Alessandra Amato

Hepcidin in obese children as a potential mediator of the association between obesity and iron deficiency.

CONTEXT Obesity and iron deficiency are two of the most common nutritional disorders worldwide. Several studies found higher rates of iron deficiency in obese than in normal-weight children. Hepcidin represents the main inhibitor of intestinal iron absorption, and its expression is increased in adipose tissue of obese patients. Leptin is able, in vitro, to raise hepcidin expression. OBJECTIVES Aims of this work were 1) to assess the association between poor iron status and obesity, 2) to investigate whether iron homeostasis of obese children may be modulated by serum hepcidin variations, and 3) to assess the potential correlation between leptin and serum hepcidin variations. METHODS Iron status and absorption as well as hepcidin, leptin, and IL-6 levels were studied in 60 obese children and in 50 controls. RESULTS Obese children showed lower iron and transferrin saturation (both P < 0.05) and higher hepcidin levels (P = 0.004) compared with controls. A direct correlation between hepcidin and obesity degree (P = 0.0015), and inverse correlations between hepcidin and iron (P = 0.04), hepcidin and transferrin saturation (P = 0.005), and hepcidin and iron absorption (P = 0.003) were observed. A correlation between leptin and hepcidin (P = 0.006) has been found. The correlation remained significant when adjusted for body mass index, sex, pubertal stage, and IL-6 values. CONCLUSIONS We propose that in obese patients, increased hepcidin production, at least partly leptin mediated, represents the missing link between obesity and disrupted iron metabolism.

Effect of body mass index reduction on serum hepcidin levels and iron status in obese children.

Iron deficiency has been linked to obesity. Hepcidin is the main regulator of iron homeostasis and is higher in obese children compared to controls. To gain insight into the link between obesity and hepcidin, we performed an intervention study in 15 obese children. These children were subjected to a 6-month weight loss program and underwent physical examination and iron status and absorption as well as hepcidin, interleukin-6 and leptin serum levels evaluation at baseline and after the weight loss program. After the program all children reduced their body mass index standard deviation score (BMI SDS) of at least 0.5. We observed a significant decrease in hepcidin (P=0.003) and leptin levels (P=0.005), and a significant increase in iron absorption (P=0.02). A direct correlation between the measure of hepcidin and leptin reduction was observed and this correlation appeared significant (r2=0.33, P=0.003) when adjusted for interleukin-6 and BMI SDS variations. In conclusion, we have shown that, in obese children, BMI reduction is associated with hepcidin reduction, potentially improving iron status and absorption. Implications of these findings could be considered in the management of obese children with poor iron status.

The association of PNPLA3 variants with liver enzymes in childhood obesity is driven by the interaction with abdominal fat.

Background and Aims A polymorphism in adiponutrin/patatin-like phospholipase-3 gene (PNPLA3), rs738409 C->G, encoding for the I148M variant, is the strongest genetic determinant of liver fat and ALT levels in adulthood and childhood obesity. Aims of this study were i) to analyse in a large group of obese children the role of the interaction of not-genetic factors such as BMI, waist circumference (W/Hr) and insulin resistance (HOMA-IR) in exposing the association between the I148M polymorphism and ALT levels and ii) to stratify the individual risk of these children to have liver injury on the basis of this gene-environment interaction. Methods 1048 Italian obese children were investigated. Anthropometric, clinical and metabolic data were collected and the PNPLA3 I148M variant genotyped. Results Children carrying the 148M allele showed higher ALT and AST levels (p = 0.000006 and p = 0.0002, respectively). Relationships between BMI-SDS, HOMA-IR and W/Hr with ALT were analysed in function of the different PNPLA3 genotypes. Children 148M homozygous showed a stronger correlation between ALT and W/Hr than those carrying the other genotypes (p: 0.0045) and, therefore, 148M homozygotes with high extent of abdominal fat (W/Hr above 0.62) had the highest OR (4.9, 95% C. I. 3.2–7.8, p = 0.00001) to develop pathologic ALT. Conclusions We have i) showed for the first time that the magnitude of the association of PNPLA3 with liver enzymes is driven by the size of abdominal fat and ii) stratified the individual risk to develop liver damage on the basis of the interaction between the PNPLA3 genotype and abdominal fat.

Predicting Metabolic Syndrome in Obese Children and Adolescents: Look, Measure and Ask

Objective: To verify in obese children whether or not the presence of i) high waist-to-height ratio (WHtR), ii) family history for type 2 diabetes (T2D) and iii) acanthosis nigricans (AN), singularly or together, might predict the occurrence of metabolic syndrome or prediabetes. Methods. 1,080 Italian obese children (567 females) were enrolled. Blood pressure, fasting plasma glucose, insulin, and lipids were measured, and oral glucose tolerance test (OGTT) was performed. The WHtR was calculated, family history for T2D was assessed, and the presence of AN was noticed. The odds ratios for showing metabolic syndrome and/or prediabetes according to the presence of these features were calculated. Results: The prevalence of metabolic syndrome was 29.2%. AN (OR1.81; p = 0.002) and WHtR higher than 0.60 (OR 2.24; p < 0.0001) were the clinical signs linked to higher risk for showing metabolic syndrome, and the odds raised significantly when these elements occurred simultaneously (OR 3.34; p < 0.0001). T2D family history (OR 2.36; p = 0.01) and WHtR higher than 0.60 (OR 2.32; p = 0.009) were the two features associated with increased odds of showing prediabetes. Conclusions: Three simple actions, i.e., looking at the patient, asking about T2D family history, and measuring WHtR, may represent a powerful tool in the hands of pediatricians to identify obese children with high cardiovascular and metabolic risk.

High-normal fasting glucose levels are associated with increased prevalence of impaired glucose tolerance in obese children.

The natural history of impaired glucose tolerance (IGT) and Type 2 diabetes among obese children is not clear. Although the cut-off for impaired fasting glucose (IFG) has recently been changed from 110 (6.1 mmol/l) to 100 mg/dl (5.6 mmol/l), it does not seem a reliable way to find all subjects with impaired glucose homeostasis. The aim of our study was to determine whether high-normal fasting glucose level could predict the occurrence of IGT and metabolic syndrome. Three hundred and twenty-three Italian obese children and adolescents were included in the study (176 females, mean age 11±2.9 yr; mean body mass index z-score: 3±0.6). Waist circumference, serum glucose, insulin, triglyceride, cholesterol HDL, blood pressure were evaluated and an oral glucose tolerance test (OGTT) was performed. The prevalence of IFG and IGT were respectively 1.5% (5 subjects) and 5% (18 patients); no diabetic patients were found. Metabolic syndrome was diagnosed in 20% of patients. Fasting glycemia values <100 mg/dl (5.6 mmol/l) have been divided in quintiles. Metabolic syndrome prevalence increased across quintiles, although not in a statistically significantly manner, but it could depend on the selected diagnostic criteria as no univocal definition exists for metabolic syndrome in youths. Interestingly high-normal fasting plasma glucose levels constitute an independent risk factor for IGT among obese children and adolescents; therefore, this very easy-to-use parameter may help to identify obese patients at increased risk of diabetes or at least could suggest in which subjects to perform an OGTT.

Effect of the rs997509 Polymorphism on the Association between Ectonucleotide Pyrophosphatase Phosphodiesterase 1 and Metabolic Syndrome and Impaired Glucose Tolerance in Childhood Obesity

CONTEXT Variants on the nucleotide pyrophosphatase/phosphodiesterase-1 (ENPP-1) gene have been associated with obesity and insulin resistance. Because insulin resistance is a pivotal factor in the development of metabolic syndrome (MS) and impaired glucose tolerance (IGT), we aimed to test the association between the K121Q and rs997509 ENPP-1 variants with obesity, MS and IGT in obese children and adolescents. METHODS We screened 809 children, 409 obese and 400 lean controls. Obese subjects underwent a standard oral glucose tolerance test, whole body insulin sensitivity index (WBISI) and homeostasis model assessment (HOMA) were calculated. RESULTS No difference in prevalence for K121Q and rs997509 polymorphisms between obese and controls (P > 0.05) were observed. Obese children carrying the rs997509 rare allele showed higher insulin (P = 0.001), HOMA (P < .001) and lower WBISI values (P = 0.04) compared with common allele homozygous. A similar observation was done for K121Q variant, with 121Q allele carriers showing higher insulin (P = 0.03) and HOMA (P = 0.04) values than 121K homozygotes. Moreover, subjects carrying the rs997509 rare allele had higher risk of MS (odds ratio 2.4, 95% confidence interval: 1.3-4.3) and IGT (odds ratio 4.7, 95% confidence interval: 1.9-11.4) than common allele homozygotes. Evaluating combined effects of both polymorphisms, which are in strong linkage disequilibrium, we showed that the effect on insulin sensitivity was due to the rs997509 T variant. CONCLUSION We conclude that the ENPP1 rs997509T allele can predispose obese children to MS and IGT and that this variant might drive the association between the ENPP1 121Q allele and insulin resistance.

Improvement of glucose homeostasis after weight loss in obese children.

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