Integrated neuromuscular training intervention applied in schools induces a higher increase in salivary high molecular weight adiponectin and a more favorable body mass index, cardiorespiratory fitness and muscle strength in children as compared to the traditional physical education classes.

Background: High-molecular-weight adiponectin (HMW-adiponectin) is a cardio-metabolic health protector. Objectives: (1) to compare body mass index (BMI), cardiorespiratory fitness (CRF) and muscle strength (MS) in healthy school-children depending on their baseline salivary-HMW-adiponectin concentration; and (2) to apply a 3-month integrated neuromuscular training (INT) and evaluate its effects on salivary-HMW-adiponectin concentration, BMI, CRF and MS in the same children. Additional goal: to identify if any potential changes during the 3-month period may be related to a potential change in salivary-HMW-adiponectin concentration. Methods: Ninety children (7.4 ± 0.3 years) were recruited in primary schools and randomly allocated into control or intervention group. The intervention consisted of a 3-month INT applied during physical education (PE) classes, twice-weekly, while the control group had traditional PE classes. Body mass and height were measured, BMI was calculated and HMW-adiponectin was quantified in saliva. To assess CRF and MS, 800 m-run and hand-dynamometry were applied, respectively. All measurements were performed twice, at baseline and after 3 months. Results: Children with higher baseline salivary-HMW-adiponectin have more favorable BMI (p = 0.006) and slightly higher CRF (p = 0.017) in comparison to the children with lower baseline salivary-HMW-adiponectin. There were no big changes after the 3-month-period neither in the control, nor the INT group. However, it is worthy to note that the INT induced slightly higher increase in salivary-HMW-adiponectin (p = 0.007), and a slightly higher improvement in BMI (p = 0.028), CRF (p = 0.043) and MS (p = 0.003), as compared to the traditional PE classes. Finally, the INT-induced improvement in CRF was associated with the increased post-salivary-HMW-adiponectin concentration (p = 0.022). Conclusion: Main findings may suggest the potential utility of an INT as a cost-effective strategy that can be applied in schools to induce cardio-protective effects in school-children.

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.

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.

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.

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.

Placental epigenetic marks related to gestational weight gain reveal potential genes associated with offspring obesity parameters.

OBJECTIVE: Offspring exposed to gestational obesity have an increased risk for chronic diseases. Increasing evidence suggests that epigenetics may play a mechanistic role in metabolic programming. This study aimed to identify placental DNA methylation marks associated with gestational weight gain (GWG) and to study their association with offspring obesity parameters at school age. METHODS: A global methylation array was performed in 24 placentas from mothers with different degrees of GWG (screening sample). The methylation percentage of four cytosine-guanine (CpG) sites and the relative expression of the respective annotated genes were studied in 90 additional placentas (validation sample). Associations of these epigenetic marks with clinical parameters in the offspring at 6 years of age were examined. RESULTS: The screening analysis identified 104 CpG sites (97 genes) associated with GWG. The validation analysis of four selected CpG sites (annotating for FRAT1, SNX5, and KCNK3 genes) showed that the upregulation of SNX5 methylation, the downregulation of FRAT1 methylation, and KCNK3 underexpression associated with an adverse metabolic phenotype in children of women with increased GWG. CONCLUSIONS: These results suggest that placental regulation of FRAT1, SNX5, and KCNK3 relates to obesity parameters in offspring exposed to excessive GWG and thereby could condition the risk for future metabolic disorders.

Raised Thyroid-Stimulating Hormone in Girls with Polycystic Ovary Syndrome: Effects of Randomized Interventions.

INTRODUCTION: Polycystic ovary syndrome (PCOS) in women associates with raised levels of circulating thyroid-stimulating hormone (TSH) and with high rates of gestational complications. A low range of preconception TSH is followed by low rates of gestational complications. It is unknown whether TSH levels are elevated in adolescents with PCOS and, if so, whether traditional or exploratory treatments can lower them into safe preconception range. We investigated TSH in nonobese adolescents with PCOS, including the effects of randomized interventions. METHODS: Morning TSH was a safety marker in randomized pilot studies comparing the effects of an oral contraceptive (OC) versus those of a low-dose combination of spironolactone-pioglitazone-metformin (SPIOMET) in nonobese adolescents with PCOS. A post hoc analysis compared TSH levels in PCOS (N = 62) versus controls, TSH changes on treatment (for 1 year), and TSH levels posttreatment (for 1 year). RESULTS: Mean TSH levels were higher in PCOS patients than in control girls (p < 0.01). On-treatment TSH levels diverged (p < 0.001), remaining elevated on OC, and descending swiftly on SPIOMET, well into safe preconception range. Posttreatment TSH levels were stable in both subgroups. On-treatment changes of circulating TSH associated to those of liver fat (R = 0.307, p = 0.017). CONCLUSION: The endocrine signature of early PCOS is herewith extended to include modestly raised levels of circulating TSH; the normalizing effects of SPIOMET intervention in nonobese adolescents with PCOS are herewith extended to include on- and posttreatment TSH.

Effects of half-dose spiomet treatment in girls with early puberty and accelerated bone maturation: a multicenter, randomized, placebo-controlled study protocol.

BACKGROUND: A "mismatch" sequence of less prenatal weight gain and more postnatal weight gain may lead to ectopic lipid accumulation, and trigger the development of early adrenarche/pubarche and the activation of the gonadotropic axis resulting in early puberty and ending up in full-blown adolescent polycystic ovary syndrome (PCOS). In the present study, we assess whether a low-dose combination of generics that collectively reduce ectopic fat through different pathways can slow down the accelerated maturation in "mismatch" girls with early puberty. METHODS: Randomized, placebo-controlled, multicenter, phase 2a, study in 64 girls [age, 8.0-9.3 years; birthweight (BW) for gestational age in lower tertile (-1.96< Z-score <-0.44), body mass index (BMI) in upper tertile (+0.44< Z-score < +1.96) and early progressive puberty (Tanner B2 at 7.7-9.0 years)]. Pharmacological intervention will be with a half-dose version of SPIOMET (mini-spiomet), a combination that reverts the PCOS phenotype in "mismatch" adolescents; mini-spiomet will contain spironolactone (25 mg/day, to raise brown adipose tissue activity), pioglitazone (3.75 mg/day, to raise adiponectin and insulin sensitivity), and metformin (425 mg/day, to raise AMPK activity and GDF15). Recruitment: 1 year; double-blind treatment: 1 year; open follow-up: 1 year; analyses and reporting: 1 year. INTERVENTIONS: randomization (1:1) for placebo vs mini-spiomet. PRIMARY OUTCOME: annualized bone age advancement (0-1 year) by BoneXpert; secondary outcomes: insulin, IGF-I, high-molecular-weight adiponectin (HMW-adip), sex hormone binding globulin (SHBG), ultra-sensitive C-reactive protein (usCRP), androgens, luteinizing hormone (LH), follicle-stimulating hormone (FSH), oestradiol, growth-and-differentiation factor 15 (GDF15), C-X-C motif chemokine ligand-14 (CXCL14), safety parameters, and quantification of hepato-visceral fat. DISCUSSION: The present study, if successful, may provide a first proof of the concept that the rapid maturation of girls with an upward mismatch between pre- and post-natal weight gain can be slowed down with a fixed low-dose combination of old and safe generics jointly targeting a reduction of ectopic fat without necessarily lowering body weight. TRIAL REGISTRATION: EudraCT 2021-006766-21. Registered on May 30, 2022.

Circulating GDF15 concentrations in girls with low birth weight: effects of prolonged metformin treatment.

BACKGROUND: Low birth weight (LBW) followed by a rapid postnatal catch-up in weight predisposes individuals to a central distribution of body fat, which is reverted by metformin. Growth-and-differentiation-factor-15 (GDF15) plays an important role in the regulation of energy homeostasis, reducing food intake and body weight. We assessed whether GDF15 concentrations are raised by long-term metformin treatment in LBW/catch-up girls with precocious pubarche (PP, pubic hair <8 years), and whether they relate to changes in endocrine-metabolic variables, body composition, and abdominal fat partitioning. METHODS: Circulating GDF15 was determined in 30 LBW/catch-up girls with PP randomly assigned to receive metformin for 4 years (n = 15; 425 mg/d for 2 years, then 850 mg/d for 2 years) or to remain untreated (n = 15). Endocrine-metabolic variables, body composition (by absorptiometry), and abdominal fat partitioning (by MRI) were assessed at the start and yearly during follow-up. RESULTS: Circulating GDF15 concentrations increased significantly in LBW-PP girls only after 3 and 4 years on metformin. GDF15 levels associated negatively with insulin, HOMA-IR, androgens, body fat, and visceral fat. CONCLUSION: Prepubertal intervention with metformin reduces central adiposity and insulin resistance in girls with reduced prenatal growth. GDF15 could be among the mediators of such effects, especially over the long term. IMPACT: Low birth weight followed by a rapid postnatal catch-up in weight predisposes individuals to a central distribution of body fat, which is reverted by metformin. Growth-and-differentiation-factor-15 (GDF15) is a peptide hormone that reduces food intake and lowers body weight; metformin is an exogenous GDF15 secretagogue. Serum GDF15 concentrations increase after 3 and 4 years on metformin and associate negatively with insulin, androgens, body fat, and visceral fat. Prepubertal intervention with metformin reduces central adiposity and insulin resistance in girls with low birth weight. GDF15 could mediate these effects, especially over the long term.

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.

miRNA expression profiles of the perilesional skin of atopic dermatitis and psoriasis patients are highly similar.

Atopic dermatitis (AD) and psoriasis vulgaris (PV) are chronic inflammatory skin diseases with heterogeneous molecular backgrounds. MicroRNAs (miRNAs) contribute to either development or regulation of many immune system related diseases. Only few miRNA profiling studies are available for AD and no comparisons between AD and PV skin miRNA profiles have been performed recently. We conducted a miRNA profiling analysis of skin, as well as serum, from adult AD and PV patients and control individuals. 130 miRNAs were differentially expressed in AD skin, of which 77 were common differentially expressed in AD and PV. No differentially expressed miRNAs were detected in serum. Pathway analyses revealed differentially expressed miRNAs to potentially target immune-system related pathways, including TNF-α, IL-2/STAT4 and IL-6/JAK/STAT3. Additional genetic analysis of published AD GWAS dataset detected association of several target genes of differentially expressed miRNAs in skin. Moreover, miR-28-5p, miR-31-5p, miR-378a-3p and miR-203a were validated as upregulated in the skin of AD and PV patients. All validated miRNAs were reliable predictive markers for AD or PV. In conclusion, miRNA expression pattern in the skin of adult AD patients is highly similar to that of PV with multiple differentially expressed miRNAs potentially involved in the regulation of immune responses in AD and PV.

Metabolic programming in the offspring after gestational overfeeding in the mother: toward neonatal rescuing with metformin in a swine model.

OBJECTIVES: Maternal overfeeding during gestation may lead to adverse metabolic programming in the offspring mediated by epigenetic alterations. Potential reversal, in early life, of these alterations may help in the prevention of future cardio-metabolic conditions. In this context, our aims were: (1) to study the effects of maternal overfeeding on the metabolic and epigenetic programming of offspring's adipose tissue; and (2) to test the potential of postnatal metformin treatment to reverse these changes. METHODS: We used a swine animal model where commercial production sows were either overfed or kept under standard diet during gestation, and piglets at birth were randomly assigned to metformin (n = 16 per group) or vehicle treatment during lactation (n = 16 per group). RESULTS: Piglets born to overfed sows showed a worse metabolic profile (higher weight, weight gain from birth and abdominal circumference; all p < 0.05) together with altered serological markers (increased HOMA-IR, fructosamine, total cholesterol, C-Reactive Protein and lower HMW adiponectin; all p < 0.05). The visceral adipose tissue also showed altered morphology (increased adipocyte area, perimeter and diameter; all p < 0.05), as well as changes in gene expression (higher CCL2 and INSR, lower DLK1; all p < 0.05), and in DNA methylation (96 hypermethylated and 99 hypomethylated CpG sites; FDR < 0.05). Metformin treatment significantly ameliorated the abnormal metabolic profile, decreasing piglets' weight, weight gain from birth, abdominal circumference and fructosamine (all p < 0.05) and reduced adipocyte area, perimeter, and diameter in visceral adipose tissue (all p < 0.05). In addition, metformin treatment potentiated several associations between gene expression in visceral adipose tissue and the altered metabolic markers. CONCLUSIONS: Maternal overfeeding during gestation leads to metabolic abnormalities in the offspring, including adipose tissue alterations. Early metformin treatment mitigates these effects and could help rescue the offspring's metabolic health.