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.

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.

Body surface area-based kidney length percentiles misdiagnose small kidneys in children with overweight/obesity.

BACKGROUND: We evaluated the diagnostic performance of height-, age- and body surface area (BSA)-based kidney length (KL) percentiles in the identification of at least one small kidney (KL < 3rd) and in the prediction of reduced estimated glomerular filtration rate (eGFR) and/or elevated blood pressure (BP) in children with and without overweight (OW)/obesity(OB). METHODS: In this cross-sectional study, 744 apparently healthy children (mean age 8.3 years) were recruited in a primary care setting. Clinical data were collected, and serum creatinine and KL were measured. Height-, age- and BSA-based percentiles of KL were calculated and the association of at least one small kidney per subject with reduced eGFR and/or elevated BP was explored by logistic regression. RESULTS: Two hundred fifty-seven out of seven hundred forty-four (34.5%) subjects were OW/OB and 127 (17.1%) had reduced eGFR or elevated BP. In separate analyses in children with OW/OB, the KL percentiles calculated on the basis of BSA were lower compared with height- and age-based KL percentiles. Consequently, the prevalence of a small kidney was significantly higher when evaluating percentiles of KL based on BSA compared with other percentiles. In logistic regression analysis, a small kidney was significantly associated with reduced eGFR and/or elevated BP only when using height-based KL percentiles. The KL percentiles according to BSA for the ideal weight (iBSA) showed similar performance compared with height-based percentiles. No differences in the diagnostic performance of different percentiles were found in children with normal weight. CONCLUSIONS: BSA-based percentiles underestimate KL in children with OW/OB. In these subjects, the use of height-based or iBSA-based percentiles should be preferred. A higher resolution version of the Graphical abstract is available as Supplementary information.

A 24-month metformin treatment study of children with obesity: Changes in circulating GDF-15 and associations with changes in body weight and visceral fat.

BACKGROUND: Metformin treatment for 24 months in children with obesity lowers body mass index (BMI), reduces liver fat, and normalizes endocrine-metabolic parameters. OBJECTIVE: Here we study whether circulating GDF-15 levels were raised by such metformin treatment and whether they related to changes in body weight and visceral fat in children with obesity. METHODS: The study population consisted of 18 pre-pubertal/early pubertal children with obesity who had participated in a randomized double-blind clinical trial receiving metformin (850 mg/day) or placebo for 24 months. Circulating GDF-15, BMI and abdominal visceral and liver fat (magnetic resonance imaging) were assessed at 0, 6, 12 and 24 months. RESULTS: Results showed that metformin-treated children had higher GDF-15 levels at 6 and 12 months. Higher rises of circulating GDF-15 associated with more loss of body weight and visceral fat. CONCLUSION: In conclusion, the concept that GDF-15 is among the mediators of metformin's normalizing effects in individuals with obesity is herewith extended into childhood.

Estimated glomerular filtration rate and cardiometabolic risk factors in a longitudinal cohort of children.

Associations between glomerular filtration rate (GFR) and cardiometabolic risk factors have been reported in adult and pediatric patients with renal disease. We aimed to assess the relationship between the estimated GFR (eGFR) and cardiometabolic risk factors in apparently healthy children. A longitudinal study in 401 asymptomatic Caucasian children (mean age 8 years) followed up after 4 years (mean age 12 years). GFR was estimated using the pediatric form of the FAS-equation. Children were classified at baseline according to their obesity status (normal weight and overweight) and according to eGFR levels (lower, average, and higher). The association of eGFR with anthropometric data [body mass index (BMI) and waist], blood pressure [systolic (SBP) and diastolic (DBP)], metabolic parameters [glucose, insulin resistance (HOMA-IR) and serum lipids], and renal ultrasonography measurements were assessed at baseline and follow-up. Baseline eGFR associated with several cardiometabolic risk factors at follow-up including higher waist, SBP, HOMA-IR, and kidney size (all p < 0.0001) in both normal weight and overweight children. In multivariate analysis, baseline eGFR was independently associated with follow-up HOMA-IR and SBP in both normal weight and overweight subjects (model R2: 0.188-0.444), and with follow-up BMI and waist in overweight subjects (model R2: 0.367-0.477). Moreover, children with higher filtration rates at baseline showed higher waist, SBP, DBP, HOMA-IR and renal size both at baseline and follow-up. eGFR is related to insulin resistance, blood pressure and adiposity measures in school-age children. eGFR may help to profile the cardiometabolic risk of children.

Effects of metformin administration on endocrine-metabolic parameters, visceral adiposity and cardiovascular risk factors in children with obesity and risk markers for metabolic syndrome: A pilot study.

BACKGROUND: Metformin treatment (1000-2000 mg/day) over 6 months in pubertal children and/or adolescents with obesity and hyperinsulinism is associated with a reduction in body mass index (BMI) and the insulin resistance index (HOMA-IR). We aimed to ascertain if long-term treatment (24 months) with lower doses of metformin (850 mg/day) normalizes the endocrine-metabolic abnormalities, improves body composition, and reduces the carotid intima-media thickness (cIMT) in pre-puberal and early pubertal children with obesity. METHODS: A pilot double-blind, placebo-controlled trial was conducted on 18 pre-puberal and early pubertal (Tanner stage I-II) children with obesity and risk markers for metabolic syndrome. Patients were randomly assigned (1:1) to receive metformin (850 mg/day) or placebo for 24 months. Clinical, biochemical (insulin, lipids, leptin, and high-sensitivity C-reactive protein [hsCRP]), and imaging (body composition [dual-energy X-ray absorptiometry and magnetic resonance imaging]) parameters as well as cIMT (ultrasonography) were assessed at baseline and at 6, 12, and 24 months. RESULTS: The 12-month treatment tend to cause a reduction in weight standard deviation scores (SDS), BMI-SDS, leptin, leptin-to-high-molecular-weight (HMW) adiponectin ratio, hsCRP, cIMT, fat mass, and liver fat in metformin-treated children compared with placebo. The effect of metformin on the reduction of BMI-SDS, leptin, leptin-to-HMW adiponectin ratio, hsCRP, and liver fat seemed to be maintained after completing the 24 months of treatment. No changes in insulin sensitivity (HOMA-IR) or adverse effects were detected. CONCLUSION: In this pilot study, metformin treatment in pre-puberal and early pubertal children with obesity seemed to improve body composition and inflammation markers. Our data encourage the development of future fully powered trials using 850 mg/day metformin in young children, highlighting its excellent tolerance and potential long-term benefits.

Umbilical Cord miRNAs in Small-for-Gestational-Age Children and Association With Catch-Up Growth: A Pilot Study.

CONTEXT: Catch-up growth in infants who are small for gestational age (SGA) is a risk factor for the development of cardiometabolic diseases in adulthood. The basis and mechanisms underpinning catch-up growth in newborns who are SGA are unknown. OBJECTIVE: To identify umbilical cord miRNAs associated with catch-up growth in infants who are SGA and study their relationship with offspring's cardiometabolic parameters. DESIGN: miRNA PCR panels were used to study the miRNA profile in umbilical cord tissue of five infants who were SGA with catch-up (SGA-CU), five without catch-up (SGA-nonCU), and five control infants [appropriate for gestational age (AGA)]. The miRNAs with the smallest nominal P values were validated in 64 infants (22 AGA, 18 SGA-nonCU, and 24 SGA-CU) and correlated with anthropometric parameters at 1 (n = 64) and 6 years of age (n = 30). RESULTS: miR-501-3p, miR-576-5p, miR-770-5p, and miR-876-3p had nominally significant associations with increased weight, height, weight catch-up, and height catch-up at 1 year, and miR-374b-3p, miR-548c-5p, and miR-576-5p had nominally significant associations with increased weight, height, waist, hip, and renal fat at 6 years. Multivariate analysis suggested miR-576-5p as a predictor of weight catch-up and height catch-up at 1 year, as well as weight, waist, and renal fat at 6 years. In silico studies suggested that miR-576-5p participates in the regulation of inflammatory, growth, and proliferation signaling pathways. CONCLUSIONS: Umbilical cord miRNAs could be novel biomarkers for the early identification of catch-up growth in infants who are SGA. miR-576-5p may contribute to the regulation of postnatal growth and influence the risk for cardiometabolic diseases associated with a mismatch between prenatal and postnatal weight gain.

Renal size and cardiovascular risk in prepubertal children.

Renal size is an important parameter for the evaluation and diagnosis of kidney disease and has been associated with several cardiovascular risk factors in patients with kidney failure. These results are however discordant and studies in healthy children are lacking. We aimed to study the association between renal size (length and volume) and cardiovascular risk parameters in healthy children. Clinical, analytical and ultrasound parameters [renal length, renal volume, perirenal fat and carotid intima-media thickness (cIMT)] were determined in 515 healthy prepubertal children (176 lean, 208 overweight and 131 obese). Renal length and volume associated significantly and positively with several anthropometric and cardiovascular risk parameters including cIMT and systolic blood pressure (SBP) (all p < 0.001). Renal length and volume associated with cIMT and SBP in all study subgroups, but these associations were predominant in obese children, in whom these associations were independent after adjusting for age, gender and BSA (all p < 0.05). In multivariate analyses in the study subjects as a whole, renal length was an independent predictor of cIMT (ß = 0.310, p < 0.0001) and SBP (ß = 0.116, p = 0.03). Renal size associates with cIMT and SBP, independent of other well-established cardiovascular risk factors, and may represent helpful parameters for the early assessment of cardiovascular risk in children.

Perirenal and epicardial fat and their association with carotid intima-media thickness in children.

Recent data suggest that subclinical atherosclerosis is more related to visceral adipose tissue distribution than to overall fat mass. Both perirenal fat and epicardial fat are visceral fat depots surrounding the kidneys and the myocardium, respectively, which can be easily assessed by ultrasound. Their clinical relevance in children is largely unknown. This review describes studies relating perirenal and epicardial fat to cardiovascular disease or carotid intima-media thickness (cIMT), a well-established surrogate for subclinical atherosclerosis, and discusses this in context with our own data from children. In adults, both perirenal and epicardial fat are useful biological markers of visceral obesity. The former has been related to hypertension in overweight subjects and with atherosclerosis in patients with human immunodeficiency virus. The latter was associated with several metabolic syndrome components and with calcification of the carotid artery. In healthy prepubertal children, both epicardial and perirenal fat thickness, rather than total body fat mass, were related to cIMT. Ultrasonography measures of perirenal and epicardial fat are related to atherosclerosis in adults and may be convenient tools for the assessment of cardiometabolic risk in children.

Dysregulation of Placental miRNA in Maternal Obesity Is Associated With Pre- and Postnatal Growth.

Context: Human placenta exhibits a specific microRNA (miRNA) expression pattern. Some of these miRNAs are dysregulated in pregnancy disorders such as preeclampsia and intrauterine growth restriction and are potential biomarkers for these pathologies. Objective: To study the placental miRNA profile in pregnant women with pregestational overweight/obesity (preOB) or gestational obesity (gestOB) and explore the associations between placental miRNAs dysregulated in maternal obesity and prenatal and postnatal growth. Methods: TaqMan Low Density Arrays and real-time polymerase chain reaction were used to profile the placental miRNAs in 70 pregnant women (20 preOB, 25 gestOB, and 25 control). Placentas and newborns were weighed at delivery, and infants were weighed at 1, 4, and 12 months of age. Results: Eight miRNAs were decreased in placentas from preOB or gestOB (miR-100, miR-1269, miR-1285, miR-181, miR-185, miR-214, miR-296, and miR-487) (all P < 0.05). Among them, miR-100, miR-1285, miR-296, and miR-487 were associated with maternal metabolic parameters (all P < 0.05) and were predictors of lower birth weight (all P < 0.05; R2 > 30%) and increased postnatal weight gain (all P < 0.05; R2 > 20%). In silico analysis showed that these miRNAs were related to cell proliferation and insulin signaling pathways. miR-296 was also present in plasma samples and associated with placental expression and prenatal and postnatal growth parameters (all P < 0.05). Conclusions: We identified a specific placental miRNA profile in maternal obesity. Placental miRNAs dysregulated in maternal obesity may be involved in mediation of growth-promoting effects of maternal obesity on offspring and could be used as early markers of prenatal and postnatal growth.

Altered Circulating miRNA Expression Profile in Pregestational and Gestational Obesity.

CONTEXT: MicroRNAs (miRNAs) are valuable circulating biomarkers and therapeutic targets for metabolic diseases. OBJECTIVE: The objective of the study was to define the pattern of circulating miRNAs in pregestational and gestational obesity and to explore their associations with maternal metabolic parameters and with markers for pre- and postnatal growth. design, settings, and main outcome measure: TaqMan low-density arrays were used to profile plasma miRNAs in six women with pregestational obesity (PregestOB), six with gestational obesity (GestOB), and six with normal pregnancies (control) during the second trimester of gestation. The most relevant miRNAs were validated in 70 pregnant women (20 PregestOB, 25 GestOB, and 25 control). Maternal metabolic parameters including glucose, glycated hemoglobin, homeostasis model assessment index of insulin resistance, C-peptide, and lipids were assessed. Placentas were weighed at delivery and newborns also during 6 months of life. RESULTS: We identified 13 circulating miRNAs differentially expressed in maternal obesity, including decreased levels of miR-29c, miR-99b, miR-103, miR-221, and miR-340 and increased levels of miR-30a-5p, miR-130a, and miR-150 in GestOB; and decreased levels of miR-122, miR-324-3p, miR-375, and miR-652 and increased levels of miR-625 in both PregestOB and GestOB (P < .05 to P < .0001 vs control). Decreased levels of several of these miRNAs associated with a more adverse maternal metabolic status (more pregnancy weight gain, glucose, glycated hemoglobin, homeostasis model assessment index of insulin resistance, C-peptide, and triacylglycerol and less high density lipoprotein cholesterol), with more placental weight, weight at birth, and weight at 6 months of life (all P < .05 to P < .001). CONCLUSIONS: This study provides the first identification of altered circulating miRNAs in maternal obesity and suggests a possible role of such miRNAS as markers for pre- and postnatal growth.