Blood cells as a source of transcriptional biomarkers of childhood obesity and its related metabolic alterations: results of the IDEFICS Study

Background: IDEFICS (Identification and Prevention of Dietary-and Lifestyle-Induced Health Effects in Children and Infants Project) is a European multicenter study on childhood obesity. One of its goals is to define early biomarkers of risk associated with obesity and its comorbid conditions. Objective: We considered blood cells as a new potential source of transcriptional biomarkers for these metabolic disorders and examined whether blood cell mRNA levels of some selected genes (LEPR, INSR, CPT1A, SLC27A2, UCP2, FASN, and PPAR alpha) were altered in overweight children and whether their expression levels could be defined as markers of the insulin-resistant or dyslipidemic state associated with overweight. Design: Blood samples were obtained from 306 normal-weight and overweight children, aged 2-9 yr, from eight different European countries. Whole-blood mRNA levels were assessed by quantitative RT-PCR. Results: LEPR, INSR, and CPT1A mRNA levels were higher in overweight compared with normal-weight children (the two latter only in males), whereas SLC27A2 mRNA levels were lower in overweight children. Significant associations were also found between expression levels of LEPR, INSR, CPT1A, SLC27A2, FASN, PPAR alpha, and different parameters, including body mass index, homeostasis model assessment index, and plasma triglycerides and cholesterol levels. These associations showed that high expression levels of CPT1A, SLC27A2, INSR, FASN, or PPAR alpha may be indicative of a lower risk for the insulin-resistant or dyslipidemic state associated with obesity, whereas low LEPR mRNA levels appear as a marker of high low-density lipoprotein cholesterol, independently of body mass index. Conclusions: These findings point toward the possibility of using the expression levels of these genes in blood cells as markers of metabolic status and can potentially provide an early warning of a future disorder

The role of neuromedin U in adiposity regulation. Haplotype analysis in European children from the IDEFICS Cohort

Background and aims: Neuromedin U (NMU) is a hypothalamic neuropeptide with important roles in several metabolic processes, recently suggested as potential therapeutic target for obesity. We analysed the associations between NMU gene variants and haplotypes and body mass index (BMI) in a large sample of European children. Methods and results: From a large European multi-center study on childhood obesity, 4,528 children (2.0–9.9 years, mean age 6.0±1.8 SD; boys 52.2%) were randomly selected, stratifying by age, sex and country, and genotyped for tag single nucleotide polymorphisms (SNPs; rs6827359, T:C; rs12500837, T:C; rs9999653,C:T) of NMU gene, then haplotypes were inferred. Regression models were applied to estimate the associations between SNPs or haplotypes and BMI as well as other anthropometric measures. BMI was associated with all NMU SNPs (p<0.05). Among five haplotypes inferred, the haplotype carrying the minor alleles (CCT, frequency = 22.3%) was the only associated with lower BMI values (beta = -0.16, 95%CI:-0.28,-0.04, p = 0.006; z-score, beta = -0.08, 95%CI:-0.14,-0.01, p = 0.019) and decreased risk of overweight/obesity (OR = 0.81, 95%CI:0.68,0.97, p = 0.020) when compared to the most prevalent haplotype (codominant model). Similar significant associations were also observed using the same variables collected after two years’ time (BMI, beta = -0.25, 95%CI:-0.41,-0.08, p = 0.004; z-score, beta = -0.10, 95%CI:-0.18,-0.03, p = 0.009; overweight/obesity OR = 0.81, 95%CI:0.66,0.99, p = 0.036). The association was age-dependent in girls (interaction between CCT haplotypes and age, p = 0.008), more evident between 7 and 9 years of age. The CCT haplotype was consistently associated with lower levels of fat mass, skinfold thickness, hip and arm circumferences both at T0 and at T1, after adjustment for multiple testing (FDR-adjusted p<0.05). Conclusions: This study shows an association between a NMU haplotype and anthropometric indices, mainly linked to fat mass, which appears to be age- and sex-specific in children. Genetic variations within or in linkage with this haplotype should be investigated to identify functional variants responsible for the observed phenotypic variation

Early life course risk factors for childhood obesity : the IDEFICS case-control study

Background: The early life course is assumed to be a critical phase for childhood obesity; however the significance of single factors and their interplay is not well studied in childhood populations. Objectives: The investigation of pre-, peri- and postpartum risk factors on the risk of obesity at age 2 to 9. Methods: A case-control study with 1,024 1: 1-matched case-control pairs was nested in the baseline survey (09/2007-05/2008) of the IDEFICS study, a population-based intervention study on childhood obesity carried out in 8 European countries in pre- and primary school settings. Conditional logistic regression was used for identification of risk factors. Results: For many of the investigated risk factors, we found a raw effect in our study. In multivariate models, we could establish an effect for gestational weight gain (adjusted OR = 1.02; 95% CI 1.00-1.04), smoking during pregnancy (adjusted OR = 1.48; 95% CI 1.08-2.01), Caesarian section (adjusted OR = 1.38; 95% CI 1.10-1.74), and breastfeeding 4 to 11 months (adjusted OR = 0.77; 95% CI 0.62-0.96). Birth weight was related to lean mass rather than to fat mass, the effect of smoking was found only in boys, but not in girls. After additional adjustment for parental BMI and parental educational status, only gestational weight gain remained statistically significant. Both, maternal as well as paternal BMI were the strongest risk factors in our study, and they confounded several of the investigated associations. Conclusions: Key risk factors of childhood obesity in our study are parental BMI and gestational weight gain; consequently prevention approaches should target not only children but also adults. The monitoring of gestational weight seems to be of particular importance for early prevention of childhood obesity

Reference values for leptin and adiponectin in children below the age of 10 based on the IDEFICS cohort

OBJECTIVE: To establish age- and sex-specific reference values for serum leptin and adiponectin in normal-weight 3.0-8.9-year old European children. SUBJECTS AND METHODS: Blood samples for hormone analysis were taken from 1338 children of the IDEFICS (Identification and prevention of Dietary-and lifestyle-induced health Effects in Children and infantS) study cohort. Only normal-weight children aged 3.0-8.9 years were included (n = 539) in our analysis. Using the General Additive Model for Location Scale and Shape, age-and sex-specific percentiles were derived. The influence of under/overweight and obesity on the proposed reference curves based on normal-weight children was investigated in several sensitivity analyses using the sample without obese children (n = 1015) and the whole study sample (n = 1338). RESULTS: There was a negative age trend of adiponectin blood levels and a positive trend of leptin levels in boys and girls. Percentiles derived for girls were generally higher than those obtained for boys. The corresponding age-specific differences of the 97th percentile ranged from -2.2 to 4.6 mu g ml(-1) and from 2.2 to 4.8 ng ml(-1) for adiponectin and leptin, respectively. CONCLUSIONS: According to our knowledge, these are the first reference values of leptin and adiponectin in prepubertal, normal-weight children. The presented adiponectin and leptin reference curves may allow for a more differentiated interpretation of children's hormone levels in epidemiological and clinical studies

Longitudinal associations of lifestyle factors and weight status with insulin resistance (HOMA-IR) in preadolescent children : the large prospective cohort study IDEFICS

Background: This study investigates prospective associations of anthropometrical and lifestyle indices with insulin resistance (IR) in European children from the IDEFICS cohort. Insulin resistance (IR) is a growing concern in childhood obesity and a central aspect of the metabolic syndrome (MS). It most likely represents the link between obesity and type 2 diabetes. Methods: This longitudinal study included 3348 preadolescent children aged 3 to 10.9 years from 8 European countries who were observed from 2007/2008 to 2009/2010. The main outcome measure in the present analysis is HOMA-IR (homeostasis model assessment as a common proxy indicator to quantify IR) at follow-up and in its longitudinal development. Anthropometrical measures and lifestyle indices, including objectively determined physical activity, were considered, among others factors, as determinants of IR. Prospective associations between IR at follow-up and anthropometrical and lifestyle indices were estimated by logistic regression models. Results: Country-specific prevalence rates of IR in the IDEFICS cohort of European children showed a positive trend with weight category. Prospective multivariate analyses showed the strongest positive associations of IR with BMI z-score (OR = 2.6 for unit change from the mean, 95 % CI 2.1-3.1) and z-score of waist circumference (OR = 2.2 for unit change from the mean, 95 % CI 1.9-2.6), which were analysed in separate models, but also for sex (OR = 2.2 for girls vs. boys, 95 % CI 1.5-3.1 up to OR 2.5, 95 % CI 1.8-3.6 depending on the model), audio-visual media time (OR = 1.2 for an additional hour per day, 95 % CI 1.0-1.4 in both models) and an inverse association of objectively determined physical activity (OR = 0.5 for 3rd compared to 1st quartile, 95 % CI 0.3-0.9 in both models). A longitudinal reduction of HOMA-IR was accompanied with a parallel decline in BMI. Conclusions: This study is, to our knowledge, the first prospective study on IR in a preadolescent children's population. It supports the common hypothesis that overweight and obesity are the main determinants of IR. Our data also indicate that physical inactivity and a sedentary lifestyle are likewise associated with the development of IR, independent of weight status. The promotion of physical activity should thus be considered as an equal option to dietary intervention for the treatment of IR in the paediatric practice

Children's propensity to consume sugar and fat predicts regular alcohol consumption in adolescence

Objective: The present study investigated the association between sugar and fat intake in childhood in relation to alcohol use in adolescence. We hypothesized that early exposure to diets high in fat and sugar may affect ingestive behaviours later in life, including alcohol use. Design/Setting/Subjects: Children from the European IDEFICS/I.Family cohort study were examined at ages 5-9 years and followed up at ages 11-16 years. FFQ were completed by parents on behalf of children, and later by adolescents themselves. Complete data were available in 2263 participants. Children's propensities to consume foods high in fat and sugar were calculated and dichotomized at median values. Adolescents' use of alcohol was classified as at least weekly v. less frequent use. Log-binomial regression linked sugar and fat consumption in childhood to risk of alcohol use in adolescence, adjusted for relevant covariates. Results: Five per cent of adolescents reported weekly alcohol consumption. Children with high propensity to consume sugar and fat were at greater risk of later alcohol use, compared with children with low fat and low sugar propensity (relative risk = 2.46; 95% CI 1.47, 4.12), independent of age, sex and survey country. The association was not explained by parental income and education, strict parenting style or child's health-related quality of life and was only partly mediated by sustained consumption of sugar and fat into adolescence. Conclusions: Frequent consumption of foods high in fat and sugar in childhood predicted regular use of alcohol in adolescence.Peer reviewe

A cross-sectional study of obesogenic behaviours and family rules according to family structure in European children

Background There has been an increase in children growing up in non-traditional families, such as single-parent and blended families. Children from such families have a higher prevalence of obesity and poorer health outcomes, but research on the relationship with obesogenic behaviours is limited. Objectives Therefore, the aim of this study was to investigate whether there are associations between family structures and obesogenic behaviours and related family rules in European children and adolescents. Methods The sample included 7664 children (mean age +/- SD: 10.9 +/- 2.9) from 4923 families who were participants of the multi-centre I.Family study (2013/2014) conducted in 8 European countries. Family structure was assessed by a detailed interview on kinship and household. Obesogenic behaviours (screen time, sleep duration, consumption of sugar-sweetened beverages (SSBs)) and family rules (rules for computer and television, bedtime routine, availability of SSBs during meals) were determined by standardized questionnaires. Multilevel mixed-effects linear and logistic regression models were used to model the associations of family structure with obesogenic behaviours and family rules. Sex, age, parental education level, number of children and adults in the household and BMI z-score were covariates in the models. Two-parent biological families were set as the reference category. Results Children from single-parent families were less likely to have family rules regarding screen time (OR: 0.62, 95% CI: 0.40-0.94, p = 0.026) with higher reported hours of screen time per week (beta = 2.70 h/week, 95% CI: 1.39-4.00, p <0.001). The frequency of weekly SSB consumption differed by family structure in a sex-specific manner: girls from single-parent (beta = 3.19 frequency/week, 95% CI: 0.91-5.47, p = 0.006) and boys from blended/adoptive families (beta = 3.01 frequency/week, 95% CI: 0.99-5.03, p = 0.004) consumed more SSBs. Sleep duration, bedtime routines and availability of SSBs during meals did not differ between children from these family structures. Parental education did not modify any of these associations. Conclusions Parents in non-traditional family structures appear to experience more difficulties in restricting screen time and the intake of SSBs in their children than parents in traditional two-parent family structures. Our findings therefore suggest that additional support and effective strategies for parents in non-traditional families may help to reduce obesogenic behaviours in children from such family types.Peer reviewe

Associations between sleep duration and insulin resistance in European children and adolescents considering the mediating role of abdominal obesity

Background Short sleep duration has been suggested to lead to insulin resistance both directly by altering glucose metabolism and indirectly through obesity. This study aims to investigate associations between nocturnal sleep duration and insulin resistance considering abdominal obesity as a mediator. Methods We analysed data of 3 900 children aged 2-15 years participating in the second (2009/10) and third (2013/14) examination wave of the European IDEFICS/I.Family study (hereafter referred to as baseline and follow-up). Information on nocturnal sleep duration was collected by questionnaires and age-standardised (SLEEP z-score). The homeostasis model assessment (HOMA) was calculated from fasting insulin and fasting glucose obtained from blood samples; waist circumference (WAIST) was measured with an inelastic tape. HOMA and WAIST were used as indicators for insulin resistance and abdominal obesity, respectively, and transformed to age- and sex-specific z-scores. Cross-sectional and longitudinal associations between SLEEP z-score and HOMA z-score were investigated based on a path model considering WAIST z-score as a mediator adjusting for relevant confounders. Results Cross-sectionally, baseline SLEEP z-score was negatively associated with baseline WAIST z-score (unstandardised effect estimate -0.120, 95% confidence interval [-0.167; -0.073]). We observed no direct effect of baseline SLEEP z-score on baseline HOMA z-score but a negative indirect effect through baseline WAIST z-score (-0.042 [-0.058; -0.025]). Longitudinally, there was no direct effect of baseline SLEEP z-score on HOMA z-score at follow-up but a negative indirect effect through both baseline WAIST z-score and WAIST z-score at follow-up (-0.028 [-0.040; -0.016]). Conclusions Our results do not support the hypothesis of an association between short sleep duration and insulin resistance independent of abdominal obesity. However, longer sleep duration may exert short and long term beneficial effects on insulin resistance through its beneficial effects on abdominal obesity

A cross-sectional study of obesogenic behaviours and family rules according to family structure in European children

Background There has been an increase in children growing up in non-traditional families, such as single-parent and blended families. Children from such families have a higher prevalence of obesity and poorer health outcomes, but research on the relationship with obesogenic behaviours is limited. Objectives Therefore, the aim of this study was to investigate whether there are associations between family structures and obesogenic behaviours and related family rules in European children and adolescents. Methods The sample included 7664 children (mean age +/- SD: 10.9 +/- 2.9) from 4923 families who were participants of the multi-centre I.Family study (2013/2014) conducted in 8 European countries. Family structure was assessed by a detailed interview on kinship and household. Obesogenic behaviours (screen time, sleep duration, consumption of sugar-sweetened beverages (SSBs)) and family rules (rules for computer and television, bedtime routine, availability of SSBs during meals) were determined by standardized questionnaires. Multilevel mixed-effects linear and logistic regression models were used to model the associations of family structure with obesogenic behaviours and family rules. Sex, age, parental education level, number of children and adults in the household and BMI z-score were covariates in the models. Two-parent biological families were set as the reference category. Results Children from single-parent families were less likely to have family rules regarding screen time (OR: 0.62, 95% CI: 0.40-0.94, p = 0.026) with higher reported hours of screen time per week (beta = 2.70 h/week, 95% CI: 1.39-4.00, p <0.001). The frequency of weekly SSB consumption differed by family structure in a sex-specific manner: girls from single-parent (beta = 3.19 frequency/week, 95% CI: 0.91-5.47, p = 0.006) and boys from blended/adoptive families (beta = 3.01 frequency/week, 95% CI: 0.99-5.03, p = 0.004) consumed more SSBs. Sleep duration, bedtime routines and availability of SSBs during meals did not differ between children from these family structures. Parental education did not modify any of these associations. Conclusions Parents in non-traditional family structures appear to experience more difficulties in restricting screen time and the intake of SSBs in their children than parents in traditional two-parent family structures. Our findings therefore suggest that additional support and effective strategies for parents in non-traditional families may help to reduce obesogenic behaviours in children from such family types.Peer reviewe