J. A. Martínez

Primary Prevention of Cardiovascular Disease with a Mediterranean Diet

BACKGROUND Observational cohort studies and a secondary prevention trial have shown an inverse association between adherence to the Mediterranean diet and cardiovascular risk. We conducted a randomized trial of this diet pattern for the primary prevention of cardiovascular events. METHODS In a multicenter trial in Spain, we randomly assigned participants who were at high cardiovascular risk, but with no cardiovascular disease at enrollment, to one of three diets: a Mediterranean diet supplemented with extra-virgin olive oil, a Mediterranean diet supplemented with mixed nuts, or a control diet (advice to reduce dietary fat). Participants received quarterly individual and group educational sessions and, depending on group assignment, free provision of extra-virgin olive oil, mixed nuts, or small nonfood gifts. The primary end point was the rate of major cardiovascular events (myocardial infarction, stroke, or death from cardiovascular causes). On the basis of the results of an interim analysis, the trial was stopped after a median follow-up of 4.8 years. RESULTS A total of 7447 persons were enrolled (age range, 55 to 80 years); 57% were women. The two Mediterranean-diet groups had good adherence to the intervention, according to self-reported intake and biomarker analyses. A primary end-point event occurred in 288 participants. The multivariable-adjusted hazard ratios were 0.70 (95% confidence interval [CI], 0.54 to 0.92) and 0.72 (95% CI, 0.54 to 0.96) for the group assigned to a Mediterranean diet with extra-virgin olive oil (96 events) and the group assigned to a Mediterranean diet with nuts (83 events), respectively, versus the control group (109 events). No diet-related adverse effects were reported. CONCLUSIONS Among persons at high cardiovascular risk, a Mediterranean diet supplemented with extra-virgin olive oil or nuts reduced the incidence of major cardiovascular events. (Funded by the Spanish governments Instituto de Salud Carlos III and others; Controlled-Trials.com number, ISRCTN35739639.).

The Diet, Obesity and Genes (Diogenes) Dietary Study in eight European countries – a comprehensive design for long-term intervention

Diogenes is a Pan‐European, randomized, controlled dietary intervention study investigating the effects of dietary protein and glycaemic index on weight (re)gain, metabolic and cardiovascular risk factors in obese and overweight families in eight European centres. The article is methodological in character, and the presentation of ‘results’ will be limited to baseline characteristics of the study populations included. A total of 891 families with at least one overweight/obese parent underwent screening. The parents started an initial 8‐week low‐calorie diet and families with minimum one parent attaining a weight loss of ≥8%, were randomized to one of five energy ad libitum, low‐fat (25–30 E%) diets for 6 or 12 months: low protein/low glycaemic index, low protein/high glycaemic index, high protein/low glycaemic index, high protein/high glycaemic index or control (national dietary guidelines). At two centres the families were provided dietary instruction plus free foods for 6 months followed by 6‐month dietary instruction only. At the remaining six centres the families received dietary instruction only for 6 months. The median weight loss during the low‐calorie diet was 10.3 kg (inter‐quartile range: 8.7–12.8 kg, n = 775). A total of 773 adults and 784 children were randomized to the 6‐month weight (re)gain prevention phase. Despite major cultural and dietary regional differences in Europe, interventions addressing effects of dietary factors are feasible with a reasonable attrition.

Flavonoids as anti-inflammatory agents: implications in cancer and cardiovascular disease.

Chronic inflammation is being shown to be increasingly involved in the onset and development of several pathological disturbances such as arteriosclerosis, obesity, diabetes, neurodegenerative diseases and even cancer. Treatment for chronic inflammatory disorders has not been solved, and there is an urgent need to find new and safe anti-inflammatory compounds. Flavonoids belong to a group of natural substances occurring normally in the diet that exhibit a variety of beneficial effects on health. The anti-inflammatory properties of flavonoids have been studied recently, in order to establish and characterize their potential utility as therapeutic agents in the treatment of inflammatory diseases. Several mechanisms of action have been proposed to explain in vivo flavonoid anti-inflammatory actions, such as antioxidant activity, inhibition of eicosanoid generating enzymes or the modulation of the production of proinflammatory molecules. Recent studies have also shown that some flavonoids are modulators of proinflammatory gene expression, thus leading to the attenuation of the inflammatory response. However, much work remains to be done in order to achieve definitive conclusions about their potential usefulness. This review summarizes the known mechanisms involved in the anti-inflammatory activity of flavonoids and the implications of these effects on the protection against cancer and cardiovascular disease.

Physical inactivity, sedentary lifestyle and obesity in the European Union.

BACKGROUND: Diverging trends of decreasing energy intake and increasing prevalence of obesity suggest that physical inactivity and sedentary lifestyle may be one of the key determinants of the growing rates of overweight/obesity in Western populations information about the impact of physical inactivity and sedentary lifestyles on the prevalence of obesity among the general adult population in the European Union is sparse.OBJECTIVES: To estimate the association of leisure-time sedentary and non-sedentary activities with body mass index (BMI, kg/m2) and with the prevalence of obesity (BMI>30 kg/m2) in a sample of the 15 member states of the European Union.METHODS: Professional interviewers administered standardized in-home questionnaires to 15,239 men and women aged 15 years upwards, selected by a multi-stage stratified cluster sampling with quotas applied to ensure national and European representativeness. Energy expenditure during leisure time was calculated based on data on frequency of and amount of time participating in various physical activities, assigning metabolic equivalents (METS) to each activity. Sedentary lifestyle was assessed by means of self-reported hours spent sitting down during leisure time. Multiple linear regression models with BMI as the dependent variable, and logistic regression models with obesity (BMI>30 kg/m2) as the outcome, were fitted.RESULTS: Independent associations of leisure-time physical activity (inverse) and amount of time spent sitting down (direct) with BMI were found. The adjusted prevalence odds ratio (OR) for obesity was 0.52 [95% confidence interval (CI): 0.43–0.64, P<0.001] for the upper quintile of physical activity (>30 METS) compared with the most physically inactive quintile (<1.75 METS). A positive independent association was also evident for the time spent sitting down, with an adjusted OR= 1.61(95% CI: 1.33–1.95, P<0.001) for those who spent more than 35 h of their leisure time sitting down compared with those who spent less than 15 h.Conclusions: Obesity and higher body weight are strongly associated with a sedentary lifestyle and lack of physical activity in the adult population of the European Union. These results, however, need to be interpreted with caution due to the cross-sectional design. Nonetheless, they are consistent with the view that a reduction in energy expenditure during leisure time may be the main determinant of the current epidemic of obesity.

Cohort Profile: Design and methods of the PREDIMED study

The Spanish Ministry of Health—Instituto de Salud Carlos III (ISCIII) funded the project for the period 2003–05 (RTIC G03/140). In 2006 a new funding modality was established by ISCIII through the CIBER (Centros de Investigacion Biomedica En Red). Fisiopatologia de la Obesidad y Nutricion (CIBERobn), which is providing funding for 7 of the original research groups, whereas the other 12 were funded by a new research network (RTIC RD 06/0045). Other official funds from Spanish government agencies have been obtained for subprojects related to intermediate outcomes (lipoproteins, inflammatory markers, vascular imaging, genomic and proteomic studies, etc.). Obviously, the donation by food companies of all the VOO and mixed nuts needed throughout the duration of the study is a substantial contribution.

Obesity and immune function relationships.

The immunological processes involved in the collaborative defence of organisms are affected by nutritional status. Thus, a positive chronic imbalance between energy intake and expenditure leads to situations of obesity, which may influence unspecific and specific immune responses mediated by humoral and cell mediated mechanisms. Furthermore, several lines of evidence have supported a link between adipose tissue and immunocompetent cells. This interaction is illustrated in obesity, where excess adiposity and impaired immune function have been described in both humans and genetically obese rodents. However, limited and often controversial information exist comparing immunity in obese and non‐obese subjects as well as about the cellular and molecular mechanisms implicated. In general terms, clinical and epidemiological data support the evidence that the incidence and severity of specific types of infectious illnesses are higher in obese persons as compared to lean individuals together with the occurrence of poor antibody responses to antigens in overweight subjects. Leptin might play a key role in linking nutritional status with T‐cell function. The complexities and heterogeneity of the host defences concerning the immune response in different nutritional circumstances affecting the energy balance require an integral study of the immunocompetent cells, their subsets and products as well as specific and unspecific inducer/regulator systems. In this context, more research is needed to clarify the clinical implications of the alterations induced by obesity on the immune function.

Randomized trial of weight-loss-diets for young adults varying in fish and fish oil content

Objective:To investigate the effect of including seafood and fish oils, as part of an energy-restricted diet, on weight loss in young overweight adults.Design:Randomized controlled trial of energy-restricted diet varying in fish and fish oil content was followed for 8 weeks. Subjects were randomized to one of four groups: (1) control (sunflower oil capsules, no seafood); (2) lean fish (3 × 150 g portions of cod/week); (3) fatty fish (3 × 150 g portions of salmon/week); (4) fish oil (DHA/EPA capsules, no seafood). The macronutrient composition of the diets was similar between the groups and the capsule groups, were single-blinded.Subjects:A total of 324 men and women aged 20–40 years, BMI 27.5–32.5 kg/m2 from Iceland, Spain and Ireland.Measurements:Anthropometric data were collected at baseline, midpoint and endpoint. Confounding factors were accounted for, with linear models, for repeated measures with two-way interactions. The most important interactions for weight loss were (diet × energy intake), (gender × diet) and (gender × initial-weight).Results:An average man in the study (95 kg at baseline receiving 1600 kcal/day) was estimated to lose 3.55 kg (95% CI, 3.14–3.97) (1); 4.35 kg (95% CI, 3.94–4.75) (2); 4.50 kg (95% CI, 4.13–4.87) (3) and 4.96 kg (95% CI, 4.53–5.40) on diet (4) in 4 weeks, from baseline to midpoint. The weight-loss from midpoint to endpoint was 0.45 (0.41–0.49) times the observed weight loss from baseline to midpoint. The diets did not differ in their effect on weight loss in women. Changes in measures of body composition were in line with changes in body weight.Conclusion:In young, overweight men, the inclusion of either lean or fatty fish, or fish oil as part of an energy-restricted diet resulted in ∼1 kg more weight loss after 4 weeks, than did a similar diet without seafood or supplement of marine origin. The addition of seafood to a nutritionally balanced energy-restricted diet may boost weight loss.

Individuality and epigenetics in obesity.

Excessive weight gain arises from the interactions among environmental factors, genetic predisposition and the individual behavior. However, it is becoming evident that interindividual differences in obesity susceptibility depend also on epigenetic factors. Epigenetics studies the heritable changes in gene expression that do not involve changes to the underlying DNA sequence. These processes include DNA methylation, covalent histone modifications, chromatin folding and, more recently described, the regulatory action of miRNAs and polycomb group complexes. In this review, we focus on experimental evidences concerning dietary factors influencing obesity development by epigenetic mechanisms, reporting treatment doses and durations. Moreover, we present a bioinformatic analysis of promoter regions for the search of future epigenetic biomarkers of obesity, including methylation pattern analyses of several obesity‐related genes (epiobesigenes), such as FGF2, PTEN, CDKN1A and ESR1, implicated in adipogenesis, SOCS1/SOCS3, in inflammation, and COX7A1 LPL, CAV1, and IGFBP3, in intermediate metabolism and insulin signalling. The identification of those individuals that at an early age could present changes in the methylation profiles of specific genes could help to predict their susceptibility to later develop obesity, which may allow to prevent and follow‐up its progress, as well as to research and develop newer therapeutic approaches.

Variables independently associated with self-reported obesity in the European Union

OBJECTIVE The rapid increase in obesity rates over recent years suggest that cultural and societal influences are affecting the adjustment in the energy balance equation in addition to other physiopathological or genetic determinants. Therefore, a pan-EU study was carried out to explore the influence of sociodemographic factors as well as some attitudes (smoking and exercise) on the prevalence of obesity in the adult population of all 15 member states of the EU. DESIGN Overall, a sample of 15,239 individuals aged 15 years and upwards in the EU completed the questionnaire. Subject selection was quota-controlled to make the sample nationally representative following a multistage stratified cluster sampling. Self-reported height and weight were used to calculate body mass index (BMI). RESULTS From the EU average results, it can be seen that only about half of the EU population (48%) is within the normal weight range, while the obesity (BMI > or = 30 kg m(-2)) prevalence was about 10% in the EU and the overweight prevalence was 36.6% and 25.6% among men and women, respectively. UK subjects had the highest prevalence of obesity (12%), while Italians, French and Swedes had the lowest levels of obesity (about 7%). Concerning age and social class interactions, logistic regression analysis showed that high social class and younger individuals in all groups had a lower odds ratio for obesity prevalence. People with a higher level of education are less likely to be obese, while the interaction between educational levels and obesity was different for men and women. A low participation in various leisure-time physical activities, the lack of interest (precontemplation) in being involved in exercise/physical activity and the increasing number of hours sitting down at work appear to be predictors of obesity. Single individuals were less prone to become obese than couples or widowed/divorced people. Finally, smoking status was statistically linked to the prevalence of obesity, since non-smokers or ex-smokers for more than 1 year presented a higher tendency for a BMI > 30. CONCLUSIONS This survey confirms that a priority area for health intervention aimed at preventing the development of obesity should be to increase levels of physical activity, although the approach will depend on the population, especially with respect to educational and socioeconomic aspects.

High fat diet-induced obesity modifies the methylation pattern of leptin promoter in rats.

Leptin is an adipokine involved in body weight and food intake regulation whose promoter region presents CpG islands that could be subject to dynamic methylation. This methylation process could be affected by environmental (e.g. diet) or endogenous (e.g., adipocyte differentiation, inflammation, hypoxia) factors, and could influence adipocyte leptin gene expression. The aim of this article was to study whether a high-energy diet may affect leptin gene promoter methylation in rats. A group of eleven male Wistar rats were assigned into two dietary groups, one fed on a control diet for 11 weeks and the other on a high-fat cafeteria diet. Rats fed a high-energy diet become overweight and hyperleptin emic as compared to the controls. DNA isolated from retroperitoneal adipocytes was treated with bisulfite and a distal portion of leptin promoter (from −694 to −372 bp) including 13 CpG sites was amplified by PCR and sequenced. The studied promoter portion was slightly more methylated in the cafeteria-fed animals, which was statistically significant (p<0.05) for one of the CpG sites (located at the position −443). In obese rats, such methy lation was associated to lower circulating leptin levels, suggesting that this position could be important in the regulation of leptin gene expression, probably by being a target sequence of different transcription factors. Our findings reveal, for the first time, that leptin methylation pattern can be influenced by diet-induced obesity, and suggest that epigenetic mechanisms could be involved in obesity by regulating the expression of important epiobesigenic genes.ResumenLa leptina es una adipoquina implicada en la regulación del peso corporal y la ingesta energética cuya región promotora presenta islas CpG que podrían ser metiladas dinámicamente. Este proceso de metilación podría verse afectado por factores ambientales, como la dieta, o endógenos, como la diferenciación adipocitaria, inflamación o hipoxia, y podría influir en la expresión de leptina por parte de los adipocitos. El objetivo de este artículo es estudiar si una dieta alta en grasa podría afectar a la metilación del promotor de la leptina en ratas. Un grupo de once ratas Wistar macho fue dividido en dos subgrupos, uno alimentado con dieta control durante 11 semanas y el otro con dieta alta en grasa (dieta de cafetería). Las ratas alimentadas con la dieta rica en grasa presentaron sobrepeso e hiperleptinemia. El ADN aislado de los adipocitos retroperitoneales fue tratado con bisulfito y una porción distal del promotor de la leptina (de la base-694 a la — 372), conteniendo 13 sitios CpG, fue amplificada por PCR y secuenciada. Esta región del promotor apareció ligeramente más metilada en los animales alimentados con dieta de cafetería, lo cuál fue especialmente significativo (p <0,05) para uno de los sitios CpG (en la posición-443). En las ratas obesas, la metilación se asoció a una disminución de los niveles de leptina circulante, lo que sugiere que esta posición podría ser importante en la regulación de la expresión génica de esta adipoquina, probablemente por ser una secuencia diana de diferentes factores de trnascripción. Nuestos resultados, por primera vez, ponen de manifiesto que el patrón de metilación del promotor de la leptina puede estar influido por la obesidad inducida por la dieta, y sugieren que los mecanismos epigenéticos podrían estar implicados en la reciente pandemia de obesidad mediante la regulación de la expresión de importantes genes epiobesigénicos.