02). Stunting at 2 years was associated with lower SAFT but not VFT, and it modified the influence of weight gain 2-4 years on SAFT in both sexes (both Pinteraction<0.05). CONCLUSIONS: Our findings reinforce the advantages of being born with an appropriate birth weight, and the hazards of rapid postnatal gains in weight relative to linear growth, particularly after the critical window of the first 1000 days.

Prenatal paracetamol exposure is associated with shorter anogenital distance in male infants.

STUDY QUESTION: What is the relationship between maternal paracetamol intake during the masculinisation programming window (MPW, 8-14 weeks of gestation) and male infant anogenital distance (AGD), a biomarker for androgen action during the MPW? SUMMARY ANSWER: Intrauterine paracetamol exposure during 8-14 weeks of gestation is associated with shorter AGD from birth to 24 months of age. WHAT IS ALREADY KNOWN: The increasing prevalence of male reproductive disorders may reflect environmental influences on foetal testicular development during the MPW. Animal and human xenograft studies have demonstrated that paracetamol reduces foetal testicular testosterone production, consistent with reported epidemiological associations between prenatal paracetamol exposure and cryptorchidism. STUDY DESIGN, SIZE, DURATION: Prospective cohort study (Cambridge Baby Growth Study), with recruitment of pregnant women at ~12 post-menstrual weeks of gestation from a single UK maternity unit between 2001 and 2009, and 24 months of infant follow-up. Of 2229 recruited women, 1640 continued with the infancy study after delivery, of whom 676 delivered male infants and completed a medicine consumption questionnaire. PARTICIPANTS/MATERIALS, SETTING, METHOD: Mothers self-reported medicine consumption during pregnancy by a questionnaire administered during the perinatal period. Infant AGD (measured from 2006 onwards), penile length and testicular descent were assessed at 0, 3, 12, 18 and 24 months of age, and age-specific Z scores were calculated. Associations between paracetamol intake during three gestational periods (<8 weeks, 8-14 weeks and >14 weeks) and these outcomes were tested by linear mixed models. Two hundred and twenty-five (33%) of six hundred and eighty-one male infants were exposed to paracetamol during pregnancy, of whom sixty-eight were reported to be exposed during 8-14 weeks. AGD measurements were available for 434 male infants. MAIN RESULTS AND THE ROLE OF CHANCE: Paracetamol exposure during 8-14 weeks of gestation, but not any other period, was associated with shorter AGD (by 0.27 SD, 95% CI 0.06-0.48, P = 0.014) from birth to 24 months of age. This reduction was independent of body size. Paracetamol exposure was not related to penile length or testicular descent. LIMITATIONS, REASONS FOR CAUTION: Confounding by other drugs or endocrine-disrupting chemicals cannot be discounted. The cohort was not fully representative of pregnant women in the UK, particularly in terms of maternal ethnicity and smoking prevalence. There is likely to have been misclassification of paracetamol exposure due to recall error. WIDER IMPLICATIONS OF THE FINDINGS: Our observational findings support experimental evidence that intrauterine paracetamol exposure during the MPW may adversely affect male reproductive development. STUDY FUNDING/COMPETING INTERESTS: This work was supported by a European Union Framework V programme, the World Cancer Research Fund International, the Medical Research Council (UK), the Newlife Foundation for Disabled Children, the Evelyn Trust, the Mothercare Group Foundation, Mead Johnson Nutrition, and the National Institute for Health Research Cambridge Comprehensive Biomedical Research Centre. The authors declare no conflict of interest.

Associations between adiposity, hormones, and gains in height, whole-body height-adjusted bone size, and size-adjusted bone mineral content in 8- to 11-year-old children.

UNLABELLED: We examined fat-independent associations of hormones with height and whole-body bone size and mineral content in 633 school children. IGF-1 and osteocalcin predict growth in height, while fat, osteocalcin, and in girls also, IGF-1 predict growth in bone size. Leptin and ghrelin are inversely associated with bone size in girls. INTRODUCTION: Obesity causes larger bone size and bone mass, but the role of hormones in this up-regulation of bone in obesity is not well elucidated. We examined longitudinal associations between baseline body fat mass (FM), and fat-independent fasting levels of ghrelin, adiponectin, leptin, insulin, insulin-like growth factor-I (IGF-1), osteocalcin, and intact parathyroid hormone, and subsequent changes in height and in whole-body height-adjusted bone area "BAheight" and size-adjusted bone mineral content "BMCsize" in 8- to 11-year-olds. METHODS: Analyses were carried out separately for boys (n = 325) and girls (n = 308) including data from baseline, 3 and 6 months from OPUS School Meal Study. RESULTS: In both sexes: gain in BAheight was positively associated with baseline FM (≥2.05 cm(2)/kg, both p ≤ 0.003). Furthermore, gain in height was positively associated with baseline IGF-1 (≥0.02 cm/ng/ml, p = 0.001) and osteocalcin (≥0.13 cm/ng/ml, p ≤ 0.009); and gain in BAheight was positively associated with baseline osteocalcin (≥0.35 cm(2)/ng/ml, p ≤ 0.019). In girls only, gain in BAheight was also positively associated with baseline IGF-1 (0.06 cm(2)/ng/ml, p = 0.017) and inversely associated with both baseline ghrelin (-0.01 cm(2)/pg/ml, p = 0.001) and leptin (-1.21 cm(2)/µg/ml, p = 0.005). In boys, gain in BMCsize was positively associated with osteocalcin (0.18 g/ng/ml, p = 0.030). CONCLUSIONS: This large longitudinal study suggests that in 8- to 11-year-old children, IGF-1 and osteocalcin predict growth in height, while FM, osteocalcin, and in girls also, IGF-1 predict growth in BAheight. Fat-independent inverse associations of leptin and ghrelin with BAheight in girls' are contrary to proposed growth-stimulating effects of leptin. Osteocalcin in boys predicts gain in BMCsize.

Even transient rapid infancy weight gain is associated with higher BMI in young adults and earlier menarche.

BACKGROUND: Early postnatal rapid 'catch-up' weight gain has been consistently associated with subsequent higher obesity risk and earlier pubertal development. In many low- and middle-income countries, infancy catch-up weight gain is transient and often followed by growth faltering. We explored the hypothesis that even transient catch-up weight gain during infancy is associated with later obesity risk and earlier puberty. METHODS: A total of 2352 (1151 male, 1201 female) black South African children in the birth to twenty prospective birth cohort study (Johannesburg-Soweto) underwent serial measurements of body size and composition from birth to 18 years of age. At the age of 18 years, whole-body fat mass and fat-free mass were determined using dual-energy X-ray absorptiometry. Pubertal development was assessed by the research team between ages 9 and 10 years, and it was recorded annually from the age of 11 years using a validated self-assessment protocol. RESULTS: Catch-up weight gain from birth to the age of 1 year, despite being followed by growth faltering between ages 1 and 2 years, was associated with greater mid-upper arm circumference (P=0.04) and skinfold thickness (P=0.048) at 8 years of age, and with higher weight (P<0.001) and body mass index (P=0.001) at 18 years of age after adjustment for sex, age, smoking during pregnancy, birth order, gestational age, formula-milk feeding and household socio-economic status. Infancy catch-up weight gain was also associated with younger age at menarche in girls (P<0.001). This association persisted after adjustment for smoking during pregnancy, birth order, gestational age, formula-milk feeding and household socio-economic status (P=0.005). CONCLUSION: Transient catch-up weight gain from birth to the age of 1 year among children born in a low-income area of South Africa was associated with earlier menarche and greater adiposity in early adulthood. This observation suggests that modifiable determinants of rapid infancy weight gain may be targeted in order to prevent later obesity and consequences of earlier puberty in girls.

Pleiotropic effects of obesity-susceptibility loci on metabolic traits: a meta-analysis of up to 37,874 individuals.

AIMS/HYPOTHESIS: Genetic pleiotropy may contribute to the clustering of obesity and metabolic conditions. We assessed whether genetic variants that are robustly associated with BMI and waist-to-hip ratio (WHR) also influence metabolic and cardiovascular traits, independently of obesity-related traits, in meta-analyses of up to 37,874 individuals from six European population-based studies. METHODS: We examined associations of 32 BMI and 14 WHR loci, individually and combined in two genetic predisposition scores (GPSs), with glycaemic traits, blood lipids and BP, with and without adjusting for BMI and/or WHR. RESULTS: We observed significant associations of BMI-increasing alleles at five BMI loci with lower levels of 2 h glucose (RBJ [also known as DNAJC27], QPTCL: effect sizes -0.068 and -0.107 SD, respectively), HDL-cholesterol (SLC39A8: -0.065 SD, MTCH2: -0.039 SD), and diastolic BP (SLC39A8: -0.069 SD), and higher and lower levels of LDL- and total cholesterol (QPTCL: 0.041 and 0.042 SDs, respectively, FLJ35779 [also known as POC5]: -0.042 and -0.041 SDs, respectively) (all p < 2.4 × 10(-4)), independent of BMI. The WHR-increasing alleles at two WHR loci were significantly associated with higher proinsulin (GRB14: 0.069 SD) and lower fasting glucose levels (CPEB4: -0.049 SD), independent of BMI and WHR. A higher GPS-BMI was associated with lower systolic BP (-0.005 SD), diastolic BP (-0.006 SD) and 2 h glucose (-0.013 SD), while a higher GPS-WHR was associated with lower HDL-cholesterol (-0.015 SD) and higher triacylglycerol levels (0.014 SD) (all p < 2.9 × 10(-3)), independent of BMI and/or WHR. CONCLUSIONS/INTERPRETATION: These pleiotropic effects of obesity-susceptibility loci provide novel insights into mechanisms that link obesity with metabolic abnormalities.

Association of the INS VNTR with size at birth. ALSPAC Study Team. Avon Longitudinal Study of Pregnancy and Childhood.

Size at birth is an important determinant of perinatal survival and has also been associated with the risk for cardiovascular disease and type 2 diabetes in adult life. Common genetic variation that regulates fetal growth could therefore influence perinatal survival and predispose to the development of adult disease. We have tested the insulin gene (INS) variable number of tandem repeats (VNTR) locus, which in Caucasians has two main allele sizes (class I and class III; ref. 3), as a functional candidate polymorphism for association with size at birth, as it has been shown to influence transcription of INS (refs 3-5). In a cohort of 758 term singletons (Avon Longitudinal Study of Pregnancy and Childhood; ALSPAC) followed longitudinally from birth to 2 years, we detected significant genetic associations with size at birth: class III homozygotes had larger mean head circumference (P=0.004) than class I homozygotes. These associations were amplified in babies who did not show postnatal realignment of growth (45%), and were also evident for length (P=0.015) and weight (P=0.009) at birth. The INS VNTR III/II genotype might have bestowed a perinatal survival during human history by conferring larger size at birth. Common genetic variation of this kind may contribute to reported associations between birth size and adult disease.

Fetally-encoded GDF15 and maternal GDF15 sensitivity are major determinants of nausea and vomiting in human pregnancy.

Human pregnancy is frequently accompanied by nausea and vomiting that may become severe and life-threatening, as in hyperemesis gravidarum (HG), the cause of which is unknown. Growth Differentiation Factor-15 (GDF15), a hormone known to act on the hindbrain to cause emesis, is highly expressed in the placenta and its levels in maternal blood rise rapidly in pregnancy. Variants in the maternal GDF15 gene are associated with HG. Here we report that fetal production of GDF15, and maternal sensitivity to it, both contribute substantially to the risk of HG. We found that the great majority of GDF15 in maternal circulation is derived from the feto-placental unit and that higher GDF15 levels in maternal blood are associated with vomiting and are further elevated in patients with HG. Conversely, we found that lower levels of GDF15 in the non-pregnant state predispose women to HG. A rare C211G variant in GDF15 which strongly predisposes mothers to HG, particularly when the fetus is wild-type, was found to markedly impair cellular secretion of GDF15 and associate with low circulating levels of GDF15 in the non-pregnant state. Consistent with this, two common GDF15 haplotypes which predispose to HG were associated with lower circulating levels outside pregnancy. The administration of a long-acting form of GDF15 to wild-type mice markedly reduced subsequent responses to an acute dose, establishing that desensitisation is a feature of this system. GDF15 levels are known to be highly and chronically elevated in patients with beta thalassemia. In women with this disorder, reports of symptoms of nausea or vomiting in pregnancy were strikingly diminished. Our findings support a causal role for fetal derived GDF15 in the nausea and vomiting of human pregnancy, with maternal sensitivity, at least partly determined by pre-pregnancy exposure to GDF15, being a major influence on its severity. They also suggest mechanism-based approaches to the treatment and prevention of HG.

Developing a programme for healthy growth and nutrition during infancy: understanding user perspectives.

BACKGROUND: Avoiding excess energy intake and rapid weight gain during infancy may be effective in preventing childhood obesity. We developed a programme for healthy growth and nutrition in formula milk-fed babies. The aim of this study was to understand users' perspectives about the programme and planned trial. METHODS: We conducted three focus group discussions (10 mothers) and nine individual interviews (seven health visitors, one midwife and one mother) discussing the programme materials and trial protocol. All sessions were transcribed verbatim and a thematic analysis was performed using the framework approach. RESULTS: Mothers reported receiving conflicting messages about infant feeding and were keen for consistent advice. They welcomed the support that the programme would offer to mothers who gave their babies formula milk, but some were sceptical about the feasibility of limiting formula milk quantities. They suggested that recommended quantities should be presented as general guidelines rather than rigid rules. Some mothers said that it was too early to intervene to prevent obesity, that babies could not be overfed and that the risks of formula milk feeding had been exaggerated. Because of the routine advice to feed on demand, babies were fed in response to crying, and crying was equated with 'hunger'. Some mothers said that growth was genetically determined so they ignored the growth charts. Health visitors used the growth charts to assess adequate weight gain rather than to identify excess weight gain. Health visitors said that mothers would need a lot of education and support to limit formula milk quantities. CONCLUSIONS: Efforts to prevent childhood obesity by avoiding excess weight gain during infancy have to address mothers' beliefs that babies cannot be overfed, that crying always signals hunger and that growth is determined by genes rather than nutrition. Mothers and healthcare providers have different motivations and understanding these are important in the development of any intervention.

Association between childhood obesity and subsequent Type 1 diabetes: a systematic review and meta-analysis.

AIMS: To review and synthesize the published evidence on the possible association between childhood obesity and the subsequent risk of Type 1 diabetes. METHODS: The PubMed database was systematically searched for studies using childhood obesity, BMI or %weight-for-height as the exposure variable and subsequent Type 1 diabetes as the outcome. Studies were only included if assessment of obesity preceded the diagnosis of Type 1 diabetes. RESULTS: Eight case-control studies and one cohort study were included, comprising a total of 2658 cases. Of these nine studies, seven reported a significant association between childhood obesity, BMI or %weight-for-height and increased risk for Type 1 diabetes. Meta-analysis of the four studies that reported childhood obesity as a categorical exposure produced a pooled odds ratio of 2.03 (95% CI 1.46-2.80) for subsequent Type 1 diabetes; however, in those studies, age at obesity assessment varied from age 1 to 12 years. A dose-response relationship was supported by a continuous association between childhood BMI and subsequent Type 1 diabetes in a meta-analysis of five studies (pooled odds ratio 1.25 (95%CI 1.04-1.51) per 1 sd higher BMI). CONCLUSION: There is overall evidence for an association between childhood obesity, or higher BMI, and increased risk of subsequent Type 1 diabetes. Several theories have been proposed for a causal relationship. Reduction in Type 1 diabetes should be considered as a potential additional benefit of preventing childhood obesity.

Lipid ratios representing SCD1, FADS1, and FADS2 activities as candidate biomarkers of early growth and adiposity.

BACKGROUND: Altered lipid metabolism in early life has been associated with subsequent weight gain and predicting this could aid in obesity prevention and risk management. Here, a lipidomic approach was used to identify circulating markers for future obesity risk in translational murine models and validate in a human infant cohort. METHODS: Lipidomics was performed on the plasma of APOE*3 Leiden, Ldlr-/-.Leiden, and the wild-type C57BL/6J mice to capture candidate biomarkers predicting subsequent obesity parameters after exposure to high-fat diet. The identified candidate biomarkers were mapped onto corresponding lipid metabolism pathways and were investigated in the Cambridge Baby Growth Study. Infants' growth and adiposity were measured at 0-24 months. Capillary dried blood spots were sampled at 3 months for lipid profiling analysis. FINDINGS: From the mouse models, cholesteryl esters were correlated with subsequent weight gain and other obesity parameters after HFD period (Spearman's r≥0.5, FDR p values <0.05) among APOE*3 Leiden and Ldlr-/-.Leiden mice, but not among the wild-type C57BL/6J. Pathway analysis showed that those identified cholesteryl esters were educts or products of desaturases activities: stearoyl-CoA desaturase-1 (SCD1) and fatty acid desaturase (FADS) 1 and 2. In the human cohort, lipid ratios affected by SCD1 at 3 months was inversely associated with 3-12 months weight gain (B±SE=-0.31±0.14, p=0.027), but positively with 12-24 months weight and adiposity gains (0.17±0.07, p=0.02 and 0.17±0.07, 0.53±0.26, p=0.04, respectively). Lipid ratios affected by SCD1 and FADS2 were inversely associated with adiposity gain but positively with height gain between 3-12 months. INTERPRETATION: From murine models to human setting, the ratios of circulating lipid species indicating key desaturase activities in lipid metabolism were associated with subsequent body size increase, providing a potential tool to predict early life weight gain.