Influencia del ambiente y la alimentación en la programación epigenética de la obesidad

El término epigenética hace referencia a los patrones hereditarios de la expresión de genes que se mantienen estables y que su- ceden sin que haya cambios en la secuencia de ADN. Los principales cambios en el patrón epigenético son: la metilación del ADN y la diferente organización de las histonas. Hay evidencias de que la metilación del genoma varía según los tejidos, los individuos o las condiciones de enfermedad, y se ha visto que la desorganización de la impronta genómica está relacionada con diferentes enfermeda- des en adultos, entre las que se encuentran la obesidad y/o el síndrome metabólico. El establecimiento de las marcas epigené- ticas durante el desarrollo puede estar in- fluenciado por factores ambientales como la dieta, principalmente por medio de nutrientes donantes de grupos metilo. Las alteraciones epigenéticas pueden ser debidas a la dieta parental (anterior al desarrollo intrauterino), al ambiente intrauterino y a la alimentación materna durante el embarazo, así como a las características de la alimentación peri y posnatal. Estas alteraciones epigenéticas INTRODUCCIÓN La programación de la obesidad puede darse por medio de al- teraciones permanentes de una o más vías relevantes durante el desarrollo embrionario y perinatal. Así, un tipo de alteraciones que afectan al desarrollo de obesidad y de síndrome metabólico en la edad adulta lo conforman los cambios en el patrón epige- nético. Dado que la obesidad es fundamentalmente un desor- den del balance energético, en el cual la energía ingerida excede pueden conservarse en el tiempo a través de sucesivas generaciones por su transmisión a la descendencia. A pesar de lo que ya se sabe, se necesitan nuevos trabajos que estudien los efectos de la alimentación en el estado epigenético del genoma y sus repercusiones fenotípicas a largo plazo para conocer mejor las posibles causas de la obesidad así como para diseñar nuevas estrategias para su prevenció

Dietary total antioxidant capacity is associated with leukocyte telomere length in a children and adolescent population

Background & Aims: Oxidative stress and inflammation seem to be potential underlying mechanisms for telomere attrition. A lack of specific antioxidants is believed to increase free radical damage and a greater risk for telomere shortening. Our aim was to evaluate the relationship between diet and leukocyte telomere length in a cross-sectional study of children and adolescents. We hypothesized that dietary total antioxidant capacity would be positively associated with telomere length. Methods: Telomere length was measured by quantitative real-time polymerase chain reaction in 287 participants (55% males, 6–18 years), who were randomly selected from the GENOI study. Results: A positive correlation between dietary total antioxidant capacity and telomere length (r=0.157, p=0.007) was found after adjustment for age and energy intake. However, higher white bread consumption was associated with shorter telomeres (β=-0.204, p=0.002) in fully-adjusted models. Interestingly, those individuals who had simultaneously higher dietary total antioxidant capacity and lower white bread consumption significantly presented the longest telomeres. Moreover, the multivariable-adjusted odds ratio for very short telomeres was 0.30 for dietary total antioxidant capacity (p=0.023) and 1.37 for white bread (p=0.025). Conclusion: It was concluded that longer telomeres were associated with higher dietary total antioxidant capacity and lower white bread consumption in S2panish children and adolescents. These findings might open a new line of investigation about the potential role of an antioxidant diet in maintaining telomere length

Asociación entre variantes genéticas relacionadas con el metabolismo lipídico y energético y la pérdida de peso tras una intervención en adolescentes con sobrepeso u obesidad

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.Research relating to this abstract was funded by grants from the Health Research Fund from the Carlos III Health Institute from Ministry of Health and Consumption, FIS (PI051579, PI051080) for the EVASYON project, Línea Especial, Nutrición y Obesidad (University of Navarra), CIBERobn and RETICS (Gob Navarra). The scholarships to A. Moleres from the Navarra Government is fully acknowledged

Il6 gene promoter polymorphism (-174G/C) influences the association between fat mass and cardiovascular risk factors

During the last decades, the prevalence of obesity has increased rapidly among young people. A polymorphism in the promoter region of the IL6 gene (-174G/C), has been previously reported to be involved in obesity and metabolic syndrome development. Therefore, the aim of the study was to examine whether the IL6 -174G/C polymorphism influence the association of body fat with low-grade inflammatory markers and blood lipids and lipoproteins in Spanish adolescents. 504 Spanish adolescents participating in the AVENA study were genotyped for the -174G/C polymorphism of the IL6 gene. Anthropometric and body composition measurements were taken and blood samples were collected for plasma molecules determinations. No differences between genotypes were observed in anthropometric values, body composition measurements and plasma markers concentration. Physical activity level differ between genotypes with subjects carrying the C allele of the polymorphism being significantly (p<0.05) more active than GG subjects. The association between body fat mass and plasma glucose was influenced by the -174G/C polymorphism of the IL6 gene. Subjects carrying the C allele of the mutation seem to have higher values of lipoprotein (a) and C-reactive protein as their percentage of body fat mass increase. Our results suggest that this promoter polymorphism influences the association between adiposity and some plasma markers

Design of the nutritional therapy for overweight and obese Spanish adolescents conducted by registered dieticians: the EVASYON study

Background: Dietary treatment for obese adolescents should aim to ensure adequate growth and development, by reducing excessive fat mass accumulation, avoiding loss of lean body mass, improving well-being and selfesteem and preventing cyclical weight regain. The aim of this article is to describe the dietary intervention design and the methods used to evaluate nutritional knowledge and behavior in the EVASYON study (Development, implementation and evaluation of the efficacy of a therapeutic programme for overweight/obese adolescents). Methods/design: EVASYON is a multi-centre study conducted in 5 Spanish hospital settings (Granada, Madrid, Pamplona, Santander and Zaragoza), where 204 overweight/obese Spanish adolescents were treated in groups of 9 to 11 subjects over 20 visits. The study was implemented in two stages: an intensive, calorie-restricted period for the first 9 weeks, and an extensive body-weight follow-up period for the last 11 months. A moderate energy intake restriction was applied in the intensive period according to the degree of obesity, on the basis of a balanced diet supplying 50-55% of daily energy as carbohydrates; 30-35% as fats and 10-15% as proteins. In the intensive period, adolescents were prescribed both a fixed full-day meal plan for the first three weeks and a full day meal plan with different food-choices for 6 weeks. Later, adolescents received a flexible meal plan based on food exchanges for the follow-up period until the end of the trial. Data on food intake, dietary and meal-related habits and behavior were collected by means of dietary questionnaires. To analyse nutritional knowledge, adolescents were examined regarding nutrient concepts and food items for a healthy diet with the appropriate tools. Participants were given nutritional information with complementary teaching material, which was available on the EVASYON website (www.estudioevasyon.com). Discussion: The dietary intervention of the EVASYON programme with a moderate calorie restriction for a limi - ted period of time could be a good strategy in treating overweight and obese adolescents and that will be tested further. Moreover, combining fixed plan with free-choice menus may help adolescents and their families to make right decisions for every day meals

Common variants in genes related to lipid and energy metabolism are associated with weight loss after an intervention in overweight/obese adolescents

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

Differential DNA methylation patterns between high and low responders to a weight loss intervention in overweight or obese adolescents: the EVASYON study

In recent years, epigenetic markers emerged as a new tool to understand the influence of lifestyle factors on obesity phenotypes. Adolescence is considered an important epigenetic window over a human's lifetime. The objective of this work was to explore baseline changes in DNA methylation that could be associated with a better weight loss response after a multidisciplinary intervention program in Spanish obese or overweight adolescents. Overweight or obese adolescents (n=107) undergoing 10 wk of a multidisciplinary intervention for weight loss were assigned as high or low responders to the treatment. A methylation microarray was performed to search for baseline epigenetic differences between the 2 groups (12 subjects/group), and MALDI-TOF mass spectrometry was used to validate (n=107) relevant CpG sites and surrounding regions. After validation, 5 regions located in or near AQP9, DUSP22, HIPK3, TNNT1, and TNNI3 genes showed differential methylation levels between high and low responders to the multidisciplinary weight loss intervention. Moreover, a calculated methylation score was significantly associated with changes in weight, BMI-SDS, and body fat mass loss after the treatment. In summary, we have identified 5 DNA regions that are differentially methylated depending on weight loss response. These methylation changes may help to better understand the weight loss response in obese adolescents

Telomere Length as a Biomarker for Adiposity Changes after a Multidisciplinary Intervention in Overweight/Obese Adolescents: The EVASYON Study

[Context] Telomeres are biomarkers of biological aging. Shorter telomeres have been associated with increased adiposity in adults. However, this relationship remains unclear in children and adolescents. [Objective] To evaluate the association between telomere length (TL) and adiposity markers in overweight/obese adolescents after an intensive program. We hypothesize that greater TL at baseline would predict a better response to a weight loss treatment. Design, Setting, Patients and Intervention The EVASYON is a multidisciplinary treatment program for adolescents with overweight and obesity that is aimed at applying the intervention to all possibly involved areas of the individual, such as dietary habits, physical activity and cognitive and psychological profiles. Seventy-four participants (36 males, 38 females, 12–16 yr) were enrolled in the intervention program: 2 months of an energy-restricted diet and a follow-up period (6 months). [Main Outcome] TL was measured by quantitative real-time polymerase chain reaction at baseline and after 2 months; meanwhile, anthropometric variables were also assessed after 6 months of follow-up. [Results] TL lengthened in participants during the intensive period (+1.9±1.0, p<0.001) being greater in overweight/obese adolescents with the shortest telomeres at baseline (r = −0.962, p<0.001). Multivariable linear regression analysis showed that higher baseline TL significantly predicted a higher decrease in body weight (B = −1.53, p = 0.005; B = −2.25, p = 0.047) and in standard deviation score for body mass index (BMI-SDS) (B = −0.22, p = 0.010; B = −0.47, p = 0.005) after the intensive and extensive period treatment respectively, in boys. [Conclusion] Our study shows that a weight loss intervention is accompanied by a significant increase in TL in overweight/obese adolescents. Moreover, we suggest that initial longer TL could be a potential predictor for a better weight loss response.Research relating to this work was funded by grants from the Health Research Fund from the Carlos III Health Institute from Ministry of Health and Consumption, Fondo de Investigación Sanitaria (FIS; PI051579, PI051080) for the EVASYON project; Línea Especial, Nutrición y Obesidad (University of Navarra); Spanish Ministry of Science and Innovation (MICINN) [SAF2010-20367]; Carlos III Health Institute [Centro de Investigación Biomédica en Red (CIBER) project, CB06/03/1017], and RETICS network. The scholarship to S. García-Calzón from the FPU ‘Formación de Profesorado Universitario’ from the Spanish Ministry is fully acknowledged

Influencia de alteraciones genéticas y epigenéticas sobre la obesidad y la pérdida de peso en niños y adolescentres españoles

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

Influencia de alteraciones genéticas y epigenéticas sobre la obesidad y la pérdida de peso en niños y adolescentres españoles

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