Effects of growth hormone therapy on metabolic parameters, adipokine and endothelial dysfunction in prepuberal children.

AIM: To determine whether non-obese prepubertal children with growth hormone deficiency (GHD) present changes in lipid metabolism, and adipokines, and to assess the short-term effects of growth hormone (GH) treatment on these parameters. METHODS: Prospective observational follow-up and case-control (36 GHD children and 38 healthy children) study lasted for six months. Means of values from groups were compared, control group versus GHD baseline group, and GHD baseline group versus GHD after six months of GH replacement therapy. Lipid profile, glucose, insulin, homeostatic model assessment - insulin resistance (HOMA-IR), leptin, adiponectin and soluble intercellular adhesion molecule-1 (sICAM-1) were all analysed. RESULTS: Growth hormone deficiency children show higher baseline levels of total cholesterol, LDL cholesterol, triglycerides, Apo B and sICAM-1, but lower levels of free fatty acids, insulin and HOMA-IR. After six months of treatment, cholesterol, LDL cholesterol, Apo B, T cholesterol/HDL cholesterol, insulin, HOMA-IR and leptin levels decreased. The changes in insulin and HOMA-IR levels correlated inversely with the changes in HDL cholesterol and Apo A1 levels. A correlation was also observed between the changes in adiponectin levels and the changes in HDL cholesterol and Apo A1 levels. Variations in leptin levels were correlated with changes in triglycerides. CONCLUSION: Prepubertal non-obese GHD children present altered lipid profiles and adipokine levels. Replacement therapy with GH improves these variables.

Leptin Receptor Gene Variant rs11804091 Is Associated with BMI and Insulin Resistance in Spanish Female Obese Children: A Case-Control Study.

Leptin is an endocrine hormone that has a critical role in body weight homoeostasis and mediates its effects via the leptin receptor (LEPR). Common polymorphisms in the genes coding leptin receptors have been associated with metabolic abnormalities. We assessed the association of 28 LEPR polymorphisms with body mass index (BMI) and their relationship with obesity-related phenotypes, inflammation and cardiovascular disease risk biomarkers. A multicentre case-control study was conducted in 522 children (286 with obesity and 236 with normal-BMI). All anthropometric, metabolic factors and biomarkers were higher in children with obesity except apolipoprotein (Apo)-AI, cholesterol, high-density lipoprotein cholesterol (HDL-c), and adiponectin, which were lower in the obesity group; and glucose, low-density lipoprotein cholesterol (LDL-c), and matrix metalloproteinase-9 that did not differ between groups. We identified the associations between rs11208659, rs11804091, rs10157275, rs9436303 and rs1627238, and BMI in the whole population, as well as the association of rs11804091, rs10157275, and rs1327118 with BMI in the female group, although only the rs11804091 remained associated after Bonferroni correction (p = 0.038). This single nucleotide polymorphisms (SNP) was also associated with insulin (p = 0.004), homeostasis model assessment for insulin resistance (HOMA-IR) (p = 0.006), quantitative insulin sensitivity check index (QUICKI) (p = 0.005) and adiponectin (p = 0.046) after adjusting for age, Tanner stage and BMI. Our results show a sex-specific association between the rs11804091 and obesity suggesting an influence of this SNP on insulin resistance.

Association of serum uric acid levels to inflammation biomarkers and endothelial dysfunction in obese prepubertal children.

BACKGROUND: High serum uric acid (SUA) levels are present in patients with metabolic syndrome (MetS), when the latter is associated with endothelial dysfunction, inflammation, and hypertension. This increase in SUA levels may have a key role in cardiovascular diseases. OBJECTIVE: We aim to quantify the differences in inflammation biomarkers, endothelial dysfunction, and parameters associated with MetS in obese prepubertal children compared to non-obese children, and determine if there is a relationship between uric acid levels and these variables. METHODS: A cross-sectional study was carried out on obese children (6-9 yr old). The study included 43 obese children and the same number of non-obese children (control group), matched by age and sex. SUA, C-reactive protein (CRP), interleukin-6 (IL-6), soluble intercellular adhesion molecule-1 (sICAM-1), glucose, insulin, lipid profile, and blood pressure were all measured. RESULTS: SUA levels, CRP, and sICAM-1 were significantly higher in obese children. In the obese group, SUA levels showed a positive correlation with body mass index (BMI), insulin, homeostasis model assessment for insulin resistance (HOMA-IR), CRP, IL-6, sICAM-1, and triglycerides (TGs), and correlated negatively with high-density lipoprotein cholesterol (HDL-C) and Apo-AI, but not with Apo-B. When adjusted for age, sex, and creatinine, it was noted that SUA levels are independent predictive factors for sICAM-1, CRP, and IL-6. CONCLUSIONS: Inflammation biomarkers, endothelial dysfunction, and parameters associated with MetS are elevated in obese prepubertal children and correlate to uric acid levels.

A Continuous Metabolic Syndrome Score Is Associated with Specific Biomarkers of Inflammation and CVD Risk in Prepubertal Children.

BACKGROUND/AIMS: We aimed to evaluate the use of a continuous metabolic syndrome (MetS) score and to assess the associations of this score with risk biomarkers of inflammation, endothelial damage and cardiovascular disease (CVD) in prepubertal children. METHODS: A total of 677 prepubertal children (295 obese, 146 overweight, and 236 normal-weight) were recruited. MetS traits, markers of inflammation, endothelial damage and CVD risk were measured, and a continuous MetS score was calculated, consisting of the sum/5 of the standardised scores of the MetS components. RESULTS: The continuous MetS score was significantly associated with active plasminogen activator inhibitor-1 (r = 0.406, p < 0.001), adiponectin (r = -0.212, p < 0.001), resistin (r = 0.263, p < 0.001), C-reactive protein (r = 0.254, p < 0.001), tumour necrosis factor alpha (r = 0.120, p = 0.003), myeloperoxidase (r = 0.188, p < 0.001) and sE-selectin (r = 0.278, p < 0.001). Children in the normal-weight, overweight and obese groups with MetS totalled 0 (0%), 1 (0.7%) and 24 (8.7%), respectively, whereas the at-risk children identified using the continuous MetS score in each group totalled 2 (0.85%), 17 (11.6%) and 167 (56.6%), respectively. CONCLUSIONS: The association of the continuous MetS score with specific risk biomarkers of inflammation, endothelial damage and CVD supports its use in the early identification of children at increased risk of metabolic dysfunction.

Successful training of self-sufficient interventional paediatric cardiology team in a sub-Saharan setting: a multicentre collaborative model.

BACKGROUND: Most children in the Third World do not have access to treatment for heart diseases, as the priorities of health care are different from the developed countries. MATERIALS AND METHODS: Since 2009, teams supported by the Chain of Hope and Spanish medical volunteers have travelled twice a year to help develop paediatric cardiac services in the Cardiac Center in Ethiopia, undertaking four missions each year. As of December 2012, 296 procedures were performed on 287 patients. The procedures included 128 duct occlusions, 55 pulmonary valve dilations, 25 atrial septal defect closures, 14 mitral valve dilations, and others. The local staff were trained to perform a majority of these cases. RESULTS: Procedural success was achieved in 264 (89.2%). There were three deaths, five device embolisations, and three complications in mitral valve dilation. During the visits, the local staff were trained including one cardiologist, six nurses, and two technicians. The local team performed percutaneous interventions on its own after a couple of years. The goal is also to enable the local team to perform interventions independently. CONCLUSION: Training of an interventional cardiology team in a sub-Saharan setting is challenging but achievable. It may be difficult for a single centre to commit to sending frequent missions to a developing country to make a meaningful contribution to the training of local teams. In our case, coordination between the teams from the two countries helped to achieve our goals.

Genome-wide expression in visceral adipose tissue from obese prepubertal children.

Characterization of the genes expressed in adipose tissue (AT) is key to understanding the pathogenesis of obesity and to developing treatments for this condition. Our objective was to compare the gene expression in visceral AT (VAT) between obese and normal-weight prepubertal children. A total of fifteen obese and sixteen normal-weight children undergoing abdominal elective surgery were selected. RNA was extracted from VAT biopsies. Microarray experiments were independently performed for each sample (six obese and five normal-weight samples). Validation by quantitative PCR (qPCR) was performed on an additional 10 obese and 10 normal-weight VAT samples. Of 1276 differentially expressed genes (p < 0.05), 245 were more than two-fold higher in obese children than in normal-weight children. As validated by qPCR, expression was upregulated in genes involved in lipid and amino acid metabolism (CES1, NPRR3 and BHMT2), oxidative stress and extracellular matrix regulation (TNMD and NQO1), adipogenesis (CRYAB and AFF1) and inflammation (ANXA1); by contrast, only CALCRL gene expression was confirmed to be downregulated. In conclusion, this study in prepubertal children demonstrates the up- and down-regulation of genes that encode molecules that were previously proposed to influence the pathogenesis of adulthood obesity, as well as previously unreported dysregulated genes that may be candidate genes in the aetiology of obesity.

Percutaneous balloon dilation of severe pulmonary valve stenosis in patients with cyanosis and congestive heart failure.

OBJECTIVES: This article reports outcomes of percutaneous balloon dilation in patients with severe pulmonary valve stenosis, in particular in those treated late with cyanosis, congestive heart failure, and pericardial effusion. BACKGROUND: Percutaneous balloon dilation is the treatment of choice for pulmonary valve stenosis. Although earlier intervention may produce better results, patients may present late with congestive heart failure and cyanosis. METHODS: Fifty-five patients who underwent pulmonary valve balloon dilation, were grouped into two groups, based on the presence or absence of congestive right heart failure and/or central cyanosis. Group I included 33 patients with severe pulmonary valve stenosis, but without clinical evidence of congestive right heart failure in the form of liver enlargement, raised jugular venous pressure, and peripheral edema and/or central cyanosis and group II included 22 patients with severe pulmonary valve stenosis and congestive right heart failure and/or central cyanosis. Their outcomes were compared. RESULTS: Doppler measured transvalvar pressure gradient decreased from 110.2 ± 34.0 mm Hg before to 52.5 ± 28.7 mm Hg in group I after dilation (P < 0.001), and from 138.4 ± 32.3 mm Hg to 53.9 ± 19.3 mm Hg in group II, (P < 0.001). Complications included ventricular tachycardia/fibrillation in three patients and severe bradycardia in one patient in group II. Twelve patients in group II developed clinical and radiologic evidence of reperfusion injury/pulmonary edema within the first 24 hr of intervention and needed ventilation for 2-9 days. Three of these patients died from intractable pulmonary edema. On follow up, clinical and echocardiographic improvement parameters were similar in the two groups. CONCLUSION: Those patients with severe pulmonary valve stenosis with congestive right heart failure, especially those with pericardial effusion, ascites and cyanosis, represent an important technical and clinical challenge. They are a high-risk group with or without treatment. If they survive the procedure, they may still remain at a high risk in the first few days afterward. Maintaining their ventilator and inotropic support after balloon dilation may increase survival. However, excellent results can be obtained.

Waist-to-height ratio, inflammation and CVD risk in obese children.

OBJECTIVE: To evaluate the association between waist-to-height ratio (WHtR) and specific biomarkers of inflammation, CVD risk and endothelial dysfunction in prepubertal obese children. DESIGN: Prospective, multicentre case-control study matched by age and sex. SETTING: Children were recruited between May 2007 and May 2010 from primary-care centres and schools in three cities in Spain (Cordoba, Santiago de Compostela and Zaragoza). SUBJECTS: Four hundred and forty-six (223 normal weight and 223 obese) Caucasian prepubertal children aged 6-12 years. RESULTS: WHtR was higher in the obese than in the normal-weight children. Blood pressure, waist circumference, weight, height, insulin, plasma lipids, leptin, resistin, abnormal neutrophil and monocyte counts, C-reactive protein, IL-6, IL-8, TNF-α, myeloperoxidase, soluble intercellular adhesion molecule-1, selectin and plasminogen activator inhibitor-1 levels were higher in the obese than in the normal-weight group. Adiponectin and HDL-cholesterol were lower and glucose and metalloproteinase-9 showed no differences. Resistin, TNF-α and active plasminogen activator inhibitor-1 were associated with WHtR, a sensitive indicator of central obesity. CONCLUSIONS: Our results lead to the hypothesis that changes in biomarker levels of insulin resistance, inflammation and CVD risk before puberty might induce metabolic consequences of obesity in obese children before reaching adulthood.

Influence of FTO variants on obesity, inflammation and cardiovascular disease risk biomarkers in Spanish children: a case-control multicentre study.

BACKGROUND: Variants in the FTO gene have been associated with obesity in children, but this association has not been shown with other biomarkers. We assessed the association of 52 FTO polymorphisms, spanning the whole gene, with obesity and estimated the influence of these polymorphisms on anthropometric, clinical and metabolic parameters as well as inflammation and cardiovascular disease (CVD) risk biomarkers among Spanish children. METHODS: A multicentre case-control study was conducted in 534 children (292 obese and 242 with normal-BMI). Anthropometric, clinical, metabolic, inflammation and CVD risk markers were compared using the Student's t-test for unpaired samples. The genotype relative risk was assessed by comparing the obese and normal-BMI group, calculating the odds ratio. The association of each SNP with phenotypic parameters was analysed using either logistic or linear regression analysis. RESULTS: All anthropometric, clinical and metabolic factors as well as inflammatory and CVD risk biomarkers were higher in the obese than in the normal-BMI group, except adiponectin and HDL-c that were lower, and glucose, LDL-c, and metalloproteinase-9 that did not show difference. Four polymorphisms (rs9935401, rs9939609, rs9928094 and rs9930333) were positively associated with obesity and in linkage disequilibrium between each other; the haplotype including the risk alleles of these polymorphisms showed a high risk for obesity. The rs8061518 was negatively associated with obesity and the haplotype including this SNP and rs3826169, rs17818902 and rs7190053 showed a decreased risk for obesity. Additionally, the rs8061518 was associated with weight, diastolic blood pressure, insulin, homeostatic model assessment of insulin resistance, leptin, and active plasminogen inhibitor activator-1 after sex and age adjustment; however, after an additional BMI adjustment, this polymorphism remained associated only with leptin. CONCLUSIONS: We validated the previous reported association of genetic variability in intron 1 of the FTO gene with the risk of obesity and found no association with other related traits in this region of the gene. We have observed strong statistical evidence for an association of rs8061518 in intron 3 of the gene with decreased risk of obesity and low concentration of leptin.

Discrete subpulmonic membrane in association with isolated severe pulmonary valvar stenosis.

BACKGROUND: Subpulmonic membrane as a cause of right ventricular outflow tract obstruction in patients with concordant ventriculoarterial connection and intact ventricular septum is considered to be rare. CASE PRESENTATION: A 7-year-old boy was referred to a tertiary care hospital with complaints of dyspnea on moderate exertion and palpitations of about 2 years duration. Physical examination revealed parasternal lift, systolic thrill and a 4/6 ejection systolic murmur, best heard over the left 2nd intercostal space. His oxygen saturation was 88% on room air. Two-dimensional echocardiography showed a thickened pulmonary valve with fused leaflets that show severe systolic doming. There was a discrete subpulmonic membrane about 1.3 cm below the pulmonary valve annulus. Continuous wave Doppler interrogation showed peak systolic pressure gradient of 185 mmHg across the pulmonary valve. Balloon dilation of the pulmonary valve was performed and the pressure gradient came down to 50 mmHg. Follow-up transthoracic echocardiography showed residual pressure gradient of about 50-60 mmHg across the pulmonary valve. The residual pressure gradient appeared to be mainly subvalvar, as seen on the continuous wave Doppler tracing. The patient reported marked improvement in terms of exercise tolerance and subjective symptoms. CONCLUSIONS: Association of subpulmonic membrane with severe pulmonary valvar stenosis, concordant ventriculoarterial connection and intact ventricular septum is rare. When it occurs, the result of percutaneous valve dilation may be suboptimal.

Relationship between changes in plasma leptin concentrations and plasminogen activator inhibitor-1 in obese prepubertal children after nine months of treatment.

BACKGROUND/AIMS: The metabolic syndrome (MS) is associated with insulin resistance (IR), inappropriate fibrinolysis and high plasma leptin concentrations. The aim of this study was to quantify fibrinolysis and MS-related variables in obese prepubertal children and to evaluate changes in these variables as a result of improved body mass index (BMI), IR and leptin levels following 9 months of treatment. METHODS: The homeostasis model assessment for insulin resistance (HOMA-IR), leptin, plasminogen activator inhibitor-1 (PAI-1) and lipid profile were studied at baseline in obese (n = 50) and nonobese children (n = 50), and after 9 months of treatment in obese children. RESULTS: In the cross-sectional study the mean values for insulin, HOMA-IR, triglycerides, leptin and PAI-1 were significantly higher in obese children than in controls. High-density lipoprotein cholesterol (HDLc) and apolipoprotein A-1 were significantly lower. In the longitudinal study, after 9 months, children with lowered BMI standard deviation score displayed a significant decrease in insulin, HOMA-IR, PAI-1, leptin and triglyceride levels, and an increase in HDLc. Only leptin proved to be an independent predictive factor for changes in PAI-1 (p = 0.010). CONCLUSION: Obesity-linked disorders appear in obese children prior to puberty; these disorders can be improved by decreasing BMI. Changes in leptin levels were found to independently predict changes in PAI-1 in obese children and can help to diagnose complications associated with the obesity.

Changes in liver enzymes are associated with changes in insulin resistance, inflammatory biomarkers and leptin in prepubertal children with obesity.

BACKGROUND: Non-alcoholic fatty liver disease is associated with obesity. A subclinical inflammation state, endothelial dysfunction, and parameters related to metabolic syndrome (MetS), have been documented in children with obesity. We aimed to determine the changes that occur in liver enzymes levels in response to the standard treatment of childhood obesity, also assessing any associations with liver enzyme levels, leptin, and markers of insulin resistance (IR), inflammation, and parameters related to MetS in prepubertal children. METHODS: We carried out a longitudinal study in prepubertal children (aged 6-9 years) of both sexes with obesity; a total of 63 participants were recruited. Liver enzymes, C-reactive protein (CRP), interleukin-6, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), soluble intercellular adhesion molecule-1 (sICAM-1), leptin, homeostasis model assessment for IR (HOMA-IR), and parameters related to MetS were measured. RESULTS: After standard treatment for 9 months, children who lowered their standardised body mass index (SDS-BMI) had significantly lower systolic blood pressure (p = 0.0242), diastolic blood pressure (p = 0.0002), HOMA-IR (p = 0.0061), and levels of alanine aminotransferase (ALT) (p = 0.0048), CRP (p = 0.0001), sICAM-1 (p = 0.0460), and IL-6 (p = 0.0438). There was a significant association between the changes that occur with treatment, in the ALT levels, and changes in leptin (p = 0.0096), inflammation biomarkers [CRP (p = 0.0061), IL-6 (p = 0.0337), NLR (p = 0.0458), PLR (p = 0.0134)], and HOMA-IR (p = 0.0322). CONCLUSION: Our results showed that a decrease in ALT levels after the standard treatment for 9 months was associated with favourable changes in IR markers (HOMA-IR) and inflammation (IL-6, CRP, NLR, and PLR).

Hormone replacement therapy in children with growth hormone deficiency: impact on immune profile.

Growth hormone (GH) may influence the immune system. The aim of this study was to assess the immune profile after treatment with GH in pre-pubertal children with a deficiency of this hormone. The study was carried out in two phases. Two groups were included in the first phase: group A) children treated with GH; group B) untreated children, prior to starting treatment. In the second phase, group B children were assessed 6 months after starting treatment. In the first phase, groups A and B were compared (case-control study). In the second phase, group B was compared in terms of baseline and final times (before and after study). We analysed: humoral immunity (immunoglobulin (Ig)A, IgG, IgM, C1 inhibitor, C3, and C4) and cell-mediated immunity (CD3+, CD4+, CD8+, CD4+/CD8+, CD19+ lymphocytes, and natural killer (NK) cells). Insulin-like growth factor 1 (IGF-1) and insulin-like growth factor-binding protein 3 (IGFBP-3) were also determined. In the first phase, CD3+, CD4+, CD19+, and NK cells and CD4+/CD8+ were greater in the treated group. CD8+ was lower in this group. No variations were seen in immunoglobulins and the complement between both groups. There were no changes to the complement in either of the two phases. In the second phase, untreated patients were assessed after 6 months of treatment. When comparing the baseline and final immune profiles, a statistically significant decrease in IgG and IgM was observed, and an increase of IGF-1 levels and monocytes. In conclusion, our study shows changes in the cellular and humoral immune profiles in children with GH deficiency who were treated.

Liver Enzymes Correlate With Metabolic Syndrome, Inflammation, and Endothelial Dysfunction in Prepubertal Children With Obesity.

Background: Metabolic syndrome (MetS) can start in children with obesity at very young ages. Non-alcoholic fatty liver disease (NAFLD) is considered to be the hepatic component of metabolic syndrome. If left untreated, the clinical course of NAFLD can be progressive and can become chronic if not detected at an early stage. Objective: We aimed to quantify the differences in liver enzymes between prepubertal children with obesity and children with normal weight to determine any associations between them and parameters related to MetS, adipokines, or markers of endothelial dysfunction and inflammation. Methods: This cross-sectional study included 54 prepuberal children with obesity (aged 6-9 years) and 54 children with normal weight, matched by age and sex. Liver enzymes, C-reactive protein (CRP), interleukin-6, soluble intercellular adhesion molecule-1 (sICAM-1), adipokines, and parameters related to metabolic syndrome (MetS) were all measured. Results: Alanine aminotransferase (ALT) levels, serum butyryl cholinesterase (BChE), leptin, CRP, sICAM-1, triglycerides, blood pressure, and homeostasis model assessment for insulin resistance were significantly higher in children with obesity, while Apolipoprotein A-1, HDL-cholesterol, and adiponectin were significantly lower. In the children with obesity group, ALT and BChE levels correlated with anthropometric measurements, insulin resistance, and lipid parameters, leptin, interleukin-6, CRP, and sICAM-1 while BChE levels negatively correlated with adiponectin. Conclusions: Compared to children with normal weight, prepubertal children with obesity had elevated values for liver enzymes, leptin, markers of insulin resistance, inflammation, and endothelial dysfunction, and variables associated with MetS. There was also a correlation between these disorders and liver enzyme levels.

Evaluation of the gut microbiota after metformin intervention in children with obesity: A metagenomic study of a randomized controlled trial.

BACKGROUND: Metformin, a first-line oral antidiabetic agent that has shown promising results in terms of treating childhood and adolescent obesity, might influence the composition of the gut microbiota. We aimed to evaluate whether the gut microbiota of non-diabetic children with obesity changes after a metformin intervention. METHODS: The study was a multicenter and double-blind randomized controlled trial in 160 children with obesity. Children were randomly assigned to receive either metformin (1 g/day) or placebo for 6 months in combination with healthy lifestyle recommendations in both groups. Then, we conducted a metagenomic analysis in a subsample obtained from 33 children (15 metformin, 18 placebo). A linear mixed-effects model (LMM) was used to determine the abundance changes from baseline to six months according to treatment. To analyze the data by clusters, a principal component analysis was performed to understand whether lifestyle habits have a different influence on the microbiota depending on the treatment group. RESULTS: Actinobacteria abundance was higher after placebo treatment compared with metformin. However, the interaction time x treatment just showed a trend to be significant (4.6% to 8.1% after placebo vs. 3.8 % to 2.6 % after metformin treatment, p = 0.055). At genus level, only the abundance of Bacillus was significantly higher after the placebo intervention compared with metformin (2.5% to 5.7% after placebo vs. 1.5 % to 0.8 % after metformin treatment, p = 0.044). Furthermore, different ensembles formed by Firmicutes, Bacteroidetes, and Verrucomicrobia were found according to the interventions under a similar food consumption. CONCLUSION: Further studies with a large sample size controlled by lifestyle patterns are required in obese children and adolescents to clarify whether metformin might trigger gut microbiota alterations. TRIAL REGISTRATION: Registered on the European Clinical Trials Database (EudraCT, ID: 2010-023061-21) on 14 November 2011.

Common Variants in 22 Genes Regulate Response to Metformin Intervention in Children with Obesity: A Pharmacogenetic Study of a Randomized Controlled Trial.

Metformin is a first-line oral antidiabetic agent that has shown additional effects in treating obesity and metabolic syndrome. Inter-individual variability in metformin response could be partially explained by the genetic component. Here, we aimed to test whether common genetic variants can predict the response to metformin intervention in obese children. The study was a multicenter and double-blind randomized controlled trial that was stratified according to sex and pubertal status in 160 children with obesity. Children were randomly assigned to receive either metformin (1g/d) or placebo for six months after meeting the defined inclusion criteria. We conducted a post hoc genotyping study in 124 individuals (59 placebo, 65 treated) comprising finally 231 genetic variants in candidate genes. We provide evidence for 28 common variants as promising pharmacogenetics regulators of metformin response in terms of a wide range of anthropometric and biochemical outcomes, including body mass index (BMI) Z-score, and glucose, lipid, and inflammatory traits. Although no association remained statistically significant after multiple-test correction, our findings support previously reported variants in metformin transporters or targets as well as identify novel and promising loci, such as the ADYC3 and the BDNF genes, with plausible biological relation to the metformin's action mechanism. Trial Registration: Registered on the European Clinical Trials Database (EudraCT, ID: 2010-023061-21) on 14 November 2011 (URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2010-023061-21/ES).

X chromosome genetic data in a Spanish children cohort, dataset description and analysis pipeline.

X chromosome genetic variation has been proposed as a potential source of missing heritability for many complex diseases, including obesity. Currently, there is a lack of public available genetic datasets incorporating X chromosome genotype data. Although several X chromosome-specific statistics have been developed, there is also a lack of readily available implementations for routine analysis. Here, we aimed: (1) to make public and describe a dataset incorporating phenotype and X chromosome genotype data from a cohort of 915 normal-weight, overweight and obese children, and (2) to deeply describe a whole implementation of the special X chromosome analytic process in genetics. Datasets and pipelines like this are crucial to get familiar with the steps in which X chromosome requires special attention and may raise awareness of the importance of this genomic region.

Effects of X-chromosome Tenomodulin Genetic Variants on Obesity in a Children's Cohort and Implications of the Gene in Adipocyte Metabolism.

Tenomodulin (TNMD) is a type II transmembrane glycoprotein that has been recently linked to obesity, and it is highly expressed in obese adipose tissue. Several sex-dependent associations have been observed between single-nucleotide polymorphisms (SNPs) of the TNMD gene, which is located in the X-chromosome, and obesity, type 2 diabetes mellitus (T2DM), and metabolic syndrome in adults. On the other hand, results are lacking for children. We aimed (i) to study the association between TNMD genetic variants and metabolic complications related to childhood obesity and (ii) to investigate the function of TNMD in human adipocytes. We conducted a case-control, multicenter study in 915 Spanish children and demonstrated significant positive associations between TNMD genetic variants and BMI z-score, waist circumference, fasting glucose, and insulin resistance in boys, highlighting the SNP rs4828038. Additionally, we showed a BMI-adjusted inverse association with waist circumference in girls. Second, in vitro experiments revealed that TNMD is involved in adipogenesis, along with glucose and lipid metabolism in differentiated adipocytes, and these effects may be mediated through AMPK activation. Hence, these results suggest that TNMD genetic variants could be potentially useful as early life risk indicators for obesity and T2DM. In addition, we support the fact that TNMD exhibits significant metabolic functions in adipocytes.

Alterations in plasma and tissue lipids associated with obesity and metabolic syndrome.

The MS (metabolic syndrome) is a cluster of clinical and biochemical abnormalities characterized by central obesity, dyslipidaemia [hypertriglyceridaemia and decreased HDL-C (high-density lipoprotein cholesterol)], glucose intolerance and hypertension. Insulin resistance, hyperleptinaemia and low plasma levels of adiponectin are also widely related to features of the MS. This review focuses on lipid metabolism alterations associated with the MS, paying special attention to changes in plasma lipids and cellular fatty acid oxidation. Lipid metabolism alterations in liver and peripheral tissues are addressed, with particular reference to adipose and muscle tissues, and the mechanisms by which some adipokines, namely leptin and adiponectin, mediate the regulation of fatty acid oxidation in those tissues. Activation of the AMPK (AMP-dependent kinase) pathway, together with a subsequent increase in fatty acid oxidation, appear to constitute the main mechanism of action of these hormones in the regulation of lipid metabolism. Decreased activation of AMPK appears to have a role in the development of features of the MS. In addition, alteration of AMPK signalling in the hypothalamus, which may function as a sensor of nutrient availability, integrating multiple nutritional and hormonal signals, may have a key role in the appearance of the MS.