Estudio de intervención en pérdida de peso y cambios en los valores de parámetros metabólicos, antropométricos y modulación de fenotipos intermedios y la aparición de fenotipos finales tras el seguimiento de una dieta mediterránea hipocalórica y actividad física

El Síndrome metabólico junto a la obesidad son las grandes pandemias del siglo XXI estimando su prevalencia global superior al 30%. El Síndrome metabólico comienza con la obesidad central, siendo ésta la que promueve la aparición de otras alteraciones y factores de riesgo (la resistencia a la insulina, la hipertensión y la dislipidemia). La prevención de la obesidad y del Síndrome metabólico permitirá reducir la incidencia actual de enfermedades crónicas, incluidas la diabetes, las enfermedades cardiovasculares y distintos tipos de cáncer, que, a su vez, son causas cada vez más importantes de discapacidad y muerte prematura. En el desarrollo del Síndrome metabólico intervienen diversos factores. En los últimos años, las ciencias ómicas han revolucionado la investigación biomédica, aumentando el potencial para investigar los mecanismos moleculares de este tipo de patologías. Actualmente existen nuevas herramientas genómicas para analizar el riesgo de enfermedad y son una gran oportunidad teniendo en cuenta que el riesgo de una persona de desarrollar una enfermedad se ve afectado no solo por su genoma (susceptibilidad genética) sino también por la exposición a factores ambientales (el llamado exposoma en una definición amplia). De esta forma, factores extrínsecos como son cambios en el estilo de vida y dieta, tratamientos con fármacos, aspectos psicosociales, etc. pueden modular estas variaciones epigenéticas y por consiguiente la expresión de estos genes vinculados al desarrollo de la enfermedad. Esta Tesis se centra en el análisis de los participantes en el estudio PREDIMED-Plus-Valencia. Se trata de una población de edad avanzada con síndrome metabólico y sobrepeso/obesidad con un elevado riesgo de sufrir enfermedades cardiovasculares y otros fenotipos cardiometabólicos relacionados. Los hábitos dietéticos de la población eran poco saludables y presentaban un elevado porcentaje de sedentarismo. Una intervención intensiva con dieta mediterránea hipocalórica junto con un incremento de la actividad física dentro de un ensayo aleatorizado de intervención, podría ser eficaz consiguiendo una pérdida de peso y una mejora de parámetros cardiometabólicos resultando una reducción del riesgo cardiovascular y de otros fenotipos relacionados, en comparación con un grupo control. Además, hemos analizado otras variables relevantes en los estudios nutricionales como la percepción del sabor y las preferencias por sabores y por alimentos, determinando que existen asociaciones importantes entre la intensidad de percepción de los distintos sabores y parámetros de adiposidad basales, difiriendo entre ellos. Es más, la creación de la denominada “total taste score” como indicador de percepción global del sabor nos ha permitido conocer que tiene una fuerte asociación inversa con la adiposidad (p<0,001). Otras variables de interés (impulsividad, cognitivas, sueño), mostraron asociaciones entre patrones de riesgo cardiometabólico y ser más impulsivo o el cronotipo vespertino, e influir también en los patrones de dieta. Del mismo modo, se determinaron resultados sobre algunos marcadores ómicos (genómicos, epigenómicos, transcriptómicos, metabolómicos), mostrando la necesidad de ser incorporados en estos estudios para conocer su contribución en los distintos fenotipos y exposiciones analizadas y valorar su posible aplicación en la denominada salud de precisión. La realización de GWAS para investigar la influencia de los marcadores genómicos en la percepción de los cinco sabores en los participantes del nodo de Valencia, ha permitido confirmar la fuerte influencia genética en la capacidad de percibir el sabor amargo, concretamente en el gen TAS2R38. Respecto a variantes genéticas asociadas con las preferencias por los distintos sabores, los resultados más relevantes los hemos obtenido con el sabor dulce. Se identificaron varios SNP en el gen PTPNR2 superando la significación estadística a nivel de GWAS. Por otra parte, en los análisis epigenómicos detectamos una importante influencia de factores del exposoma en la metilación del ADN. Esta asociación fue muy significativa entre el estado de fumador y la metilación del ADN, caracterizando la huella metilómica de exposición al tabaco (fumadores, exfumadores y nunca fumadores) en esta población. De todos los lugares de metilación estadísticamente asociados, podemos destacar como más significativo el cg21566642 en el cromosoma 2, en el que el consumo de tabaco ocasiona una hipometilación, al igual que sucede con otros lugares de metilación de la huella metilómica. Esta hipometilación, en algunos lugares CpG puede ser modulada por una mayor adherencia a la dieta mediterránea. Igualmente, hemos visto que la intervención con dieta mediterránea puede modular expresión de varios genes, tanto a nivel de genes candidatos como de transcriptoma completo en un análisis piloto. A pesar de que el periodo de intervención coincidió con la pandemia de COVID-19, las medidas de contingencia para realizar las intervenciones online y otras alternativas exitosas pudieron mitigar el impacto de la pandemia en los resultados.Metabolic syndrome together with obesity are the great pandemics of the 21st century, with an estimated global prevalence of more than 30%. Metabolic syndrome begins with abdominal obesity that often leads to the appearance of other alterations and risk factors (insulin resistance, high blood pressure and dyslipidemia). Preventing obesity and metabolic syndrome will reduce the currently high rate of chronic diseases, including diabetes, cardiovascular diseases and different types of cancer, which are all increasingly important causes of disability and premature death. Various factors are involved in the development of metabolic syndrome. In recent years, omic sciences have revolutionized biomedical research, allowing us to investigate the molecular mechanisms of this type of pathology. There are now new genomic tools for analyzing disease risk and these provide a great opportunity, as an individual's risk of developing a disease is affected not only by their genome (genetic susceptibility) but also by exposure to environmental factors (referred to as the exposome in a broad definition). Hence, extrinsic factors such as changes in lifestyle and diet, drug treatments, psychosocial aspects, etc. can modulate these epigenetic variations and, therefore, the expression of those genes linked to the development of the disease. This Thesis focuses on the analysis of participants in the PREDIMED-Plus-Valencia study. This is an elderly population with metabolic syndrome and overweight/obesity at high risk of cardiovascular disease and other related cardiometabolic phenotypes. The dietary habits of the population were not very healthy as well as presenting a high percentage of sedentary lifestyle. An intensive intervention with a hypocaloric Mediterranean diet together with an increase in physical activity in a randomized intervention trial proved to be effective, achieving weight loss and an improvement in cardiometabolic parameters, resulting in a reduction in cardiovascular risk and other related phenotypes, in comparison with the control group. In addition, we analyzed other relevant variables in nutritional studies such as taste perception and food and taste preferences, finding that there are important associations between the intensity of different taste perceptions and baseline adiposity parameters, there being differences between them. Moreover, the creation of the so-called "total taste score" as an indicator of global taste perception allowed us to observe that this has a strong inverse association with adiposity (p<0.001). Other variables of interest (impulsivity, cognitive, sleep) revealed associations between cardiometabolic risk patterns and being more impulsive or the evening chronotype, also influencing dietary patterns. Moreover, results were obtained for several omic markers (genomic, epigenomic, transcriptomic, metabolomic), so underlining the need for these to be incorporated into these studies to better understand their contribution to the different phenotypes and exposures analyzed, and to assess their possible application in so-called precision health. Carrying out GWAS to investigate the influence of genomic markers on the perception of the five tastes in participants of the Valencia field center, confirmed a strong genetic influence on the ability to perceive bitter taste, specifically in the TAS2R38 gene. Regarding genetic variants associated with different taste preferences, the most relevant results were found for sweet taste. Several SNPs were identified in the PTPNR2 gene that exceeded statistical significance at the GWAS level. Furthermore, in epigenomic analyses we detected a significant influence of exposome factors on DNA methylation. This association was highly significant between smoking status and DNA methylation, having characterized the methylomic fingerprint of tobacco exposure (smokers, ex-smokers, and never smokers) in this population. Of all the statistically associated methylation sites, we can highlight the cg21566642 on chromosome 2 as the most significant, where tobacco consumption causes hypomethylation, as it does at other methylation sites of the DNA methylation signature. This hypomethylation, at some CpG sites, can be modulated by increased adherence to the Mediterranean diet. Likewise, we observed in a pilot analysis that a Mediterranean diet intervention can modulate the expression of several genes, both at the level of candidate genes and of the whole transcriptome. Despite the intervention period coinciding with the COVID-19 pandemic, contingency measures were taken to carry out online interventions and other successful alternatives that were able to mitigate the impact of the pandemic on the results

Associations between taste perception profiles and empirically derived dietary patterns: an exploratory analysis among older adults with metabolic syndrome

Taste perception is a primary driver of food choices; however, little is known about how perception of all five tastes (sweet, salt, sour, bitter, umami) collectively inform dietary patterns. Our aim was to examine the associations between a multivariable measure of taste perception—taste perception profiles—and empirically derived dietary patterns. The cohort included 367 community-dwelling adults (55–75 years; 55% female; BMI = 32.2 ± 3.6 kg/m2) with metabolic syndrome from PREDIMED-Plus, Valencia. Six taste perception profiles were previously derived via data-driven clustering (Low All, High Bitter, High Umami, Low Bitter and Umami, High All But Bitter, High All But Umami); three dietary patterns were derived via principal component analysis (% variance explained = 20.2). Cross-sectional associations between profiles and tertials of dietary pattern adherence were examined by multinomial logistic regression. Overall, there were several significant differences in dietary pattern adherence between profiles: the vegetables, fruits, and whole grains pattern was significantly more common for the High All But Umami profile (OR range for high vs. low adherence relative to other profiles (1.45–1.99; 95% CI minimum lower, maximum upper bounds: 1.05, 2.74), the non-extra virgin olive oils, sweets, and refined grains pattern tended to be less common for Low All or High Bitter profiles (OR range: 0.54–0.82), while the alcohol, salty foods, and animal fats pattern tended to be less common for Low Bitter and Umami and more common for High All But Bitter profiles (OR range: 0.55–0.75 and 1.11–1.81, respectively). In conclusion, among older adults with metabolic syndrome, taste perception profiles were differentially associated with dietary patterns, suggesting the benefit of integrating taste perception into personalized nutrition guidance

Dietary diversity and nutritional adequacy among an older Spanish population with Metabolic Syndrome in the PREDIMED-Plus study: a cross-sectional analysis

Dietary guidelines emphasize the importance of a varied diet to provide an adequate nutrient intake. However, an older age is often associated with consumption of monotonous diets that can be nutritionally inadequate, increasing the risk for the development or progression of diet-related chronic diseases, such as metabolic syndrome (MetS). To assess the association between dietary diversity (DD) and nutrient intake adequacy and to identify demographic variables associated with DD, we cross-sectionally analyzed baseline data from the PREDIMED-Plus trial: 6587 Spanish adults aged 55–75 years, with overweight/obesity who also had MetS. An energy-adjusted dietary diversity score (DDS) was calculated using a 143-item validated semi-quantitative food frequency questionnaire (FFQ). Nutrient inadequacy was defined as an intake below 2/3 of the dietary reference intake (DRI) forat least four of 17 nutrients proposed by the Institute of Medicine (IOM). Logistic regression models were used to evaluate the association between DDS and the risk of nutritionally inadequate intakes. In the higher DDS quartile there were more women and less current smokers. Compared with subjects in the highest DDS quartile, those in the lowest DDS quartile had a higher risk of inadequate nutrient intake: odds ratio (OR) = 28.56 (95% confidence interval (CI) 20.80–39.21). When we estimated food varietyfor each of the food groups, participants in the lowest quartile had a higher risk of inadequate nutrient intake for the groups of vegetables, OR = 14.03 (95% CI 10.55–18.65), fruits OR = 11.62 (95% CI 6.81–19.81), dairy products OR = 6.54 (95% CI 4.64–9.22) and protein foods OR = 6.60 (95% CI 1.96–22.24). As DDS decreased, the risk of inadequate nutrients intake rose. Given the impact of nutrient intake adequacy on the prevention of non-communicable diseases, health policies should focus on the promotion of a healthy varied diet, specifically promoting the intake of vegetables and fruit among population groups with lower DDS such as men, smokers or widow(er)s. View Full-Tex

Nut Consumptions as a Marker of Higher Diet Quality in a Mediterranean Population at High Cardiovascular Risk

Background: Nut consumption has been associated with improved nutrient adequacy and diet quality in healthy adult populations but this association has never been explored in individuals at high cardiovascular risk. Objective: to assess the associations between consumption of nuts and nutrient adequacy and diet quality in a Mediterranean population at high cardiovascular risk. Design: baseline assessment of nutritional adequacy in participants (n = 6060, men and women, with ages 55⁻75 years old, with overweight/obesity and metabolic syndrome) in the PREDIMED-PLUS primary cardiovascular prevention randomized trial. Methods: nut intake was assessed using a validated food frequency questionnaire. Participants who reported consuming zero quantity of nuts were classified as 'non-nut consumers'. 'Nut consumers' were participants who reported consuming any quantity of nuts. Nineteen micronutrients were examined (vitamins B1, B2, B3, B6, B12, A, C, D, E and folic acid; Ca, K, P, Mg, Fe, Se, Cr, Zn, and iodine). The proportion of micronutrient inadequacy was estimated using the estimated average requirements (EAR) or adequate intake (AI) cut-points. Diet quality was also assessed using a 17-item Mediterranean dietary questionnaire (Mediterranean diet score, MDS), a carbohydrate quality index (CQI) and a fat quality index (FQI). Results: eighty-two percent of participants were nut consumers (median of nut consumption 12.6 g/day; interquartile range: 6.0⁻25.2). Nut consumers were less likely to be below the EAR for vitamins A, B1, B2, B6, C, D, E, folic acid, and Ca, Mg, Se and Zn than non-nut consumers. Nut consumers were also more likely to be above the AI for K and Cr than non-nut consumers. Nut consumers had lower prevalence of inadequate micronutrient intakes, but also higher CQI, higher FQI, and better scores of adherence to the Mediterranean diet (Mediterranean diet score, MDS). Conclusions: nut consumers had better nutrient adequacy, diet quality, and adherence to the MedDiet than those non-nut consumers

Dietary folate intake and metabolic syndrome in participants of PREDIMED-Plus study: a cross-sectional study.

We examined the association between dietary folate intake and a score of MetS (metabolic syndrome) and its components among older adults at higher cardiometabolic risk participating in the PREDIMED-Plus trial. A cross-sectional analysis with 6633 with overweight/obesity participants with MetS was conducted. Folate intake (per 100 mcg/day and in quintiles) was estimated using a validated food frequency questionnaire. We calculated a MetS score using the standardized values as shown in the formula: [(body mass index + waist-to-height ratio)/2] + [(systolic blood pressure + diastolic blood pressure)/2] + plasma fasting glucose-HDL cholesterol + plasma triglycerides. The MetS score as continuous variable and its seven components were the outcome variables. Multiple robust linear regression using MM-type estimator was performed to evaluate the association adjusting for potential confounders. We observed that an increase in energy-adjusted folate intake was associated with a reduction of MetS score (β for 100 mcg/day = - 0.12; 95% CI: - 0.19 to - 0.05), and plasma fasting glucose (β = - 0.03; 95% CI: - 0.05 to - 0.02) independently of the adherence to Mediterranean diet and other potential confounders. We also found a positive association with HDL-cholesterol (β = 0.07; 95% CI: 0.04-0.10). These associations were also observed when quintiles of energy-adjusted folate intake were used instead. This study suggests that a higher folate intake may be associated with a lower MetS score in older adults, a lower plasma fasting glucose, and a greater HDL cholesterol in high-risk cardio-metabolic subjects

Nut Consumptions as a Marker of Higher Diet Quality in a Mediterranean Population at High Cardiovascular Risk

Background: Nut consumption has been associated with improved nutrient adequacy and diet quality in healthy adult populations but this association has never been explored in individuals at high cardiovascular risk. Objective: to assess the associations between consumption of nuts and nutrient adequacy and diet quality in a Mediterranean population at high cardiovascular risk. Design: baseline assessment of nutritional adequacy in participants (n = 6060, men and women, with ages 55⁻75 years old, with overweight/obesity and metabolic syndrome) in the PREDIMED-PLUS primary cardiovascular prevention randomized trial. Methods: nut intake was assessed using a validated food frequency questionnaire. Participants who reported consuming zero quantity of nuts were classified as 'non-nut consumers'. 'Nut consumers' were participants who reported consuming any quantity of nuts. Nineteen micronutrients were examined (vitamins B1, B2, B3, B6, B12, A, C, D, E and folic acid; Ca, K, P, Mg, Fe, Se, Cr, Zn, and iodine). The proportion of micronutrient inadequacy was estimated using the estimated average requirements (EAR) or adequate intake (AI) cut-points. Diet quality was also assessed using a 17-item Mediterranean dietary questionnaire (Mediterranean diet score, MDS), a carbohydrate quality index (CQI) and a fat quality index (FQI). Results: eighty-two percent of participants were nut consumers (median of nut consumption 12.6 g/day; interquartile range: 6.0⁻25.2). Nut consumers were less likely to be below the EAR for vitamins A, B1, B2, B6, C, D, E, folic acid, and Ca, Mg, Se and Zn than non-nut consumers. Nut consumers were also more likely to be above the AI for K and Cr than non-nut consumers. Nut consumers had lower prevalence of inadequate micronutrient intakes, but also higher CQI, higher FQI, and better scores of adherence to the Mediterranean diet (Mediterranean diet score, MDS). Conclusions: nut consumers had better nutrient adequacy, diet quality, and adherence to the MedDiet than those non-nut consumers

Dietary diversity and nutritional adequacy among an older Spanish population with Metabolic Syndrome in the PREDIMED-Plus study: a cross-sectional analysis

Dietary guidelines emphasize the importance of a varied diet to provide an adequate nutrient intake. However, an older age is often associated with consumption of monotonous diets that can be nutritionally inadequate, increasing the risk for the development or progression of diet-related chronic diseases, such as metabolic syndrome (MetS). To assess the association between dietary diversity (DD) and nutrient intake adequacy and to identify demographic variables associated with DD, we cross-sectionally analyzed baseline data from the PREDIMED-Plus trial: 6587 Spanish adults aged 55–75 years, with overweight/obesity who also had MetS. An energy-adjusted dietary diversity score (DDS) was calculated using a 143-item validated semi-quantitative food frequency questionnaire (FFQ). Nutrient inadequacy was defined as an intake below 2/3 of the dietary reference intake (DRI) forat least four of 17 nutrients proposed by the Institute of Medicine (IOM). Logistic regression models were used to evaluate the association between DDS and the risk of nutritionally inadequate intakes. In the higher DDS quartile there were more women and less current smokers. Compared with subjects in the highest DDS quartile, those in the lowest DDS quartile had a higher risk of inadequate nutrient intake: odds ratio (OR) = 28.56 (95% confidence interval (CI) 20.80–39.21). When we estimated food varietyfor each of the food groups, participants in the lowest quartile had a higher risk of inadequate nutrient intake for the groups of vegetables, OR = 14.03 (95% CI 10.55–18.65), fruits OR = 11.62 (95% CI 6.81–19.81), dairy products OR = 6.54 (95% CI 4.64–9.22) and protein foods OR = 6.60 (95% CI 1.96–22.24). As DDS decreased, the risk of inadequate nutrients intake rose. Given the impact of nutrient intake adequacy on the prevention of non-communicable diseases, health policies should focus on the promotion of a healthy varied diet, specifically promoting the intake of vegetables and fruit among population groups with lower DDS such as men, smokers or widow(er)s. View Full-Tex