A proposed simplified definition of metabolic syndrome in children and adolescents: a global perspective.

Metabolic syndrome (MetS) is becoming prevalent in the pediatric population. The existing pediatric MetS definitions (e.g., the International Diabetes Federation (IDF) definition and the modified National Cholesterol Education Program (NCEP) definition) involve complex cut-offs, precluding fast risk assessment in clinical practice.We proposed a simplified definition for assessing MetS risk in youths aged 6-17 years, and compared its performance with two existing widely used pediatric definitions (the IDF definition, and the NCEP definition) in 10 pediatric populations from 9 countries globally (n = 19,426) using the receiver operating characteristic (ROC) curve analyses. In general, the total MetS prevalence of 6.2% based on the simplified definition was roughly halfway between that of 4.2% and 7.7% estimated from the IDF and NCEP definitions, respectively. The ROC curve analyses showed a good agreement between the simplified definition and two existing definitions: the total area under the curve (95% confidence interval) of the proposed simplified definition for identifying MetS risk achieved 0.91 (0.89-0.92) and 0.79 (0.78-0.81) when using the IDF or NCEP definition as the gold standard, respectively.The proposed simplified definition may be useful for pediatricians to quickly identify MetS risk and cardiometabolic risk factors (CMRFs) clustering in clinical practice, and allow direct comparison of pediatric MetS prevalence across different populations, facilitating consistent pediatric MetS risk monitoring and the development of evidence-based pediatric MetS prevention strategies globally.

Insulin resistance, C-reactive protein, diastolic to systolic blood pressure ratio and epicardial fat are related to sedentary time, and inversely related to physical activity in school-aged children.

Background: Physical activity (PA) is beneficial for the overall health. Objectives are: (1) To compare metabolic (MRM) and cardiovascular-risk-markers (CRM) in children according to their PA-level; (2) to explore the associations of MRM and CRM with PA and sedentary time (ST); and (3) to identify the associations between MRM and CRM in less (LA) and more active (MA) children. Methods: A total of 238 apparently healthy school-aged children were enrolled (132 boys/106 girls; 9.1 ± 1.8 years) and body mass index standard deviation score (BMI SDS) and blood pressure were assessed. Fasting venous blood sampling was performed to assess insulin resistance (HOMA-IR) and high-sensitivity-C-reactive protein (hsCRP). Epicardial fat, interventricular septal and left ventricular posterior wall thicknesses were assessed by high-resolution ultrasonography. PA and ST were assessed by enKid-questionnaire. Children were classified based on enKid-score as being LA and MA (below and above 50th percentile for PA). Results: MA-children had lower values for: BMI SDS, diastolic-to-systolic blood pressure ratio, HOMA-IR and hsCRP (7.02 to 61.5% lower, p = 0.040 to p < 0.0001) compared to LA-children. MRM and CRM were positively associated with ST (p = 0.003 to p < 0.001), and negatively associated with PA (p = 0.044 to p < 0.001). Finally, MRM were positively associated with CRM (p = 0.008 to p < 0.0001). Interestingly, the latter associations were observed in LA-children but were not present in MA-children. Conclusion: More PA is associated with better cardio-metabolic profile in school-aged children. PA seems to modulate the associations between MRM and CRM, thus reinforcing the idea that fostering PA in children may lower the risk for development of a cardio-metabolic disease.

Risk Factors for Thyroid Dysfunction in Pregnancy: An Individual Participant Data Meta-Analysis.

Background: International guidelines recommend targeted screening to identify gestational thyroid dysfunction. However, currently used risk factors have questionable discriminative ability. We quantified the risk for thyroid function test abnormalities for a subset of risk factors currently used in international guidelines. Methods: We included prospective cohort studies with data on gestational maternal thyroid function and potential risk factors (maternal age, body mass index [BMI], parity, smoking status, pregnancy through in vitro fertilization, twin pregnancy, gestational age, maternal education, and thyroid peroxidase antibody [TPOAb] or thyroglobulin antibody [TgAb] positivity). Exclusion criteria were pre-existing thyroid disease and use of thyroid interfering medication. We analyzed individual participant data using mixed-effects regression models. Primary outcomes were overt and subclinical hypothyroidism and a treatment indication (defined as overt hypothyroidism, subclinical hypothyroidism with thyrotropin >10 mU/L, or subclinical hypothyroidism with TPOAb positivity). Results: The study population comprised 65,559 participants in 25 cohorts. The screening rate in cohorts using risk factors currently recommended (age >30 years, parity ≥2, BMI ≥40) was 58%, with a detection rate for overt and subclinical hypothyroidism of 59%. The absolute risk for overt or subclinical hypothyroidism varied <2% over the full range of age and BMI and for any parity. Receiver operating characteristic curves, fitted using maternal age, BMI, smoking status, parity, and gestational age at blood sampling as explanatory variables, yielded areas under the curve ranging from 0.58 to 0.63 for the primary outcomes. TPOAbs/TgAbs positivity was associated with overt hypothyroidism (approximate risk for antibody negativity 0.1%, isolated TgAb positivity 2.4%, isolated TPOAb positivity 3.8%, combined antibody positivity 7.0%; p < 0.001), subclinical hypothyroidism (risk for antibody negativity 2.2%, isolated TgAb positivity 8.1%, isolated TPOAb positivity 14.2%, combined antibody positivity 20.0%; p < 0.001) and a treatment indication (risk for antibody negativity 0.2%, isolated TgAb positivity 2.2%, isolated TPOAb positivity 3.0%, and combined antibody positivity 5.1%; p < 0.001). Twin pregnancy was associated with a higher risk of overt hyperthyroidism (5.6% vs. 0.7%; p < 0.001). Conclusions: The risk factors assessed in this study had poor predictive ability for detecting thyroid function test abnormalities, questioning their clinical usability for targeted screening. As expected, TPOAb positivity (used as a benchmark) was a relevant risk factor for (subclinical) hypothyroidism. These results provide insights into different risk factors for gestational thyroid dysfunction.

Salivary cardiac-enriched FHL2-interacting protein is associated with higher diastolic-to-systolic-blood pressure ratio, sedentary time and center of pressure displacement in healthy 7-9 years old school-children.

Introduction: Cardiac-enriched FHL2-interacting protein (CEFIP) is a recently identified protein, first found in the z-disc of striated muscles, and related to cardiovascular diseases. Our objectives are: 1) to quantify CEFIP in saliva in healthy 7-9 years old school-children; and 2) to assess the associations of salivary CEFIP concentration and blood pressure, physical (in)activity and physical fitness in these children. Methods: A total of 72 children (7.6 ± 0.3 years) were included in the study, recruited in primary schools in Girona (Spain). A sandwich enzyme-linked immunosorbent assay was used (abx506878; Abbexa, United Kingdom) to quantify CEFIP in saliva. Anthropometric evaluation was performed [body mass, height and body mass index (BMI)]. Systolic and diastolic blood pressure were measured by means of an electronic oscillometer and the diastolic-to-systolic blood pressure ratio (D/S BP ratio) was calculated. Physical (in)activity [sedentary time and time spent in physical activity (PA)] were assessed by means of a triaxial Actigraph GT3X accelerometer (Actigraph, Pensacola, FL, USA) that children were instructed to wear for 24h during 7 conssecutive days. Finally, physical fitness (speed and agility, explosive power of legs, handgrip strength, flexibility and balance) were assessed through validated and standardized testing batteries. Results: CEFIP was easily detected and measured in all saliva samples (mean concentration: 0.6 ± 0.2 pg/ml). Salivary CEFIP was positively associated with D/S BP ratio (r=0.305, p=0.010) and sedentary time (r=0.317, p=0.012), but negatively associated with PA in 7-9 years old school-children (r=-0.350, p=0.002). Furthermore, salivary CEFIP was related to lower level of balance i.e., higher center of pressure (CoP) displacement in these children (r=0.411, p<0.001). The associations of salivary CEFIP with D/S BP ratio (Beta=0.349, p=0.004), sedentary time (Beta=0.354, p=0.009) and CoP displacement (Beta=0.401, p=0.001), were maintained significant after adjustment for potential confounding variables such as age, gender and BMI in linear regression analyses. Conclusion: CEFIP can be easily assessed in saliva as a promising biomarker associated with cardiovascular health in 7-9 years old school-children. Interestingly, higher salivary CEFIP concentration was related to higher D/S BP ratio, more sedentary time and higher CoP displacement i.e., lower level of balance in these children.

DNA Methylation Signatures in Paired Placenta and Umbilical Cord Samples: Relationship with Maternal Pregestational Body Mass Index and Offspring Metabolic Outcomes.

An epigenomic approach was used to study the impact of maternal pregestational body mass index (BMI) on the placenta and umbilical cord methylomes and their potential effect on the offspring's metabolic phenotype. DNA methylome was assessed in 24 paired placenta and umbilical cord samples. The differentially methylated CpGs associated with maternal pregestational BMI were identified and the metabolic pathways and the potentially related diseases affected by their annotated genes were determined. Two top differentially methylated CpGs were studied in 90 additional samples and the relationship with the offspring's metabolic phenotype was determined. The results showed that maternal pregestational BMI is associated with the methylation of genes involved in endocrine and developmental pathways with potential effects on type 2 diabetes and obesity. The methylation and expression of HADHA and SLC2A8 genes in placenta and umbilical cord were related to several metabolic parameters in the offspring at 6 years (weight SDS, height SDS, BMI SDS, Δ BW-BMI SDS, FM SDS, waist, SBP, TG, HOMA-IR, perirenal fat; all p < 0.05). Our data suggest that epigenetic analysis in placenta and umbilical cord may be useful for identifying individual vulnerability to later metabolic diseases.

Gestational Caloric Restriction Alters Adipose Tissue Methylome and Offspring's Metabolic Profile in a Swine Model.

Limited nutrient supply to the fetus results in physiologic and metabolic adaptations that have unfavorable consequences in the offspring. In a swine animal model, we aimed to study the effects of gestational caloric restriction and early postnatal metformin administration on offspring's adipose tissue epigenetics and their association with morphometric and metabolic variables. Sows were either underfed (30% restriction of total food) or kept under standard diet during gestation, and piglets were randomly assigned at birth to receive metformin (n = 16 per group) or vehicle treatment (n = 16 per group) throughout lactation. DNA methylation and gene expression were assessed in the retroperitoneal adipose tissue of piglets at weaning. Results showed that gestational caloric restriction had a negative effect on the metabolic profile of the piglets, increased the expression of inflammatory markers in the adipose tissue, and changed the methylation of several genes related to metabolism. Metformin treatment resulted in positive changes in the adipocyte morphology and regulated the methylation of several genes related to atherosclerosis, insulin, and fatty acids signaling pathways. The methylation and gene expression of the differentially methylated FASN, SLC5A10, COL5A1, and PRKCZ genes in adipose tissue associated with the metabolic profile in the piglets born to underfed sows. In conclusion, our swine model showed that caloric restriction during pregnancy was associated with impaired inflammatory and DNA methylation markers in the offspring's adipose tissue that could predispose the offspring to later metabolic abnormalities. Early metformin administration could modulate the size of adipocytes and the DNA methylation changes.

Physical Exercise-Induced DNA Methylation in Disease-Related Genes in Healthy Adults-A Systematic Review With Bioinformatic Analysis.

ABSTRACT: Vasileva, F, Hristovski, R, Font-Lladó, R, Georgiev, G, Sacot, A, López-Ros, V, Calleja-González, J, Barretina-Ginesta, J, López-Bermejo, A, and Prats-Puig, A. Physical exercise-induced DNA methylation in disease-related genes in healthy adults-A systematic review with bioinformatic analysis. J Strength Cond Res 38(2): 384-393, 2024-This study aimed to systematically review the existing literature regarding physical exercise (PE) and DNA methylation (DNAm) in healthy adults. Specific goals were to (a) identify differently methylated genes (DMGs) after PE intervention, their imprinting status, chromosome and genomic location, function, and related diseases; and (b) to screen for core genes and identify methylation changes of the core genes that can be modified by PE intervention. Our search identified 2,869 articles from which 8 were finally included. We identified 1851 DMGs ( p < 0.05) after PE intervention, although 45 of them were imprinted. Aerobic exercise (AE) seems to induce more DNA hypermethylation rather than hypomethylation, whereas anaerobic exercise (AN) seems to induce more DNA hypomethylation rather than hypermethylation. Aerobic exercise induced highest % of methylation changes on chromosome 6, whereas AN and mixed type (MT) on chromosome 1. Mixed type induced higher % of methylation changes close to transcription start site in comparison to AE and AN. After PE intervention, DMGs were mainly involved in fat metabolism, cell growth, and neuronal differentiation, whereas diseases regulated by those genes were mainly chronic diseases (metabolic, cardiovascular, neurodegenerative). Finally, 19 core genes were identified among DMGs, all related to protein metabolism. In conclusion, our findings may shed some light on the mechanisms explaining PE-induced health benefits such as the potential role that PE-induced DNAm may have in disease prevention and disease treatment.

TSH and FT4 Reference Interval Recommendations and Prevalence of Gestational Thyroid Dysfunction: Quantification of Current Diagnostic Approaches.

CONTEXT: Guidelines recommend use of population- and trimester-specific thyroid-stimulating hormone (TSH) and free thyroxine (FT4) reference intervals (RIs) in pregnancy. Since these are often unavailable, clinicians frequently rely on alternative diagnostic strategies. We sought to quantify the diagnostic consequences of current recommendations. METHODS: We included cohorts participating in the Consortium on Thyroid and Pregnancy. Different approaches were used to define RIs: a TSH fixed upper limit of 4.0 mU/L (fixed limit approach), a fixed subtraction from the upper limit for TSH of 0.5 mU/L (subtraction approach) and using nonpregnancy RIs. Outcome measures were sensitivity and false discovery rate (FDR) of women for whom levothyroxine treatment was indicated and those for whom treatment would be considered according to international guidelines. RESULTS: The study population comprised 52 496 participants from 18 cohorts. Compared with the use of trimester-specific RIs, alternative approaches had a low sensitivity (0.63-0.82) and high FDR (0.11-0.35) to detect women with a treatment indication or consideration. Sensitivity and FDR to detect a treatment indication in the first trimester were similar between the fixed limit, subtraction, and nonpregnancy approach (0.77-0.11 vs 0.74-0.16 vs 0.60-0.11). The diagnostic performance to detect overt hypothyroidism, isolated hypothyroxinemia, and (sub)clinical hyperthyroidism mainly varied between FT4 RI approaches, while the diagnostic performance to detect subclinical hypothyroidism varied between the applied TSH RI approaches. CONCLUSION: Alternative approaches to define RIs for TSH and FT4 in pregnancy result in considerable overdiagnosis and underdiagnosis compared with population- and trimester-specific RIs. Additional strategies need to be explored to optimize identification of thyroid dysfunction during pregnancy.

Association of Gestational Free and Total Triiodothyronine With Gestational Hypertension, Preeclampsia, Preterm Birth, and Birth Weight: An Individual Participant Data Meta-analysis.

CONTEXT: Triiodothyronine (T3) is the bioactive form of thyroid hormone. In contrast to thyroid-stimulating hormone and free thyroxine, we lack knowledge on the association of gestational T3 with adverse obstetric outcomes. OBJECTIVE: To investigate the associaiton of gestational free or total T3 (FT3 or TT3) with adverse obstetric outcomes. METHODS: We collected individual participant data from prospective cohort studies on gestational FT3 or TT3, adverse obstetric outcomes (preeclampsia, gestational hypertension, preterm birth and very preterm birth, small for gestational age [SGA], and large for gestational age [LGA]), and potential confounders. We used mixed-effects regression models adjusting for potential confounders. RESULTS: The final study population comprised 33 118 mother-child pairs of which 27 331 had data on FT3 and 16 164 on TT3. There was a U-shaped association of FT3 with preeclampsia (P = .0069) and a J-shaped association with the risk of gestational hypertension (P = .029). Higher TT3 was associated with a higher risk of gestational hypertension (OR per SD of TT3 1.20, 95% CI 1.08 to 1.33; P = .0007). A lower TT3 but not FT3 was associated with a higher risk of very preterm birth (OR 0.72, 95% CI 0.55 to 0.94; P = .018). TT3 but not FT3 was positively associated with birth weight (mean difference per 1 SD increase in TT3 12.8, 95% CI 6.5 to 19.1 g, P < .0001) but there was no association with SGA or LGA. CONCLUSION: This study provides new insights on the association of gestational FT3 and TT3 with major adverse pregnancy outcomes that form the basis for future studies required to elucidate the effects of thyroid function on pregnancy outcomes. Based on the current study, routine FT3 or TT3 measurements for the assessment of thyroid function during pregnancy do not seem to be of added value in the risk assessment for adverse outcomes.

Total bilirubin and bilirubin-to-triglycerides ratio predict changes in glycated hemoglobin in healthy children.

Objective: Bilirubin and triglycerides can regulate insulin secretion and glucose uptake. The aim of our study is to analyze associations between total bilirubin (TB) and the bilirubin-to-triglycerides ratio (BTR) with metabolic markers in healthy prepubertal children. Methods: Subjects were 246 healthy children (mean age 8), of whom 142 (58%) were reevaluated 4 years later (mean age 12). The subjects were stratified according to age into three groups (<7.8 years; 7.8-9.6 years; and >9.6 years; n=82 each) at baseline and into two groups (<12.9 years and ≥12.9 years; n=71 each) at follow-up. Anthropometrics and laboratory parameters [TB and its fractions (direct and indirect bilirubin), triglycerides, HDL-cholesterol, glucose, insulin, HOMA-IR, HOMA-B and glycated hemoglobin (HbA1c)] were assessed at both baseline and follow-up. Results: TB and BTR showed independent and negative association with baseline and follow-up HbA1c. These associations were stronger for BTR and in the highest age group. No independent associations were observed with HOMA-IR or HOMA-B. Conclusion: TB and BTR are independently associated with HbA1c and predict its changes over time in healthy children. Our results indicate that TB and BTR may be useful parameters in studies of glucose tolerance in healthy children.

Circulating exosomes decrease in size and increase in number between birth and age 7: relations to fetal growth and liver fat.

Purpose: Exosomes play a key role in cell-to-cell communication by transferring their cargo to target tissues. Little is known on the course of exosome size and number in infants and children. Methods: Longitudinally, we assessed the size and number of circulating exosomes at birth and at ages 2 and 7 yr in 75 infants/children born appropriate-for-gestational-age (AGA; n=40) or small-for-gestational-age (SGA; n=35 with spontaneous catch-up), and related those results to concomitantly assessed measures of endocrine-metabolic health (HOMA-IR; IGF-1), body composition (by DXA at ages 0 and 2) and abdominal fat partitioning (subcutaneous, visceral and hepatic fat by MRI at age 7). Results: Circulating exosomes of AGAs decreased in size (on average by 4.2%) and increased in number (on average by 77%) between birth and age 7. Circulating exosomes of SGAs (as compared to those of AGAs) had a larger size at birth [146.8 vs 137.8 nm, respectively; p=0.02], and were in lower number at ages 2 [4.3x1011 vs 5.6x1011 particles/mL, respectively; p=0.01] and 7 [6.3x1011 vs 6.8x1011 particles/mL, respectively; p=0.006]. Longitudinal changes were thus more pronounced in SGAs for exosome size, and in AGAs for exosome number. At age 7, exosome size associated (P<0.0001) to liver fat in the whole study population. Conclusion: Early-life changes in circulating exosomes include a minor decrease in size and a major increase in number, and these changes may be influenced by fetal growth. Exosome size may become one of the first circulating markers of liver fat in childhood.

Establishing international optimal cut-offs of waist-to-height ratio for predicting cardiometabolic risk in children and adolescents aged 6-18 years.

BACKGROUND: Waist-to-height ratio (WHtR) has been proposed as a simple and effective screening tool for assessing central obesity and cardiometabolic risk in both adult and pediatric populations. However, evidence suggests that the use of a uniform WHtR cut-off of 0.50 may not be universally optimal for pediatric populations globally. We aimed to determine the optimal cut-offs of WHtR in children and adolescents with increased cardiometabolic risk across different countries worldwide. METHODS: We used ten population-based cross-sectional data on 24,605 children and adolescents aged 6-18 years from Brazil, China, Greece, Iran, Italy, Korea, South Africa, Spain, the UK, and the USA for establishing optimal WHtR cut-offs. We performed an external independent test (9,619 children and adolescents aged 6-18 years who came from other six countries) to validate the optimal WHtR cut-offs based on the predicting performance for at least two or three cardiometabolic risk factors. RESULTS: Based on receiver operator characteristic curve analyses of various WHtR cut-offs to discriminate those with ≥ 2 cardiometabolic risk factors, the relatively optimal percentile cut-offs of WHtR in the normal weight subsample population in each country did not always coincide with a single fixed percentile, but varied from the 75th to 95th percentiles across the ten countries. However, these relatively optimal percentile values tended to cluster irrespective of sex, metabolic syndrome (MetS) criteria used, and WC measurement position. In general, using ≥ 2 cardiometabolic risk factors as the predictive outcome, the relatively optimal WHtR cut-off was around 0.50 in European and the US youths but was lower, around 0.46, in Asian, African, and South American youths. Secondary analyses that directly tested WHtR values ranging from 0.42 to 0.56 at 0.01 increments largely confirmed the results of the main analyses. In addition, the proposed cut-offs of 0.50 and 0.46 for two specific pediatric populations, respectively, showed a good performance in predicting ≥ 2 or ≥ 3 cardiometabolic risk factors in external independent test populations from six countries (Brazil, China, Germany, Italy, Korea, and the USA). CONCLUSIONS: The proposed international WHtR cut-offs are easy and useful to identify central obesity and cardiometabolic risk in children and adolescents globally, thus allowing international comparison across populations.

SPIOMET4HEALTH-efficacy, tolerability and safety of lifestyle intervention plus a fixed dose combination of spironolactone, pioglitazone and metformin (SPIOMET) for adolescent girls and young women with polycystic ovary syndrome: study protocol for a multicentre, randomised, double-blind, placebo-controlled, four-arm, parallel-group, phase II clinical trial.

BACKGROUND: Polycystic ovary syndrome (PCOS) is the most prevalent, chronic endocrine-metabolic disorder of adolescents and young women (AYAs), affecting 5-10% of AYAs worldwide. There is no approved pharmacological therapy for PCOS. Standard off-label treatment with oral contraceptives (OCs) reverts neither the underlying pathophysiology nor the associated co-morbidities. Pilot studies have generated new insights into the pathogenesis of PCOS, leading to the development of a new treatment consisting of a fixed, low-dose combination of two so-called insulin sensitisers [pioglitazone (PIO), metformin (MET)] and one mixed anti-androgen and anti-mineralocorticoid also acting as an activator of brown adipose tissue [spironolactone (SPI)], within a single tablet (SPIOMET). The present trial will evaluate the efficacy, tolerability and safety of SPIOMET, on top of lifestyle measures, for the treatment of PCOS in AYAs. METHODS: In this multicentre, randomised, double-blind, placebo-controlled, four-arm, parallel-group, phase II clinical trial, AYAs with PCOS will be recruited from 7 clinical centres across Europe. Intention is to randomise a total of 364 eligible patients into four arms (1:1:1:1): Placebo, PIO, SPI + PIO (SPIO) and SPI + PIO + MET (SPIOMET). Active treatment over 12 months will consist of lifestyle guidance plus the ingestion of one tablet daily (at dinner time); post-treatment follow-up will span 6 months. Primary endpoint is on- and post-treatment ovulation rate. Secondary endpoints are clinical features (hirsutism, menstrual regularity); endocrine-metabolic variables (androgens, lipids, insulin, inflammatory markers); epigenetic markers; imaging data (carotid intima-media thickness, body composition, abdominal fat partitioning, hepatic fat); safety profile; adherence, tolerability and acceptability of the medication; and quality of life in the study participants. Superiority (in this order) of SPIOMET, SPIO and PIO will be tested over placebo, and if present, subsequently the superiority of SPIOMET versus PIO, and if still present, finally versus SPIO. DISCUSSION: The present study will be the first to evaluate-in a randomised, double-blind, placebo-controlled way-the efficacy, tolerability and safety of SPIOMET treatment for early PCOS, on top of a lifestyle intervention. TRIAL REGISTRATION: EudraCT 2021-003177-58. Registered on 22 December 2021. https://www.clinicaltrialsregister.eu/ctr-search/search?query=%092021-003177-58 .

Gestational Weight Gain Relates to DNA Methylation in Umbilical Cord, Which, In Turn, Associates with Offspring Obesity-Related Parameters.

Excessive gestational weight gain (GWG) has a negative impact on offspring's health. Epigenetic modifications mediate these associations by causing changes in gene expression. We studied the association between GWG and DNA methylation in umbilical cord tissue; and determined whether the DNA methylation and the expression of corresponding annotated genes were associated with obesity-related parameters in offspring at 6 years of age. The methylated CpG sites (CpGs) associated with GWG were identified in umbilical cord tissue by genome-wide DNA methylation (n = 24). Twelve top CpGs were validated in a wider sample by pyrosequencing (n = 87), and the expression of their 5 annotated genes (SETD8, TMEM214, SLIT3, RPTOR, and HOXC8) was assessed by RT-PCR. Pyrosequencing results validated the association of SETD8, SLIT3, and RPTOR methylation with GWG and showed that higher levels of SETD8 and RPTOR methylation and lower levels of SLIT3 methylation relate to a higher risk of obesity in the offspring. The association of SETD8 and SLIT3 gene expression with offspring outcomes paralleled the association of methylation levels in opposite directions. Epigenetic changes in the umbilical cord tissue could explain, in part, the relationship between GWG and offspring obesity risk and be early biomarkers for the prevention of overweight and obesity in childhood.

Higher levels of serum α-Klotho are longitudinally associated with less central obesity in girls experiencing weight gain.

Introduction: Klotho is an anti-aging protein that reduces adiposity and increases caloric expenditure, among others. Although associations between secreted α-Klotho levels and obesity have been described, its relationship with central obesity and visceral fat accumulation during childhood is poorly understood. Our objective was to study the longitudinal associations between serum α-Klotho concentrations and obesity-related parameters in apparently healthy children. Subjects and methods: We studied a cohort of 208 apparently healthy school-age children (107 girls and 101 boys) assessed at baseline (mean age 8.5 ± 1.8 years) and at follow-up 4 years later. Serum α-Klotho concentrations were measured at baseline in all subjects. Obesity-related parameters, such as BMI, waist circumference, body fat, visceral fat, triglyceride levels, HOMA-IR index, and C-reactive protein were studied. Boys and girls were classified into 3 groups according to weight change between baseline and follow-up visits: weight loss, stable weight, or weight gain (based on a BMI-SDS change cut-off > 0.35 SD). Results: In girls (N=107), but not in boys, we observed negative associations of serum α-Klotho protein with BMI, waist circumference, body fat, visceral fat, HOMA IR index, and C-reactive protein at baseline and also at follow-up. The associations of α-Klotho and obesity-related parameters were more evident in girls who exhibited weight gain. In such girls, multivariate regression analyses (adjusting for age, puberty and baseline weight/height ratio) showed that α-Klotho protein was negatively associated with follow-up BMI, waist circumference, and visceral fat (p = 0.003 to 0.028). For each 1 SD-increase in baseline α-Klotho, follow-up waist circumference decreased by 4.15 cm and visceral fat by 1.38 mm. Conclusions: In school-age girls, serum α-Klotho concentrations are longitudinally related to a more favorable metabolic profile. In girls experiencing weight gain, α-Klotho may prove to be a protective factor against the accumulation of visceral fat.

Circulating free T3 associates longitudinally with cardio-metabolic risk factors in euthyroid children with higher TSH.

Introduction: Thyroid hormones play major roles in the regulation of body composition and metabolism, and therefore, the relationship between thyroid hormones and cardio-metabolic risk has been extensively studied in adults. In this study, we aimed to test whether free triiodothyronine (fT3) associates longitudinally with cardio-metabolic risk factors in euthyroid children. Methods: A prospective study cohort of 599 apparently healthy school-age children were assessed at baseline (mean age 8.1 ± 2.1 years), of whom 270 children were also assessed at follow-up (4 years later). Circulating thyroid-stimulating hormone (TSH), free thyroxine (fT4), and fT3 were measured, and cardio-metabolic risk was assessed by means of body mass index (BMI), waist circumference, visceral fat (by ultrasound), blood pressure, circulating lipids, and homeostasis model assessment of insulin resistance (HOMA-IR) index, both at baseline and at follow-up. Results: All studied children had normal thyroid function tests. Independent associations between baseline fT3 and both baseline and follow-up BMI, systolic blood pressure, mean arterial blood pressure, triglycerides, and HOMA-IR were found using multivariate regression analysis (adjusting for sex and baseline age and BMI). Analyses of effect sizes showed that for each 1 unit-increase in baseline fT3 (pg/ml), follow-up BMI-standard deviation score (SDS) increased by 0.31 units (z-score) and systolic blood pressure by 6.6 units (mmHg). The observed longitudinal associations were more robust in children belonging to the upper TSH tertile who showed higher TSH levels and were characterized by weighing more and having the highest fT3 levels. In these children, for each 1 unit-increase in baseline fT3 (pg/ml), follow-up BMI-SDS increased by 0.67 units (z-score) and systolic blood pressure by 10.2 units (mmHg). Conclusions: Circulating fT3 associates longitudinally with cardio-metabolic risk factors in euthyroid children with higher TSH. The observed associations of thyroid hormones in these children could conceivably respond to a homeostatic attempt to reduce their cardio-metabolic risk.

Iron status and cardiometabolic risk in children.

AIM: We aimed to evaluate associations between serum ferritin and transferrin and variables related to the metabolic syndrome (MetS) in children. METHODS: Cross-sectional and longitudinal study in prepubertal children (n = 832) aged 3-14 years. A subset (n = 203) were re-examined after a mean follow-up of 3.7 ± 0.8 years[range 2-6]. Outcomes were MetS and MetS components scores, glycosylated haemoglobin (HbA1c), and their follow-up change. RESULTS: Children with low ferritin had increased HbA1c Z scores (ANCOVA, P = 0.003). Ferritin was inversely associated with glycaemia [fully adjusted ß (95% confidence interval): -2.35(-4.36 to -0.34)]. Transferrin was associated with diastolic blood pressure [ß: 0.02(0.01-0.04)] and log-HOMA-IR [ß:0.001(0.0005-0.002)]. MetS risk score worsened during follow-up in children with the lowest baseline ferritin levels. In contrast, at baseline ferritin was positively associated with all (except glycaemia) the MetS-related variables but adjustments for inflammatory, hepatic function, and body mass markers attenuated those associations (P > 0.05). CONCLUSIONS: Lower iron status was independently associated with glycaemic markers and MetS in children, whereas higher ferritin levels were related to other cardiometabolic risk markers under the influence of inflammation, hepatic injury and body mass. Research is required to study whether this mixed pattern is part of an early risk or would be explained by a normal transition during growth and development.

Placental AA/EPA Ratio Is Associated with Obesity Risk Parameters in the Offspring at 6 Years of Age.

During pregnancy, maternal polyunsaturated fatty acids (PUFA) are transferred to the fetus through the placenta by specific FA transporters (FATP). A higher perinatal exposure to n-6 over n-3 PUFA could be linked to excess fat mass and obesity development later in life. In this context, we aimed to assess the associations between long chain PUFAs (LC-PUFAs) (n-6, n-3, and n-6/n-3 ratios) measured in the placenta at term birth with obesity-related parameters in the offspring at 6 years of age and assess whether these associations are dependent on the placental relative expression of fatty acid transporters. As results, the PUFAn-6/PUFAn-3 ratio was 4/1, which scaled up to 15/1 when considering only the arachidonic acid/eicosapentaenoic acid ratio (AA/EPA ratio). Positive associations between the AA/EPA ratio and offspring's obesity risk parameters were found with weight-SDS, BMI-SDS, percent fat mass-SDS, visceral fat, and HOMA-IR (r from 0.204 to 0.375; all p < 0.05). These associations were more noticeable in those subjects with higher expression of fatty acid transporters. Therefore, in conclusion, a higher placental AA/EPA ratio is positively associated with offspring's visceral adiposity and obesity risk parameters, which become more apparent in subjects with higher expressions of placental FATPs. Our results support the potential role of n-6 and n-3 LC-PUFA in the fetal programming of obesity risk in childhood. For the present study, 113 healthy pregnant women were recruited during the first trimester of pregnancy and their offspring were followed up at 6 years of age. The fatty acid profiles and the expression of fatty acid transporters (FATP1 and FATP4) were analyzed from placental samples at birth. Associations between LC-PUFA (n-6, n-3, and n-6/n-3 ratios) and obesity risk parameters (weight, body mass index (BMI), percent fat mass, visceral fat, and homeostatic model assessment of insulin resistance (HOMA-IR)) in the offspring at 6 years of age were examined.