L Ibáñez

Placental FTO expression relates to fetal growth

Objective:The fat mass and obesity-associated gene (FTO) participates in the control of postnatal weight gain. We assessed whether FTO is expressed in human placenta and whether such expression relates to prenatal weight gain and to the rs9939609 single nucleotide polymorphism (SNP) in FTO.Design and subjects:In a birth cohort study, placentas from women (n=147) with an uncomplicated, singleton, term pregnancy were weighed at delivery. Real-time PCR was used to study, in placental tissue, the expression of FTO and of housekeeping genes (TATA box binding protein and succinate dehydrogenase complex, subunit A) and to genotype the rs9939609 SNP in FTO. Weights and lengths of the newborns were measured; circulating insulin and insulin-like growth factor-I (IGF-I) were quantified in cord blood.Results:FTO was highly expressed in placenta and was associated with increased fetal weight and length (P<0.001 to P<0.0001). Maternal parity showed an interaction (P<0.001) in the association between placental FTO expression and placental weight. Placental FTO mRNA expression was associated with increased fetal-to-placental weight ratio (P<0.005) in infants from primiparous women, and was associated with increased fetal weight and length and placental weight (P<0.001 to P<0.0001) in infants from nonprimiparous women. These associations were not explained by either cord insulin or IGF-I. Placental FTO expression was unrelated to placental FTO rs9939609 SNPConclusion:FTO is expressed in the human placenta. In a maternal parity-dependent manner, placental FTO may participate either in the control of fetal weight gain or in the partitioning between placental and fetal growth.

Variations in the obesity genes FTO, TMEM18 and NRXN3 influence the vulnerability of children to weight gain induced by short sleep duration.

OBJECTIVE:Shorter sleep duration predisposes to obesity, but the mechanisms whereby sleep deprivation affects body weight are poorly understood. We tested whether this association is modulated by the obesity genes FTO, TMEM18 and NRXN3.SUBJECTS:Body mass index (BMI), waist circumference, visceral fat (abdominal ultrasound), homeostasis model assessment for insulin resistance (HOMA-IR), systolic blood pressure (SBP) and sleep time per 24u2009h were assessed in 297 asymptomatic children (151 boys, 146 girls; age range 5–9 years; BMI s.d. score range −2.0–4.0). Associations between sleep duration and the abovementioned outcomes were tested for three common single-nucleotide polymorphisms (SNPs), namely FTO (rs9939609), TMEM 18 (rs4854344) and NRXN3 (rs10146997), as well as for their combination.RESULTS:TT homozygotes (but not A* carriers) for the FTO SNP, exhibited nominal associations between decreasing sleep duration and increasing BMI, waist circumference, visceral fat and HOMA-IR (all P<0.05). Similar associations were observed in children with risk alleles (but not in those without risk alleles) for the TMEM18 and NRXN3 SNPs (P<0.05 to P<0.0001). The three SNPs had additive effects on the negative associations between sleep and, respectively, BMI (P<0.001), waist (P<0.005), visceral fat (P<0.001), HOMA-IR (P=0.010) and SBP (P<0.0005). The combined effects on obesity measures and SBP remained significant after correction for multiple testing. On average, 2u2009h of sleep less per night was associated with an increase in BMI of 1.0 s.d. (95% confidence interval 0.5–1.6 s.d.) and with 8.0u2009cm (95% confidence interval 3.6–12.2u2009cm) more waist circumference in genetically susceptible children.CONCLUSION:By age 7, common variations in FTO, TMEM18 and NRXN3 influence the vulnerability to metabolic complications of sleep deprivation. Further genetic studies are warranted to replicate these findings in other populations.

Metabolic Impact of Growth Hormone Treatment in Short Children Born Small for Gestational Age

Background: Growth hormone (GH) treatment in short children born small for gestational age (SGA) may result in metabolic changes with potential long-term effects. Methods: 149 short SGA children (mean birth weight 2.0 ± 0.6 kg, age 5.5 ± 1.5 years, height standard deviation score (SDS) –3.1 ± 0.6) were randomised to: low-dose GH therapy (0.033 mg/kg/day) for 2 years; high-dose GH therapy (0.100 mg/kg/day) for 1 year, or mid-dose GH therapy (0.067 mg/kg/day) for 1 year. Leptin, ghrelin, insulin-like growth factor-I (IGF-I), IGF binding protein-1 (IGFBP-1), lipids, fasting blood glucose and fasting insulin were assessed at baseline, 12 and 24 months. Results: After 1 year of active treatment, GH significantly reduced serum ghrelin and increased IGF-I SDS and insulin levels. Regression analysis showed an inverse correlation between ghrelin and IGF-I SDS (p < 0.001). Leptin and IGFBP-1 also declined (both p < 0.05). Changes in insulin levels reversed upon discontinuation. Improvements in lipid profile were nonsignificant and fasting blood glucose levels remained within the normal range. Conclusion: In short SGA children, ghrelin and leptin reductions associated with GH treatment may occur through a negative feedback loop of the GH–IGF-I axis. Consequently, via ghrelin and leptin suppression, GH treatment may modify food intake and body composition and potentially improve long-term metabolic outcomes.

Ethinyl Estradiol-Cyproterone Acetate Versus Low-Dose Pioglitazone-Flutamide-Metformin for Adolescent Girls with Androgen Excess: Divergent Effects on CD163, TWEAK Receptor, ANGPTL4, and LEPTIN Expression in Subcutaneous Adipose Tissue

OBJECTIVEnThe aim was to compare the effects of a traditional therapy (an oral estroprogestagen) to those of a novel treatment (a low-dose combination of generics) in adolescent girls with androgen excess.nnnSTUDY DESIGN AND METHODSnIn an open-label trial over 1 yr, 34 adolescents (age, 16 yr; body mass index, 23 kg/m2) with hyperinsulinemic androgen excess and without pregnancy risk were randomized to receive daily ethinyl estradiol-cyproterone acetate (EE-CA; Diane 35 Diario) or a low-dose combination of pioglitazone 7.5 mg/d, flutamide 62.5 mg/d, and metformin 850 mg/d (PioFluMet). Markers of androgen excess, C-reactive protein, high molecular weight adiponectin, lipids, carotid intima media thickness, body composition (absorptiometry), abdominal fat partitioning (magnetic resonance imaging), and gene expression in longitudinal biopsies of sc adipose tissue at the abdominal level (RT-PCR) were assessed at baseline and after 1 yr.nnnRESULTSnEE-CA and low-dose PioFluMet reduced androgen excess comparably, but had divergent effects on C-reactive protein, high molecular weight adiponectin, lipids, carotid intima media thickness, lean mass, abdominal and visceral fat, and on the expression of CD163, leptin, TNF-like weak inducer of apoptosis receptor, and angiopoietin-like protein 4, respectively, related to macrophage activation, fat accretion, inflammation, and lipoprotein metabolism in adipose tissue. All these divergences pointed to a healthier condition on low-dose PioFluMet.nnnCONCLUSIONnEE-CA and PioFluMet are similarly effective in reversing androgen excess over 1 yr, but low-dose PioFluMet is superior in reversing inflammatory, metabolic, and cardiovascular anomalies that are often associated with androgen excess.

Neutrophil-to-lymphocyte ratio: an inflammation marker related to cardiovascular risk in children

Low-grade chronic inflammation plays a pathogenic role in cardiovascular disease. An increase in the ratio of circulating neutrophils to lymphocytes (N/L ratio) may serve as a marker of cardiovascular risk in adults. It was the study objective to study whether N/L ratio associates with vascular parameters in children. Subjects were 501 prepubertal and early pubertal Caucasian children (mean age 8.0 years; mean body mass index (BMI) Z-score 0.2 ± 0.9; 266 boys and 235 girls) recruited within an ongoing population-based study. The subjects were stratified into three groups according to age. Neutrophil, lymphocyte, BMI, waist circumference, systolic blood pressure (SBP) and carotid intima-media thickness (cIMT), assessed in all children. The N/L ratio, derived from the absolute neutrophil and lymphocyte counts. In children aged < 7 years (n=190, all prepubertal), no associations were observed between N/L ratio and either anthropometric or cardiovascular parameters. In children aged 7-9 years (n=171, 1.7% early pubertal), higher N/L ratio associated with higher BMI Z-score and waist circumference (p=0.008 to p < 0.0001). In children aged >9 years (n=140, 29.2% early pubertal), N/L ratio associated again with BMI Z-score and waist circumference and also positively with SBP and cIMT (all p=0.008 to p<0.0001). These associations remained significant in linear regression models following adjustment for possible confounding variables such as age, gender, fasting triglycerides, C-reactive protein and puberty (and for SBP and cIMT, adjustment also for BMI). In conclusion, our results provide the first evidence that a higher N/L ratio is associated with a less favourable cardiovascular profile in children and delineate the development of these associations from late childhood onwards.

Circulating GLP-1 in infants born small-for-gestational-age: breast-feeding versus formula-feeding

Prenatal growth restraint associates with the risk for later diabetes, particularly if such restraint is followed by postnatal formula-feeding (FOF) rather than breast-feeding (BRF). Circulating incretins can influence the neonatal programming of hypothalamic setpoints for appetite and energy expenditure, and are thus candidate mediators of the long-term effects exerted by early nutrition. We have tested this concept by measuring (at birth and at age 4 months) the circulating concentrations of glucagon-like peptide-1 (GLP-1) in BRF infants born appropriate-for-gestational-age (AGA; n=63) and in small-for-gestational-age (SGA) infants receiving either BRF (n=28) or FOF (n=26). At birth, concentrations of GLP-1 were similar in AGA and SGA infants. At 4 months, pre-feeding GLP-1 concentrations were higher than at birth; SGA-BRF infants had GLP-1 concentrations similar to those in AGA-BRF infants but SGA-FOF infants had higher concentrations. In conclusion, nutrition appears to influence the circulating GLP-1 concentrations in SGA infants and may thereby modulate long-term diabetes risk.

Circulating FGF19 and FGF21 surge in early infancy from infra- to supra-adult concentrations

Background/Objective:Fibroblast growth factor 19 (FGF19) and 21 (FGF21) have been linked to obesity and type 2 diabetes in adults. We assessed the circulating concentrations of these factors in human neonates and infants, and their association with the endocrine–metabolic changes associated to prenatal growth restraint.Subjects/Methods:Circulating FGF19 and FGF21, selected hormones (insulin, insulin-like growth factor I and high- molecular-weight (HMW) adiponectin) and body composition (absorptiometry) were assessed longitudinally in 44 infants born appropriate- (AGA) or small-for-gestational-age (SGA). Measurements were performed at 0, 4 and 12 months in AGA infants; at 0 and 4 months in SGA infants; and cross-sectionally in 11 first-week AGA newborns.Results:Circulating FGF19 and FGF21 surged >10-fold in early infancy from infra- to supra-adult concentrations, the FGF19 surge appearing slower and more pronounced than the FGF21 surge. Whereas the FGF21 surge was of similar magnitude in AGA and SGA infants, FGF19 induction was significantly reduced in SGA infants. In AGA and SGA infants, cord-blood FGF21 and serum FGF19 at 4 months showed a positive correlation with HMW adiponectin (r=0.49, P=0.013; r=0.43, P=0.019, respectively).Conclusions:Our results suggest that these early FGF19 and FGF21 surges are of a physiological relevance that warrants further delineation and that may extend beyond infancy.

Less Myostatin and More Lean Mass in Large-Born Infants From Nondiabetic Mothers

CONTEXT AND OBJECTIVEnSexagenarians born large are at lower risk for type 2 diabetes than those born small, a key feature of their body composition being a higher muscle mass, which explains their higher body mass index and also their lower fat-to-lean-mass ratio. Myogenesis is completed in early infancy under the inhibitory control of myostatin. We tested whether large-born infants from nondiabetic mothers develop an early surplus of lean mass while having a lower myostatinemia. Design, Methods, Study Participants, and Main Outcomes: In a longitudinal study (0-4 mo), we compared the body composition and endocrine markers (fasting glucose, insulin, IGF-1, high molecular weight adiponectin) of breast-fed appropriate- vs large-for-gestational-age infants (n = 125) from nondiabetic mothers. Circulating myostatin concentrations were assayed after collection of the above-mentioned data.nnnSETTINGnThe study was conducted at the University Hospital for Women and Children.nnnINTERVENTIONnThere were no interventions.nnnRESULTSnBetween 0-4 months, large-for-gestational-age infants switched from an adipose to a lean body composition (due to a nearly 20% excess of lean mass) and to an insulin-sensitive and hyperadiponectinemic state while having low IGF-1 concentrations and the lowest myostatinemia hitherto reported in the human (all between P ≤ .01 and P ≤ .0001).nnnCONCLUSIONnLarge-born infants from nondiabetic mothers were found to combine a low myostatinemia with an excess of lean mass. The fetal-neonatal control of myostatinemia deserves further attention because it could become a target of interventions that aim at reducing the risk for diabetes in later life by augmenting myogenesis in early life.

Liver volume and hepatic adiposity in childhood: Relations to body growth and visceral fat

Background and objective:The sequence of prenatal growth restraint and postnatal catch-up growth may lead to hepato-visceral adiposity, insulin resistance and low-grade inflammation before the onset of puberty. In prepubertal children born appropriate for gestational age (AGA) or small for gestational age (SGA), we assessed potential relationships between the aforementioned sequence and liver volume.Subjects/Methods:The study population consisted of 86 children (41 AGA and 45 SGA with catch-up growth; age (mean±s.e.m.), 8.5±0.1 years), recruited into two prospective longitudinal studies. Anthropometry, endocrine–metabolic variables and inflammatory and hepatic markers were assessed, along with liver volume, hepatic adiposity and abdominal fat partitioning (by magnetic resonance imaging).Results:AGA and SGA children differed in hepato-visceral adiposity, but had similar liver volumes. Boys had larger livers than girls, and higher sex hormone binding globulin and inflammation markers. Liver volume correlated with height Z-score, body mass index Z-score, HOMA-IR (homeostasis model assessment-insulin resistance) and with subcutaneous and visceral fat, but not with birth weight Z-score or with hepatic adiposity. Height, visceral fat, gender and HOMA-IR were major determinants of liver volume, together explaining 61% of its variance.Conclusions:The trajectory from prenatal restraint, via postnatal catch-up, to hepato-visceral adiposity and insulin resistance does not appear to be detectably influenced by prepubertal alterations of liver volume. Further follow-up will disclose the potential role of liver volume in the pubertal segment of this trajectory, and whether the augmented fat content and visceral adiposity in SGA subjects is followed by the development of metabolic syndrome and hepatic dysfunction in adulthood.

Hirsutismo y trastornos menstruales en la adolescencia

Lourdes Ibaneza,c, Maria Victoria Marcosb,c y Ruben Diaza aSeccion de Endocrinologia. Hospital Sant Joan de Deu. Universidad de Barcelona. Esplugues de Llobregat. Barcelona. Espana. bUnidad de Endocrinologia. Hospital de Terrassa. Terrassa. Barcelona. Espana. cCIBER de Diabetes y Enfermedades Metabolicas Asociadas. Instituto de Salud Carlos III. Madrid. Espana. libanez@hsjdbcn.org; mvmarcos@csdt.es; rdiaz@hsjdbcn.org Puntos clave