ANGPTL-4 is Associated with Obesity and Lipid Profile in Children and Adolescents

Angiopoietin-like protein 4 (ANGPTL-4) regulates lipidic metabolism and affects energy homeostasis. However, its function in children with obesity remains unknown. We investigated plasma ANGPTL-4 levels in children and its relationship with body mass index (BMI) and different lipidic parameters such as free fatty acids (FFA). Plasma ANGPTL-4 levels were analyzed in two different cohorts. In the first cohort (n = 150, age 3–17 years), which included children with normal weight or obesity, we performed a cross-sectional study. In the second cohort, which included only children with obesity (n = 20, age 5–18 years) followed up for two years after an intervention for weight loss, in which we performed a longitudinal study measuring ANGPTL-4 before and after BMI-loss. In the cross-sectional study, circulating ANGPTL-4 levels were lower in children with obesity than in those with normal weight. Moreover, ANGPTL-4 presented a negative correlation with BMI, waist circumference, weight, insulin, homeostasis model assessment of insulin resistance index (HOMA index), triglycerides, and leptin, and a positive correlation with FFA and vitamin-D. In the longitudinal study, the percent change in plasma ANGPTL-4 was correlated with the percent change in FFA, total-cholesterol and high-density lipoprotein cholesterol. This study reveals a significant association of ANGPTL-4 with pediatric obesity and plasma lipid profile.This research was funded by INSTITUTO DE SALUD CARLOS III cofounded by FEDER, grants number PI18/00998, PI15/01272, PI11/02042, PI16/01301, and PI16/00871, and FUNDACIÓN MUTUA MADRILEÑ

Cluster Analysis of Physical Activity Patterns, and Relationship with Sedentary Behavior and Healthy Lifestyles in Prepubertal Children: Genobox Cohort

The authors would like to thank the children and parents who participated in the study and Ana Yara Postigo-Fuentes for the assistance with the English editing.Sedentary habits during childhood are associated with adverse health outcomes. The aim of this work was to cluster lifestyle behaviors and metabolic biomarkers to establish different patterns in children. Their physical and sedentary activities were evaluated by accelerometry, and questionnaires that included lifestyle behaviors, such as adherence to a Mediterranean diet, anthropometry and blood biochemical markers. Cluster analysis was performed to establish different groups based on physical activity levels. A total of 489 children were finally selected. Cluster 1 included children with a mostly sedentary state, whereas Cluster 3 included the most active children and Cluster 2 included children that did not fit into either the sedentary or the highly active groups. In Cluster 3, 56% of children were in a sports club, and a lower percentage used electronic devices in their rooms compared to the other groups. Cluster 1 children exhibited higher insulin, HOMA-IR and triacylglycerides with respect to the other groups. No differences were found regarding adherence to a Mediterranean diet. The choice to practice an extracurricular sport could be an influencing factor to increase exercise and ensure an active lifestyle in children. Reducing or limiting screen time mainly in children’s rooms could contribute to an active lifestyle.Plan Nacional de Investigacion Cientifica, Desarrollo e InnovacionTecnologica (I + D + I)Instituto de Salud Carlos III-Health Research Funding (FONDOS FEDER) PI051968 PI1102042 PI1600871Redes tematicas de investigacion cooperativa RETIC (Red SAMID) RD12/0026/0015Instituto de Salud Carlos III IFI17/0004

Genetic Factors and Molecular Mechanisms of Vitamin D and Obesity Relationship

This is the peer-reviewed but unedited manuscript version of the following article: [Ann Nutr Metab 2018;73:89–99 (DOI: 10.1159/000490669)]. The final, published version is available at http://www.karger.com/?doi=[10.1159/000490669].Vitamin D (vitD) deficiency is associated with a wide range of chronic diseases and conditions, including obesity, and with an increasing severity of metabolic dysregulation, such as insulin resistance, hyperlipidemia, liver disease, and hypertension, both in children and adults. However, the nature of the association between low vitD status and obesity remains unclear. This fact has motivated the scientific community to conduct genetic association analyses between 25-hydroxyvitamin D (25[OH]D)-related genes and obesity traits. In this line, the variation in the vitD receptor (VDR) gene represents the bulk of the findings. Specifically, polymorphisms in the VDR gene have been associated with obesity traits in some but not all, studies. Thus, results regarding this matter remain inconclusive. Other genes aside from VDR have also been investigated in relation to obesity-related traits. However, again, findings have been inconsistent. In general, results point to the fact that the DBP/GC gene could be an important protein-linking obesity and vitD status. On the other hand, several studies have attempted to determine the molecular mechanism of the relationship between 25(OH)-D levels and obesity. Some of these studies suggest that vitD, due to its fat-soluble characteristic, is retained by the adipose tissue and has the capacity to metabolize 25(OH)-D locally, and this can be altered during obesity. Additionally, vitD is capable of regulating the gene expression related to adipogenesis process, inflammation, oxidative stress, and metabolism in mature adipocytes. Therefore, the aim of the present review was to evaluate the association between obesity and vitD deficiency describing the main molecular mechanism of the relationship and the link with genetic factorsThis work was supported by Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica (I+D+I), Instituto de Salud Carlos III-Fondo de Investigación Sanitaria (PI1600871 and IFI17/00048) and Fondo Europeo De Desarrollo Regional (FEDER)

Circulating miRNAs as Biomarkers of Obesity and Obesity-Associated Comorbidities in Children and Adolescents: A Systematic Review

Early detection of obesity and its associated comorbidities in children needs priority for the development of effective therapeutic intervention. Circulating miRNAs (microRNAs) have been proposed as biomarkers for obesity and its comorbidities; therefore, we conducted a systematic review to summarize results of studies that have quantified the profile of miRNAs in children and adolescents with obesity and/or associated disorders. Nine studies aiming to examine differences in miRNA expression levels between children with normal weight and obesity or between obese children with or without cardiometabolic diseases were included in this review. We identified four miRNAs overexpressed in obesity (miR-222, miR-142–3, miR-140-5p, and miR-143) and two miRNAs (miR-122 and miR-34a) overexpressed in children with obesity and nonalcoholic fatty liver disease (NAFLD) and/or insulin resistance. In conclusion, circulating miRNAs are promising diagnostic biomarkers of obesity-associated diseases such as NAFLD and type 2 diabetes already in childhood. However, more studies in children, using massive search technology and with larger sample sizes, are required to draw any firm conclusions.This research was funded by the Spanish Ministry of Industry and Competitiveness (DEP2016-78377-R) and by the European Regional Development Fund (ERDF), M.O. is supported by a grant from the Spanish Ministry of Economy and Competitiveness, grant number; BES-2017-080770 and the APC was funded by additional support from the University of Granada, UGR Research and Knowledge Transfer Fund (PPIT) 2016, Excellence Actions Programme, and Excellence Actions Programe. C.M.A. and I.L.G. are part of the “URG Plan propio de Investigación 2016” and the “Excellence actions: Unit of Excellence on Exercise and Health (UCEES), University of Granada

Progression of metabolic syndrome and associated cardiometabolic risk factors from prepuberty to puberty in children: The PUBMEP study

Introduction: Metabolic syndrome (MetS) is a cluster of clinical and metabolic alterations related to the risk of cardiovascular diseases (CVD). Metabolic changes occurring during puberty, especially in children with overweight and obesity, can influence the risk of developing chronic diseases, especially CVD. Methods: Longitudinal study based on the follow-up until puberty of a cohort of 191 prepubertal Spanish boys and girls without congenital, chronic, or inflammatory diseases: undernutrition: or intake of any drug that could alter blood glucose, blood pressure, or lipid metabolism. The following parameters were used to determine the presence of MetS: obesity, hypertension, hyperglycemia, hypertriglyceridemia, and low HDL-c. Results: A total of 75·5% of participants stayed in the same BMI category from prepuberty to puberty, whereas 6·3% increased by at least one category. The prevalence of MetS was 9·1% (prepubertal stage) and 11·9% (pubertal stage). The risk of presenting alterations in puberty for systolic blood pressure (SBP), plasma triacylglycerols, HDL cholesterol (HDL-c), and HOMA-IR was significantly higher in those participants who had the same alterations in prepuberty. MetS prevalence in puberty was predicted by sex and levels of HOMA-IR, BMI-z, and waist circumference in the prepubertal stage, in the whole sample: in puberty, the predictors were levels of HOMA-IR, BMI-z, and diastolic blood pressure in participants with obesity. Two fast-and-frugal decision trees were built to predict the risk of MetS in puberty based on prepuberty HOMA-IR (cutoff 2·5), SBP (cutoff 106 mm of Hg), and TAG (cutoff 53 mg/dl). Discussion: Controlling obesity and cardiometabolic risk factors, especially HOMA-IR and blood pressure, in children during the prepubertal stage appears critical to preventing pubertal MetS effectively.Plan Nacional de Investigación Cientı́fica, Desarrollo e Innovación Tecnológica (I+D+I)Instituto de Salud Carlos III-Health Research Funding (FONDOS FEDER) (PI05/1968, PI11/01425, PI11/02042, PI11/ 02059, PI16/01301, PI16/01205, PI16/00871, PI20/00988, PI20/ 00924 and PI20/00563)CIBEROBN Network (CB15/00131, CB15/00043)Acción Estratégica en Salud 2013– 2016 (IFI17/00048)Research Plan of the Vice-Rectorate of Research and Transfer of the University of Granada, Spai

Serum levels of the novel adipokine isthmin‑1 are associated with obesity in pubertal boys

Objectives To evaluate whether there is an association between the serum levels of the novel insulin-like adipokine isthmin- 1 (ISM1) and obesity-related phenotypes in a population of Spanish children and to investigate the plausible molecular alterations behind the alteration of the serum levels of this protein in children with obesity. Methods The study population is a sub-cohort of the PUBMEP research project, consisting of a cross-sectional population of 119 pubertal children with overweight (17 boys, 19 girls), obesity (20 boys, 25 girls), and normal weight (17 boys, 21 girls). All subjects were classified into experimental groups according to their sex, obesity, and insulin resistance (IR) status. They were counted anthropometry, glucose and lipid metabolism, inflammation and cardiovascular biomarkers as well as isthmin-1 (ISM1) serum levels. This population was intended as a discovery population to elucidate the relationship between obesity and ISM1 levels in children. Furthermore, the study population had blood whole-genome DNA methylation examined, allowing deepening into the obesity–ISM1 molecular relationship. Results Higher serum ISM1 levels were observed in boys with obesity than in normal weight (P = 0.004) and overweight (P = 0.007) boys. ISM1 serum levels were positively associated with body mass index (BMI) Z-score (P = 0.005) and fat mass (P = 0.058) and negatively associated with myeloperoxidase (MPO) (P = 0.043) in boys. Although we did not find associations between ISM1 serum levels and metabolic outcomes in girls, which may indicate a putative sexual dimorphism, fat mass was positively associated in all children, including boys and girls (P = 0.011). DNA methylation levels in two-enhancer-related CpG sites of ISM1 (cg03304641 and cg14269097) were associated with serum levels of ISM1 in children. Conclusions ISM1 is associated with obesity in boys at the pubertal stage, elucidating how this protein might be of special relevance as a new biomarker of obesity in children. Further studies including a longitudinal design during puberty are needed.Universidad de Granada/CBUAPlan Nacional de Investigacion Cientifica, Desarrollo e Innovacion Tecnologica (I + D + I), Instituto de Salud Carlos III-Health Research Funding (FONDOS FEDER) PI051968 PI1102042 PI1600871Redes tematicas de Investigacion cooperativa RETIC Red SAMID RD12/0026/0015Mapfre Foundatio

Dietary Patterns and Their Association with Body Composition and Cardiometabolic Markers in Children and Adolescents: Genobox Cohort

Diet is a key factor for obesity development; however, limited data are available on dietary cluster analysis in children with obesity. We aimed to assess the associations between dietary patterns and obesity and several cardiometabolic markers. Anthropometry, bioelectrical impedance, blood pressure and plasma biomarkers of oxidative stress, inflammation and endothelial damage were determined in 674 Caucasian children, aged 5–16, with normal or excess weight. Using a food frequency questionnaire and cluster analysis, two consistent dietary patterns were shown, labeled as health conscious (HC) and sweet and processed (SP). The HC pattern included a greater proportion of participants with overweight/obesity than the SP cluster (80.1% vs. 63.8%). However, children with obesity within the HC cluster, showed less abdominal fat, through waist to hip (0.93 vs. 0.94) and waist to height (0.61 vs. 0.63) indexes (p < 0.01). Univariate general models showed several additional di erences in cardiometabolic risk biomarkers in the global and stratified analyses, with a healthier profile being observed mainly in the HC cluster. However, multivariate models questioned these findings and pointed out the need for further studies in this field. Anyhow, our findings support the benefits of a healthy diet and highlight the importance of dietary patterns in the cardiometabolic risk assessment of children with overweight/obesity, beyond weight control.Plan Nacional de Investigacion Cientifica, Desarrollo e Innovacion Tecnologica (I+D+I), Instituto de Salud Carlos III-Health Research Funding (FONDOS FEDER) PI05/1968 PI11/01425 PI11/02042 PI11/02059 PI16/01301 PI16/01205 PI1600871CIBEROBN Network CB15/00131 CB15/00043Juan de la Cierva-Formacion from the Spanish Government FJCI-2017-34967 FJCI-2014-19795Vice-Rectorate of Research and Transfer of the University of Granada, Spai

Extracellular Matrix Remodeling of Adipose Tissue in Obesity and Metabolic Diseases

The extracellular matrix (ECM) is a network of di erent proteins and proteoglycans that controls di erentiation, migration, repair, survival, and development, and it seems that its remodeling is required for healthy adipose tissue expansion. Obesity drives an excessive lipid accumulation in adipocytes, which provokes immune cells infiltration, fibrosis (an excess of deposition of ECM components such as collagens, elastin, and fibronectin) and inflammation, considered a consequence of local hypoxia, and ultimately insulin resistance. To understand the mechanism of this process is a challenge to treat the metabolic diseases. This review is focused at identifying the putative role of ECM in adipose tissue, describing its structure and components, its main tissue receptors, and how it is a ected in obesity, and subsequently the importance of an appropriate ECM remodeling in adipose tissue expansion to prevent metabolic diseases

Learning positive-negative rule-based fuzzy associative classifiers with a good trade-off between complexity and accuracy

Nowadays, the call for transparency in Artificial Intelligence models is growing due to the need to understand how decisions derived from the methods are made when they ultimately affect human life and health. Fuzzy Rule-Based Classification Systems have been used successfully as they are models that are easily understood by models themselves. However, complex search spaces hinder the learning process, and in most cases, lead to problems of complexity (coverage and specificity). This problem directly affects the intention to use them to enable the user to analyze and understand the model. Because of this, we propose a fuzzy associative classification method to learn classifiers with an improved trade-off between accuracy and complexity. This method learns the most appropriate granularity of each variable to generate a set of simple fuzzy association rules with a reduced number of associations that consider positive and negative dependencies to be able to classify an instance depending on the presence or absence of certain items. The proposal also chooses the most interesting rules based on several interesting measures and finally performs a genetic rule selection and adjustment to reach the most suitable context of the selected rule set. The quality of our proposal has been analyzed using 23 real-world datasets, comparing them with other proposals by applying statistical analysis. Moreover, the study carried out on a real biomedical research problem of childhood obesity shows the improved trade-off between the accuracy and complexity of the models generated by our proposal.Funding for open access charge: Universidad de Granada / CBUA.ERDF and the Regional Government of Andalusia/Ministry of Economic Transformation, Industry, Knowledge and Universities (grant numbers P18-RT-2248 and B-CTS-536-UGR20)ERDF and Health Institute Carlos III/Spanish Ministry of Science, Innovation and Universities (grant number PI20/00711)Spanish Ministry of Science and Innovation (grant number PID2019-107793GB-I00