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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., (© 2021 World Obesity Federation.)

Background: Diazepam-binding inhibitor (DBI) controls feeding behaviour and glucose homeostasis. Individuals born small-for-gestational-age (SGA) with excessive postnatal catch-up in weight are at risk for obesity and type 2 diabetes., Objective: To assess serum concentrations of DBI (0-2 years) in appropriate-for-gestational-age (AGA, n = 70) vs SGA infants (n = 33) with spontaneous catch-up and their relationship with endocrine-metabolic and adiposity markers., Methods: Longitudinal assessments included auxology, fasting glucose, insulin, insulin-like growth factor, high-molecular-weight adiponectin, DBI and body composition (absorptiometry). DBI was measured cross-sectionally in pregnant and non-pregnant women and in 2-day-old newborns. DBI mRNA expression levels were assessed in adult and neonatal tissues., Results: Cord blood DBI concentrations were similar in AGA and SGA newborns and about fivefold higher than those in women. Serum DBI levels decreased by age 2 days, were higher in SGA vs AGA infants at age 2 years and associated negatively with markers of adiposity and insulin resistance and positively with high-molecular-weight adiponectin. DBI mRNA expression was lower in placenta than in other tissues., Conclusion: The increased DBI concentrations at birth are unrelated to prenatal growth. The higher DBI levels in SGA subjects at age 2 years may be related to catch-up growth or represent an adaptive mechanism to promote lipogenesis., (© 2021 World Obesity Federation.)

Background: Girls with obesity and polycystic ovary syndrome (PCOS) and women with PCOS have altered gut microbiota., Objective: To study the gut microbiota composition of girls with PCOS without obesity (age, 15.8 years; body mass index [BMI] 25 kg/m 2 ) and the effects of randomized treatments with an oral contraceptive (OC, N = 15) or with spironolactone-pioglitazone-metformin (SPIOMET, N = 15) for 1 year. Thirty-one age-matched girls served as controls., Methods: 16S ribosomal subunit gene amplicon sequencing was performed in stool samples from all subjects; samples from 23 out of 30 girls with PCOS (OC, N = 12; SPIOMET, N = 11) were available for analysis post-treatment. Clinical and endocrine-metabolic variables were measured before and after intervention., Results: Girls with PCOS had decreased diversity alpha, altered microbiota pattern and taxonomic profile with more abundance of Family XI (P = .002), and less abundance of family Prevotellaceae (P = .0006) the genus Prevotella (P = .0001) and Senegalimassilia (P < .0001), as compared to controls. Family XI abundance related positively to hepato-visceral fat (R = 0.453; P = .0003). SPIOMET treatment, but not OC, normalized the abundance of Family XI. Prevotellaceae, Prevotella and Senegalimassilia abundance remained unchanged after either treatment., Conclusion: SPIOMET's spectrum of normalizing effects in girls with PCOS is herewith broadened as to include Family XI abundance in gut microbiota., (© 2020 World Obesity Federation.)

PCOS is already a prevalent endocrinopathy in adolescent girls, and its prevalence is rising further since, in essence, it is the result of a mismatch between an energy-sparing (epi)genetic background and a (relatively) obesogenic environment. This mismatch results in an excess of fat storage in ectopic depots, notably in the liver and viscera (= hepato-visceral, or central fat). There is still no FDA-approved treatment for adolescent PCOS. The prime aim should be a preferential loss of central fat, through lifestyle measures. Failure to sustain these measures is frequent, and the standard approach is to add an estroprogestagen contraceptive, even for girls who do not need contraception. Treatment with SPIOMET, a low-dose combination of spironolactone (to antagonize androgen and mineralocorticoid effects, and to activate BAT thereby raising energy expenditure), pioglitazone (to raise circulating HMW adiponectin concentrations) and metformin, is an alternative approach that holds the potential to revert the PCOS phenotype., (© 2019 World Obesity Federation.)

Background: Insulin resistance and hepato-visceral (central) fat excess are thought to contribute to an earlier timing of adrenarche/pubarche and puberty/menarche; this earlier timing in turn relates often to a mismatch between prenatal and postnatal weight gain, which can be estimated by calculating the Z-score change from birth weight (BW) to body mass index (BMI) in childhood., Methods: We tested the hypothesis that this calculation may serve as a proxy of insulin resistance and hepato-visceral adiposity in prepuberty by reappraising a cohort of children (mean age, 8.5 years), born appropriate- (AGA, n = 41) or small-for-gestational age (SGA, n = 45), followed since birth (n = 76) or since the age of 3 years (n = 10). Assessments included anthropometry; fasting glucose and insulin; liver volume; and hepatic fat, subcutaneous fat, and visceral fat in the abdominal region (by magnetic resonance imaging [MRI])., Results: Z-score change BW-BMI closely associated to central fat (R = 0.74; P < .0001) and insulin resistance (R = 0.71; P < .0001)., Conclusion: These results suggest that Z-score change BW-BMI could be viewed as a simple candidate-marker for hepato-visceral adiposity and insulin resistance in prepubertal children., (© 2019 World Obesity Federation.)

S100A4 is a marker of subcutaneous adipose tissue dysfunction. Polycystic ovary syndrome (PCOS) is often driven by hepato-visceral adiposity. PCOS phenotypes are normalized more by reduction of central fat with spironolactone/pioglitazone/metformin (SPIOMET) than by oral contraceptive (OC) treatment. We studied whether circulating S100A4 concentrations are high in adolescents with PCOS and, if so, whether they normalize more with OC or SPIOMET. Assessments included circulating S100A4, endocrine markers, body composition, abdominal fat partitioning in controls (n = 12) and girls with PCOS (n = 51; age 15.8 y; body mass index [BMI] 24.5 kg/m 2 ), and 1-year changes in girls with PCOS randomized for OC (n = 27) or SPIOMET (n = 24) treatment. Mean S100A4 concentrations were 71% higher (P < 0.001) in girls with PCOS than in controls and associated with hepato-visceral adiposity (r = 0.47; P = 0.001); S100A4 concentrations decreased more (P < 0.01) with SPIOMET, those decreases associating to hepato-visceral fat loss (r = 0.50; P < 0.0001). S100A4 may become a circulating marker of hepato-visceral fat excess in adolescents with PCOS., (© 2019 World Obesity Federation.)

Background: The sequence of prenatal growth restraint and postnatal catch-up growth leads to a thicker intima-media and more pre-peritoneal fat by age 3-6 years., Objectives: To study whether carotid intima-media thickness (cIMT) and pre-peritoneal fat differ already between catch-up small-for-gestational-age (SGA) infants and appropriate-for-gestational-age (AGA) controls in late infancy (ages 1 and 2 years) and whether such differences - if any - are accompanied by differences in cardiac morphology and function., Methods: Longitudinal assessments included body height and weight; fasting glucose, insulin, Insulin-like growth factor (IGF-I), high-molecular-weight adiponectin; body composition (by absorptiometry); cIMT, aortic IMT, pre-peritoneal fat partitioning (by ultrasound); cardiac morphometry and function (by echocardiography) in AGA and SGA infants at birth, at age 1 year (N = 87), and again at age 2 years (N = 68)., Results: Catch-up SGA infants had already a thicker cIMT than AGA controls at ages 1 and 2 years, and more pre-peritoneal fat by age 2 years (all p values between <0.01 and <0.0001); all cardiac and endocrine-metabolic results were similar in AGA and SGA infants at ages 1 and 2 years., Conclusions: From late infancy onwards, catch-up SGA infants have a thicker cIMT and more pre-peritoneal fat than AGA controls, but their cardiac morphology and function remain reassuringly similar., (© 2018 World Obesity Federation.)

Background: Telomere length at birth is a major determinant of telomere length in late adulthood. However, the prenatal setting of telomere length is poorly understood. Individuals born large from non-diabetic mothers are at lower risk for later-life disorders than those born small, a feature of their longer health span being a higher lean mass that provides more muscle strength and that is already present in infancy., Methods: At birth, we studied leukocyte telomere length (by quantitative polymerase chain reaction) in 103 small-for-gestational-age, appropriate-for-gestational-age or large-for-gestational-age (SGA, AGA or LGA) infants born after uncomplicated, term, singleton pregnancies. All infants were breastfed for ≥4 months. At 2 weeks and 12 months, body composition was assessed by dual X-ray absorptiometry., Results: Telomere lengths were shorter in SGA newborns and longer in LGA newborns than in AGA newborns (P < 0.001), also after adjustment for maternal age, pre-gestational body mass index, gestational weight gain and gestational age. Telomere length at birth associated (all P ≤ 0.001) to birthweight (r = 0.50) and to both lean mass (r = 0.43) and fat mass (r = 0.48) at age 2 weeks, but only to lean mass at 12 months (r = 0.51)., Conclusion: Higher weight and longer telomeres at birth are followed by more lean mass in late infancy. Relatively large, breastfed infants from non-diabetic mothers may become models of how to make a healthy start., (© 2016 World Obesity Federation.)

Objectives: The aim of this paper is to test whether α-defensins and bacterial/permeability-increasing protein were related to obesity and cardiovascular risk factors in prepubertal children., Methods: Plasma α-defensins and bacterial/permeability-increasing protein, body mass index (BMI), waist circumference, systolic blood pressure (SBP), carotid intima media thickness (cIMT), HOMA-IR and HMW-adiponectin were assessed., Results: In a cross-sectional study (N = 250), higher α-defensins concentrations were positively associated with BMI, waist, SBP, cIMT, HOMA-IR and negative correlated with HMW-adiponectin (all between r = 0.191 and r = 0.377, p ≤ 0.01 and p ≤ 0.0001). Conversely, plasma bacterial/permeability-increasing protein concentrations presented inversed associated with the same parameters (all between r = -0.124 and r = -0.329; p ≤ 0.05 and p ≤ 0.0001). In a longitudinal study (N = 91), α-defensins at age 7 were associated with BMI (β = 0.189, p = 0.002; model R 2  = 0.847) and waist (β = 0.241, pthinsp;= 0.001; model R 2  = 0.754) at age 10., Conclusions: α-Defensins and bacterial/permeability-increasing protein may be the markers of childhood obesity. Increased concentrations of α-defensins may predict BMI and abdominal fat deposition in children., (© 2016 World Obesity Federation.)

Background: Increased uric acid is an independent biomarker for cardiovascular disease in obese adolescents and adults., Objective: We investigated whether uric acid relates to carotid intima-media thickness (cIMT) in prepubertal children, and whether body mass index (BMI) and preperitoneal fat modulate this association., Methods: 359 asymptomatic prepubertal Caucasian children were stratified according to BMI categories (171 with BMI-SDS < 0; 188 with BMI-SDS ≥ 0) and according to preperitoneal fat levels (180 with preperitoneal fat <50th centile; 179 with preperitoneal fat >50th centile). Uric acid levels, insulin resistance (homeostasis model assessment insulin resistance; HOMA-IR), C-reactive protein (CRP), triacylglycerol (TG), systolic blood pressure (SBP), abdominal fat and cIMT (both by ultrasound) were assessed., Results: Uric acid was associated with several cardiovascular risk factors, namely higher HOMA-IR, CRP, TG, BMI, waist, SBP, preperitoneal fat and cIMT (all P < 0.001 to P < 0.0001). Significant BMI and preperitoneal fat interactions were documented in the relationship between uric acid and cIMT (both P < 0.05), as uric acid was preferentially related to cIMT in heavier children (β = 0.247, P < 0.001, r(2)  = 9.1%) and in children with more preperitoneal fat (β = 0.263, P < 0.0001, r(2)  = 11.9%)., Conclusions: Serum uric acid is associated with cIMT in asymptomatic prepubertal children. Both higher BMI and preperitoneal fat aggravate the potential risk of atherosclerotic disease imposed by higher concentrations of uric acid., (© 2015 World Obesity.)

Background: Infants born small-for-gestational-age (SGA) who develop post-natal weight catch-up are at risk for insulin resistance, central adiposity and cardiovascular disease in later life, even in the absence of overweight., Objective: In young (age 3-6 years) non-obese SGA children, we assessed arterial health (as judged by intima-media thickness [IMT]) and abdominal fat distribution (subcutaneous, visceral, preperitoneal and hepatic components by magnetic resonance imaging [MRI] and/or ultrasound [US]) besides a selection of endocrine markers., Methods: Comparisons of measures in SGA (n = 27) vs. appropriate-for-GA (AGA) children (n = 19) of similar height, weight and body mass index. Longitudinal outcomes (age 3-6 years) were carotid IMT (cIMT); fasting glucose, circulating insulin, IGF-I and high-molecular-weight (HMW) adiponectin; abdominal fat partitioning by US. Cross-sectional outcomes (age 6 years) were aortic IMT (aIMT) and abdominal fat partitioning by MRI., Results: At 3 and 6 years, cIMT and IGF-I results were higher and HMW adiponectin lower in SGA than AGA children; at 6 years, SGA subjects had also a thicker aIMT and more pre-peritoneal and hepatic fat, and were less insulin sensitive (all P values between <0.05 and <0.0001). cIMT correlated positively with pre-peritoneal fat, particularly at 6 years. Post-SGA status and weight gain in early childhood (between 3 and 6 years) were independent predictors of cIMT at 6 years, explaining 48 % of its variance., Conclusion: SGA children aged 3-6 years were found to have a thicker intima- media and more pre-peritoneal and hepatic fat than AGA children of comparable size., (© 2015 World Obesity.)