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Childhood obesity has increased in recent years. In Spain about one in four children are overweight or obese, and most of them will carry this status into adulthood. Health consequences derived from obesity are numerous and complex, but the most frequent are those related to cardiometabolic risk and the future development of type 2 diabetes mellitus and cardiovascular disease. Different strategies have been proposed to reduce adiposity and improve metabolic outcomes in children with obesity. Lifestyle interventions that combined dietary, physical activity and behavioural approaches with family involvement appear to be the best options to prevent weight regain. Since, obesity development stands from the interplay between lifestyle and genetic factors it is important to understand how genetic markers could influence the weight loss response. Thus, the general objective of the present project is to evaluate the effect of two lifestyle interventions on cardiometabolic risk in children with obesity. The role of genetic markers in the individual response to the intervention will also be evaluated. This thesis project includes two different lifestyle programs: 1) the NUGENOI study based on a dietary intensive intervention (10 weeks), and 2) the IGENOI study, an integral intervention with a 2-year duration (2 months + 22 months of follow up). Both lifestyle interventions were able to reduce adiposity and improve metabolic outcomes. Parameters related to cardiometabolic risk such as inflammatory cytokines and oxidized LDL cholesterol were also diminished in children with obesity. In addition, changes in glucose metabolism derived from the lifestyle intervention were associated with cardiotrophin-1 gene expression at baseline. The integral intervention of IGENOI study includes the promotion of physical activity in children. Concerning this, children with abdominal obesity from the intensive care group were more physically active (+5.5 minutes of daily increase in moderate-to-vigorous physical activity assessed by accelerometry) and lowered their cardiometabolic risk after the intervention. In fact, favorable changes in MVPA were related to changes in leptin levels. Telomere length is influenced by oxidative stress and inflammatory status, these two processes are present in obese subjects. We observed inverse associations between telomere length and adiposity indices. Moreover, baseline telomere length seemed to be a marker of changes in glucose levels. Moreover, no change in TL was observed, despite achieving a successful decrease in BMI-SDS after the integral lifestyle intervention. Finally, IGENOI participants were screened for functional mutations in Melanocortin 4 Receptor (MC4R) and Lipocalin 2 (LCN2) genes. The prevalence for the two gene variants were 2.42% and 0.84% for MC4R and LCN2, respectively. These genetic variants seem to partially explain eating behaviours. Nevertheless, subjects with those functional mutations were able to decrease adiposity after our integral lifestyle intervention. In summary, lifestyle interventions conducted in children with obesity were effective in the reduction of adiposity and metabolic outcomes. It appears that telomere length and cardiotrophin-1 gene expression could have a predictive role in glucose metabolism outcomes. Meanwhile, MC4R and LCN2 mutations could influence eating behaviours but did not change the weight loss response.

Background: Some SNPs related to lipid and energy metabolism may be implicated not only in the development of obesity and associated comorbidities, but also in the weight loss response after a nutritional intervention. Objective: In this context, the present study analyzed four SNPs located within four genes known to be associated with obesity and other obesity-related complications, and their putative role in a weight-loss intervention in overweight/obese adolescents. Methods: The study population consisted of 199 overweight/obese adolescents (13-16 yr old) undergoing 10 weeks of a weight loss multidisciplinary intervention: the EVASYON programme (www.estudioevasyon.org). Adolescents were genotyped for 4 SNPs, and anthropometric measurements and biochemical markers were analyzed at the beginning and after the intervention. Results: Interestingly, APOA5(rs662799) was associated with the baseline anthropometric and biochemical outcomes, whereas FTO (rs9939609) seemed to be related with the change of these values after the 10-week intervention. The other two SNPs, located in the CETP (rs1800777) and the APOA1 (rs670) genes, showed important relationships with adiposity markers. Specifically, a combined model including both SNPs turned up to explain up to 24% of BMI-SDS change after 10 weeks of the multidisciplinary intervention, which may contribute to under - stand the weight loss response. Conclusion: Common variants in genes related to lipid and energy metabolism may influence not only biochemical outcomes but also weight loss response after a multidisciplinary intervention carried out in obese/overweight adolescents.. Antecedentes: Algunas variantes genéticas relacionadas con el metabolismo lipídico y energético pueden estar implicadas en la respuesta a una intervención nutricional además de estar asociadas con el desarrollo de obesidad y comorbilidades asociadas. Objetivo: En este sentido, este artículo analiza cuatro polimorfismos situados en cuatro genes que han sido previamente asociados con la obesidad u otras complicaciones asociadas a la misma, así como su posible papel en la respuesta a una intervención para la pérdida de peso en adolescentes con sobrepeso u obesidad. Métodos: La población en estudio está formada por 199 adolescentes con sobrepeso u obesidad (13-16 años) llevando a cabo una intervención multidisciplinar de 10 semanas para la pérdida de peso: programa EVASYON (www.estudioevasyon.org). Los adolescentes fueron genotipados para los 4 SNPs y tanto al comienzo como al final de la intervención se analizaron marcadores bioquímicos y se tomaron medidas antropométricas. Resultados: Rs662799 del gen APOA5 se asoció al inicio con parámetros antropométricos y bioquímicos, mientras que el rs9939609 del gen FTO parecía estar asociado con el cambio de estas variables tras 10 semanas de intervención. Las variantes rs1800777 del gen CETP y rs670 del gen APOA1 mostraron una importante asociación con marcadores de adiposidad. Concretamente, un modelo combinado incluyendo los dos polimorfismos logró explicar hasta un 24% del cambio en el IMC-SDS tras 10 semanas de intervención. Conclusión: Variantes genéticas previamente relacionadas con el metabolismo lipídico y energético, pueden repercutir no solamente en valores bioquímicos sino también en la respuesta a una intervención multidisciplinar para la pérdida de peso en adolescentes con sobrepeso u obesidad.

Dietary and serum total antioxidant capacity (TAC) are considered appropriate tools for investigating the potential healthy effects of dietary antioxidants consumed in mixed diets. The aim was to analyse the impact of a dietary intervention on macronutrient intakes and to evaluate the improvement on oxidative status after weight loss (WL) by measuring dietary and serum TAC, and urinary F2-isoprostane levels as markers of oxidative stress. Forty-four overweight/obese children (mean age 11.5yr) were enrolled to undergo a 10-week WL program. They were dichotomized at the median of Body Mass Index-Standard Deviation Score (BMI-SDS) change, as high (HR) and low responders (LR) after intervention. Subjects were prescribed a fixed full-day meal diet, calculated according to their basal metabolic rate and physical activity levels. A validated food-frequency questionnaire was used to retrospectively calculate TAC and daily nutrient intake. The HR subjects were able to reduce anthropometric indices and to improve lipid and glucose profile. They also significantly diminished fat intake (p=0.013). Moreover, baseline serum TAC values did significantly predict the reduction in urinary F2 isoprostane [B= -0.236 (-0.393 to -0.078); p=0.014] in the HR group after the WL program. Notably, changes in dietary TAC after the treatment were associated with a decrease in body weight after the 10-week intervention [B=-2.815 (-5.313 to -0.318), p=0.029] in the HR group. The -SerumTAC/DietaryTAC and the -F2Isoprostane/DietaryTAC ratios revealed that the relationships between oxidative markers and antioxidants dietary intake were more favourable in the HR than in the LR group. Conclusion: Our study showed that a 10-week WL program was able to reduce adiposity indices in obese children. Moreover, after the intervention changes in dietary TAC and WL were significantly associated. Our result suggests that specific food with a high TAC content (such as fruits, vegetables and legumes) could be recommended to improve WL.

This Doctoral Thesis reports the role of genetic and epigenetic variations on obesity risk, and weight loss response in three different populations of Spanish children and adolescents between 6 and 18 years old. The first manuscript examines the association of the -174 G/C SNP of the IL-6 gene and adiposity and inflammatory markers. For this purpose, 504 Spanish adolescents from the AVENA study were genotyped for the SNP, body measurements were taken and blood samples were collected. The association between body fat mass and some plasma markers was influenced by the presence of this polymorphism. Adolescents carrying the C allele showed higher values of lipoprotein(a) , C-reactive protein and triglycerides as their body fat mass increases. In the second study, the effect of the rs9939609 of the FTO on obesity risk was studied. The trial involved 354 children and adolescents (GENOI study) following a case-control study. In this study, we confirmed the association between the FTO SNP and obesity risk. Interestingly, an interaction between SFA consumption on the effect and the polymorphism on obesity risk was evidenced. The third research article evaluates the contribution of 9 SNPs on anthropometric and biochemical parameters before and after a weight loss intervention programme in 168 adolescents participating in the EVASYON programme. A genetic predisposition score (GPS) calculated from these polymorphisms revealed a significant effect size on body composition both at baseline and after 10 weeks of treatment. Adolescents with a lower GPS seemed to have greater benefit of weight loss after the intervention. Finally, the fourth publication explored baseline changes in DNA methylation that could be associated with a better weight loss response after an intervention in obese/overweight adolescents. A methylation score calculated from differentially methylated genes was associated with changes in anthropometric parameters after treatment. In addition, after a methylation array, five regions showed differential methylation levels between high and low responders to the intervention. In summary, data from the current Doctoral Thesis contribute to provide evidence of the influence that some genetic variants and epigenetic alterations could have on obesity and the weight loss response.

The rs9939609 polymorphism of the FTO gene has been widely associated with childhood obesity in several European cohorts. This association appears to be depending on dietary macronutrients. Therefore, our aim was to evaluate whether dietary fatty acid distribution intake could interact with this FTO genetic variation and obesity in a Spanish children and adolescents case-control study. 354 Spanish children and adolescents aged 6-18 (49% males) were genotyped for the rs9939609 variant of the FTO gene. Anthropometric parameters were taken and energy intake was measured. We observed an interaction between the percentage of saturated fatty acids (SFA) of diet over total energy intake as well as polyunsaturated/saturated (PUFA/SFA) fatty acid ratio and the association of the polymorphism with obesity risk. In our population the risk allele carriers consuming more than 12.6% SFA of their total energy value had an increased obesity risk compared with TT carriers. In the same way, A allele carriers that intake less than 0.43 PUFA/SFA ratio presented higher obesity risk than non A allele carriers. In summary, this study reports for the first time, the influence of dietary fatty acid distribution on the effect of the rs9939609 polymorphism of the FTO gene on obesity risk.

Dietary antioxidant intake has been suggested to protect against oxidative damage and related clinical complications. The aim of this study was to assess the potential relationships between the dietary total antioxidant capacity (TAC) and obesity-related features in children and adolescents. Anthropometric variables from 369 children and adolescents were measured (184 obese and 185 control). A validated food-frequency questionnaire was used to calculate the TAC and the daily nutrient and energy intake. Dietary TAC showed positive associations with fiber, folic acid, magnesium, and vitamins A, C and E. BMI, SDS-BMI and total body fat were inversely associated with dietary TAC only in obese subjects. These data suggest that dietary TAC may be a potential indicator of the risk to develop obesity-related features and could be considered as a useful method in assessing antioxidant intake.

Objective The melanocortin 4 receptor gene (MC4R) is involved in body weight regulation. While many studies associated MC4R mutations with childhood obesity, information on MC4R mutations in Spanish children and adolescents is lacking. Our objective was to screen a population of children and adolescents from the north of Spain (Navarra) for MC4R mutations and to study the phenotypes of carriers and their families. In addition, functional assays were performed for a novel MC4R mutation. Methods The study was composed of 451 Spanish children and adolescents (49% boys), aged 5–18 year. According to the International Obesity Task Force (IOTF) criteria, the groups included 160 obese, 132 overweight and 159 normal-weight control subjects. Results One novel (Thr162Arg) and three known nonsynonymous mutations in the MC4R gene (Ser30Phe, Thr150Ile, Ala244Glu) were detected heterozygously. The MC4R mutations were found in three male (one obese and two overweight) and two female subjects (one obese and one overweight). The novel mutation did not appear to lead to an impaired receptor function. An unequivocal relationship of MC4R mutations with obesity in pedigrees together with an impaired function of the encoded receptor could not be established for any of the mutations. Conclusions The presence of heterozygous MC4R mutations in obese and overweight subjects indicates that these mutations may be a susceptibility factor for obesity development, but lifestyle factors, such as exercise or sedentary activities, may modify their effect.