Effects of exercise on whole-blood transcriptome profile in children with overweight/obesity

Spanish Ministry of Economy and Competitiveness; MCIN/AEI/10.13039/ 501100011033ERFD A way of making Europe, Grant/Award Number: PID2021-127280OB-I00University of Jaén, Grant/Award Number: PAIUJAEI_ CTS02; Spanish Ministry of EducationCulture and Sport, Grant/Award Numbers: FPU 16/02760DEP2016-79512-R, DEP2013-47540; National Institutes of HealthGrant/Award Number: U01TR002004; Unit of Excellence on Exercise and Health; EXERNET Research Network on Exercise and Health in Special Populations, Grant/Award Number: DEP2005-00046/ ACTIUniversity of Granada, Plan Propio de Investigación 2016, Excellence actions; Junta de AndalucíaConsejería de Conocimiento, Investigaci on y UniversidadesEuropean Regional Development FundSigrid Jusélius Foundation; Jane and Aatos Erkko Foundation; Funding for open access charge: Universidad de Granada/CBU

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)

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

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

Transparent but Accurate Evolutionary Regression Combining New Linguistic Fuzzy Grammar and a Novel Interpretable Linear Extension

Scientists must understand what machines do (systems should not behave like a black box), because in many cases how they predict is more important than what they predict. In this work, we propose a new extension of the fuzzy linguistic grammar and a mainly novel interpretable linear extension for regression problems, together with an enhanced new linguistic tree-based evolutionary multiobjective learning approach. This allows the general behavior of the data covered, as well as their specific variability, to be expressed as a single rule. In order to ensure the highest transparency and accuracy values, this learning process maximizes two widely accepted semantic metrics and also minimizes both the number of rules and the model mean squared error. The results obtained in 23 regression datasets show the effectiveness of the proposed method by applying statistical tests to the said metrics, which cover the different aspects of the interpretability of linguistic fuzzy models. This learning process has obtained the preservation of high-level semantics and less than 5 rules on average, while it still clearly outperforms some of the previous state-of-the-art linguistic fuzzy regression methods for learning interpretable regression linguistic fuzzy systems, and even to a competitive, pure accuracyoriented linguistic learning approach. Finally, we analyze a case study in a real problem related to childhood obesity, and a real expert carries out the analysis shown.Andalusian Government P18-RT-2248Health Institute Carlos III/Spanish Ministry of Science, Innovation and Universities PI20/00711Spanish Government PID2019-107793GB-I00 PID2020-119478GB-I0

Longitudinal associations between cardiovascular biomarkers and metabolic syndrome during puberty: the PUBMEP study

Puberty has been described as a life stage of considerable metabolic risk specially for those with obesity. The low-grade systemic inflammatory status associated with obesity could be one of the connections with metabolic syndrome (MetS). Thus, we aimed to assess the relationship between inflammatory and cardiovascular biomarkers and the development of MetS during puberty. Seventy-five children from the PUBMEP study (33 females), aged 4–18 years, were included. Cardiovascular and inflammatory biomarkers were measured in the prepubertal and pubertal stage, including high-sensitivity C-reactive protein (CRP), leptin, tumor necrosis factor-alpha (TNFα), interleukin 8 (IL8), monocyte chemoattractant protein 1 (MCP-1), total plasminogen activator inhibitor-1 (tPAI), resistin, adiponectin, myeloperoxidase (MPO), and soluble intercellular adhesion molecule-1 (sICAM-1). MetS was diagnosed at each measurement point. Mixed-effects and logistic regressions were performed. Those children with MetS in puberty presented higher prepubertal values of several cardiometabolic biomarkers in comparison to those without MetS (z-score body mass index (zBMI), waist circumference, insulin, HOMA-IR, leptin, and tPAI (p < 0.05)). For prepubertal children with obesity, the odds of developing MetS in puberty were significantly higher in those having high zBMI (OR = 4.27; CI: 1.39–22.59) or high concentrations of tPAI (OR = 1.19; CI: 1.06–1.43). Conclusion: Those with obesity with higher prepubertal tPAI plasma levels had 19% higher odds of having MetS at puberty highlighting the existence of association between MetS, obesity, and inflammation already in puberty. Thus, assessing cardiometabolic and inflammatory status in children with obesity already at prepuberty is key to avoiding future comorbidities.CRUE-CSIC agreementSpringer NaturePlan Nacional de Investigacion Cientifica, Desarrollo e Innovacion Tecnologica (I + D + I), Instituto de Salud Carlos III-Health Research PI11/01425 PI11/02042 PI11/02059 PI16/01301 PI16/01205 PI16/00871 PI20/00563CIBEROBN Network CB15/00131 CB15/00043Redes tematicas de investigacion cooperativa RETIC Red SAMID RD12/0026/001

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

The Vitamin D Decrease in Children with Obesity Is Associated with the Development of Insulin Resistance during Puberty: The PUBMEP Study

This work was supported by the Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica (I + D + I), Instituto de Salud Carlos III-Health Research Funding (FONDOS FEDER) (PI11/01425, PI11/02042, PI11/02059, PI16/01301, PI16/01205, PI16/00871 and PI20/00563); CIBEROBN Network (CB15/00131, CB15/00043); Redes temáticas de investigación cooperativa RETIC (Red SAMID RD12/0026/0015). The authors also acknowledge Instituto de Salud Carlos III for personal funding: Contratos i-PFIS: doctorados IIS-empresa en ciencias y tecnologías de la salud de la convocatoria 2017 de la Acción Estratégica en Salud 2013–2016 (IFI17/00048). E.M.G.-G. holds a Juan de la Cierva-Formación grant (FJCI-2017-34967) from the Ministerio de Ciencia e Innovación (Spanish Government). L.V.P. acknowledges financial support of the Visiting Professor Program from the Coordination for the Improvement of Higher Education Personnel (CAPES—Grant 88881.337237/2019-01), Brazil.Obesity and cardiometabolic risk have been associated with vitamin D levels even in children. The objective of the present study was to evaluate the association between insulin resistance (IR), cardiometabolic risk factors, and vitamin D in children from prepubertal to pubertal stages. A total of 76 children from the PUBMEP study, aged 4-12 years at baseline, were included. Children were evaluated in prepubertal and pubertal stages. Anthropometric measurements and selected cardiometabolic risk biomarkers, such as plasma glucose, blood lipids, insulin, adiponectin, leptin, and blood pressure, and serum 25-hydroxyvitamin D (25(OH)D) were determined. Children were categorized by obesity degree and IR status combined before and after puberty. Paired t-test and multivariate linear regression analyses were conducted. During puberty, the increase in triacylglycerols, insulin, and HOMA-IR and the decrease in QUICKI were significantly associated with the reduction in 25(OH)D (B = -0.274, p = 0.032; B = -0.219, p = 0.019; B = -0.250, p = 0.013; B = 1.574, p = 0.013, respectively) after adjustment by BMI-z, sex, and pubertal stage. Otherwise, prepubertal non-IR children with overweight/obesity that became IR during puberty showed a significant decrease in 25(OH)D and HDL-c, and an increase in waist circumference and triacylglycerol concentrations (p < 0.05 for all) over time. These results suggest that changes in IR seem to be associated with an effect on 25(OH)D levels during puberty, especially in children with overweight.Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica (I + D + I)Instituto de Salud Carlos III-Health Research Funding (FONDOS FEDER) (PI11/01425, PI11/02042, PI11/02059, PI16/01301, PI16/01205, PI16/00871 and PI20/00563)CIBEROBN Network (CB15/00131, CB15/00043)Redes temáticas de investigación cooperativa RETIC (Red SAMID RD12/0026/0015)Instituto de Salud Carlos III (IFI17/00048)Juan de la Cierva-Formación grant (FJCI-2017-34967) Ministerio de Ciencia e Innovación (Spanish Government)Coordination for the Improvement of Higher Education Personnel (CAPES—Grant 88881.337237/2019-01), Brazi

Shared gene expression signatures between visceral adipose and skeletal muscle tissues are associated with cardiometabolic traits in children with obesity

Obesity in children is related to the development of cardiometabolic complications later in life, where molecular changes of visceral adipose tissue (VAT) and skeletal muscle tissue (SMT) have been proven to be fundamental. The aim of this study is to unveil the gene expression architecture of both tissues in a cohort of Spanish boys with obesity, using a clustering method known as weighted gene co-expression network analysis. For this purpose, we have followed a multi-objective analytic pipeline consisting of three main approaches; identification of gene co-expression clusters associated with childhood obesity, individually in VAT and SMT (intra-tissue, approach I); identification of gene co-expression clusters associated with obesitymetabolic alterations, individually in VAT and SMT (intra-tissue, approach II); and identification of gene co-expression clusters associated with obesity-metabolic alterations simultaneously in VAT and SMT (intertissue, approach III). In both tissues, we identified independent and inter-tissue gene co-expression signatures associated with obesity and cardiovascular risk, some of which exceeded multiple-test correction filters. In these signatures, we could identify some central hub genes (e.g., NDUFB8, GUCY1B1, KCNMA1, NPR2, PPP3CC) participating in relevant metabolic pathways exceeding multiple-testing correction filters. We identified the central hub genes PIK3R2, PPP3C and PTPN5 associated with MAPK signaling and insulin resistance terms. This is the first time that these genes have been associated with childhood obesity in both tissues. Therefore, they could be potential novel molecular targets for drugs and health interventions, opening new lines of research on the personalized care in this pathology. This work generates interesting hypotheses about the transcriptomics alterations underlying metabolic health alterations in obesity in the pediatric populationERDF/Health Institute Carlos III (grant numbers PI20/00711 and PI20/00563)ERDF/Regional Government of Andalusia/Ministry of Economic Transformation, Industry, Knowledge and Universities (grant numbers P18- RT-2248 and B-CTS-536-UGR20