The Impact of Gender and Protein Intake on the Success of Weight Maintenance and Associated Cardiovascular Risk Benefits, Independent of the Mode of Food Provision: The DiOGenes Randomized Trial.

OBJECTIVE: Maintenance of weight loss and associated cardiovascular benefits after following energy-restricted diets is still a challenging field, and thorough investigation is needed. The present research aimed to determine the role of protein and gender in relation to two different intervention models related to food supply, in a weight maintenance trial. SUBJECTS AND METHODS: The DiOGenes trial was a long-term, multicenter, randomized, dietary intervention study, conducted in eight European countries (Clinical Trials.gov, NCT00390637), focusing on assessing the effectiveness of weight maintenance over 6 months. This secondary analysis intended to evaluate the different benefits for weight maintenance and cardiometabolic markers of two dietary advice delivery models: "shop + instruction intervention" vs "instruction-alone intervention," which were further categorized for gender and macronutrient intake. RESULTS: The weight maintenance intervention based on different macronutrient intake showed, independently of the advice delivery model, in both sexes that higher protein consumption was more effective for weight stability, showing better results in obese women (low protein: 1.65 kg in males and 0.73 Kg in females vs high protein: 1.45 kg in males and -0.93 Kg in females) . Measurements concerning cardiovascular risk markers from subjects on both structured models produced similar trends in the subsequent follow-up period, with a lower rebound in women for most of the markers analyzed. CONCLUSION: The reported dietary benefits for weight sustainability should be ascribed to the macronutrient distribution (higher protein diets) rather than to the structured mode of delivery. Higher weight regain in males was noted, as well as a metabolic divergence attributable to the sex, with a better biochemical outcome in women.

Genome-wide association and longitudinal analyses reveal genetic loci linking pubertal height growth, pubertal timing and childhood adiposity.

The pubertal height growth spurt is a distinctive feature of childhood growth reflecting both the central onset of puberty and local growth factors. Although little is known about the underlying genetics, growth variability during puberty correlates with adult risks for hormone-dependent cancer and adverse cardiometabolic health. The only gene so far associated with pubertal height growth, LIN28B, pleiotropically influences childhood growth, puberty and cancer progression, pointing to shared underlying mechanisms. To discover genetic loci influencing pubertal height and growth and to place them in context of overall growth and maturation, we performed genome-wide association meta-analyses in 18 737 European samples utilizing longitudinally collected height measurements. We found significant associations (P < 1.67 × 10(-8)) at 10 loci, including LIN28B. Five loci associated with pubertal timing, all impacting multiple aspects of growth. In particular, a novel variant correlated with expression of MAPK3, and associated both with increased prepubertal growth and earlier menarche. Another variant near ADCY3-POMC associated with increased body mass index, reduced pubertal growth and earlier puberty. Whereas epidemiological correlations suggest that early puberty marks a pathway from rapid prepubertal growth to reduced final height and adult obesity, our study shows that individual loci associating with pubertal growth have variable longitudinal growth patterns that may differ from epidemiological observations. Overall, this study uncovers part of the complex genetic architecture linking pubertal height growth, the timing of puberty and childhood obesity and provides new information to pinpoint processes linking these traits.

Determinants of human adipose tissue gene expression: impact of diet, sex, metabolic status, and cis genetic regulation.

Weight control diets favorably affect parameters of the metabolic syndrome and delay the onset of diabetic complications. The adaptations occurring in adipose tissue (AT) are likely to have a profound impact on the whole body response as AT is a key target of dietary intervention. Identification of environmental and individual factors controlling AT adaptation is therefore essential. Here, expression of 271 transcripts, selected for regulation according to obesity and weight changes, was determined in 515 individuals before, after 8-week low-calorie diet-induced weight loss, and after 26-week ad libitum weight maintenance diets. For 175 genes, opposite regulation was observed during calorie restriction and weight maintenance phases, independently of variations in body weight. Metabolism and immunity genes showed inverse profiles. During the dietary intervention, network-based analyses revealed strong interconnection between expression of genes involved in de novo lipogenesis and components of the metabolic syndrome. Sex had a marked influence on AT expression of 88 transcripts, which persisted during the entire dietary intervention and after control for fat mass. In women, the influence of body mass index on expression of a subset of genes persisted during the dietary intervention. Twenty-two genes revealed a metabolic syndrome signature common to men and women. Genetic control of AT gene expression by cis signals was observed for 46 genes. Dietary intervention, sex, and cis genetic variants independently controlled AT gene expression. These analyses help understanding the relative importance of environmental and individual factors that control the expression of human AT genes and therefore may foster strategies aimed at improving AT function in metabolic diseases.

Body mass index in childhood and adult risk of primary liver cancer.

BACKGROUND & AIMS: Childhood overweight increases the risk of early development of non-alcoholic fatty liver disease, which may predispose to carcinogenesis. We investigated if childhood body size during school ages was associated with the risk of primary liver cancer in adults. METHODS: A cohort of 285,884 boys and girls, born 1930 through 1980, who attended school in Copenhagen, were followed from 1977 to 31 December 2010. Their heights and weights were measured by school doctors or nurses at ages 7 through 13 years. Body mass index (BMI) z-scores were calculated from an internal age- and sex-specific reference. Information on liver cancer was obtained from the National Cancer Registry. Hazard ratios and 95% confidence intervals (95% CI) of liver cancer were estimated by Cox regression. RESULTS: During 6,963,105 person-years of follow-up, 438 cases of primary liver cancer were recorded. The hazard ratio (95% CI) of adult liver cancer was 1.20 (1.07-1.33) and 1.30 (1.16-1.46) per 1-unit BMI z-score at 7 years and 13 years of age, respectively. Similar associations were found in boys and girls, for hepatocellular carcinoma only, across years of birth, and after accounting for diagnoses of viral hepatitis, alcohol-related disorders, and biliary cirrhosis. CONCLUSIONS: Higher BMI in childhood increases the risk of primary liver cancer in adults. In view of the high case fatality of primary liver cancer, this result adds to the future negative health outcomes of the epidemic of childhood overweight, reinforcing the need for its prevention.

TFAP2B -dietary protein and glycemic index interactions and weight maintenance after weight loss in the DiOGenes trial.

BACKGROUND: TFAP2B rs987237 is associated with obesity and has shown interaction with the dietary fat-to-carbohydrate ratio, which has an effect on weight loss. We investigated interactions between rs987237 and protein-to-carbohydrate ratio or glycemic index (GI) in relation to weight maintenance after weight loss. METHODS: This study included 742 obese individuals from 8 European countries who participated in the Diet, Obesity, and Genes (DiOGenes) trial, lost ≥ 8% of their initial body weight during an 8-week low-calorie diet and were randomized to one of 5 ad libitum diets with a fixed energy percentage from fat: either low-protein/low-GI, low-protein/high-GI, high-protein/low-GI, or high-protein/high-GI diets, or a control diet for a 6-month weight maintenance period. Using linear regression analyses and additive genetic models, we investigated main and dietary interaction effects of TFAP2B rs987237 in relation to weight maintenance. RESULTS: In total, 468 completers of the trial were genotyped for rs987237. High-protein diets were beneficial for weight maintenance in the AA genotype group (67% of participants), but in the AG and GG groups no differences were observed for low- or high-protein diets. On the high-protein diet, carriers of the obesity risk allele (G allele) regained 1.84 kg (95% CI: 0.02; 3.67, p = 0.047) more body weight per risk allele than individuals on a low-protein diet. There was no interaction effect between rs987237 and GI on weight maintenance. CONCLUSION: TFAP2B rs987237 and dietary protein/carbohydrate interacted to modify weight maintenance. Considering the carbohydrate proportion of the diet, the interaction was different from the previously reported rs987237-fat-to-carbohydrate ratio interaction for weight loss. Thus, TFAP2B-macronutrient interactions might diverge depending on the nutritional state.

Diets with high or low protein content and glycemic index for weight-loss maintenance.

BACKGROUND: Studies of weight-control diets that are high in protein or low in glycemic index have reached varied conclusions, probably owing to the fact that the studies had insufficient power. METHODS: We enrolled overweight adults from eight European countries who had lost at least 8% of their initial body weight with a 3.3-MJ (800-kcal) low-calorie diet. Participants were randomly assigned, in a two-by-two factorial design, to one of five ad libitum diets to prevent weight regain over a 26-week period: a low-protein and low-glycemic-index diet, a low-protein and high-glycemic-index diet, a high-protein and low-glycemic-index diet, a high-protein and high-glycemic-index diet, or a control diet. RESULTS: A total of 1209 adults were screened (mean age, 41 years; body-mass index [the weight in kilograms divided by the square of the height in meters], 34), of whom 938 entered the low-calorie-diet phase of the study. A total of 773 participants who completed that phase were randomly assigned to one of the five maintenance diets; 548 completed the intervention (71%). Fewer participants in the high-protein and the low-glycemic-index groups than in the low-protein-high-glycemic-index group dropped out of the study (26.4% and 25.6%, respectively, vs. 37.4%; P=0.02 and P=0.01 for the respective comparisons). The mean initial weight loss with the low-calorie diet was 11.0 kg. In the analysis of participants who completed the study, only the low-protein-high-glycemic-index diet was associated with subsequent significant weight regain (1.67 kg; 95% confidence interval [CI], 0.48 to 2.87). In an intention-to-treat analysis, the weight regain was 0.93 kg less (95% CI, 0.31 to 1.55) in the groups assigned to a high-protein diet than in those assigned to a low-protein diet (P=0.003) and 0.95 kg less (95% CI, 0.33 to 1.57) in the groups assigned to a low-glycemic-index diet than in those assigned to a high-glycemic-index diet (P=0.003). The analysis involving participants who completed the intervention produced similar results. The groups did not differ significantly with respect to diet-related adverse events. CONCLUSIONS: In this large European study, a modest increase in protein content and a modest reduction in the glycemic index led to an improvement in study completion and maintenance of weight loss. (Funded by the European Commission; ClinicalTrials.gov number, NCT00390637.).

Influence of SNPs in nutrient-sensitive candidate genes and gene-diet interactions on blood lipids: the DiOGenes study.

Blood lipid response to a given dietary intervention could be determined by the effect of diet, gene variants or gene-diet interactions. The objective of the present study was to investigate whether variants in presumed nutrient-sensitive genes involved in lipid metabolism modified lipid profile after weight loss and in response to a given diet, among overweight European adults participating in the Diet Obesity and Genes study. By multiple linear regressions, 240 SNPs in twenty-four candidate genes were investigated for SNP main and SNP-diet interaction effects on total cholesterol, LDL-cholesterol, HDL-cholesterol and TAG after an 8-week low-energy diet (only main effect) ,and a 6-month ad libitum weight maintenance diet, with different contents of dietary protein or glycaemic index. After adjusting for multiple testing, a SNP-dietary protein interaction effect on TAG was identified for lipin 1 (LPIN1) rs4315495, with a decrease in TAG of 20.26 mmol/l per A-allele/protein unit (95% CI 20.38, 20.14, P=0.000043). In conclusion, we investigated SNP-diet interactions for blood lipid profiles for 240 SNPs in twenty-four candidate genes, selected for their involvement in lipid metabolism pathways, and identified one significant interaction between LPIN1 rs4315495 and dietary protein for TAG concentration.

The influence of early exposure to vitamin D for development of diseases later in life.

BACKGROUND: Vitamin D deficiency is common among otherwise healthy pregnant women and may have consequences for them as well as the early development and long-term health of their children. However, the importance of maternal vitamin D status on offspring health later in life has not been widely studied. The present study includes an in-depth examination of the influence of exposure to vitamin D early in life for development of fractures of the wrist, arm and clavicle; obesity, and type 1 diabetes (T1D) during child- and adulthood. METHODS/DESIGN: The study is based on the fact that in 1961 fortifying margarine with vitamin D became mandatory in Denmark and in 1972 low fat milk fortification was allowed. Apart from determining the influences of exposure prior to conception and during prenatal life, we will examine the importance of vitamin D exposure during specific seasons and trimesters, by comparing disease incidence among individuals born before and after fortification. The Danish National databases assure that there are a sufficient number of individuals to verify any vitamin D effects during different gestation phases. Additionally, a validated method will be used to determine neonatal vitamin D status using stored dried blood spots (DBS) from individuals who developed the aforementioned disease entities as adults and their time and gender-matched controls. DISCUSSION: The results of the study will contribute to our current understanding of the significance of supplementation with vitamin D. More specifically, they will enable new research in related fields, including interventional research designed to assess supplementation needs for different subgroups of pregnant women. Also, other health outcomes can subsequently be studied to generate multiple health research opportunities involving vitamin D. Finally, the results of the study will justify the debate of Danish health authorities whether to resume vitamin D supplementation policies.

Effects of weight loss and long-term weight maintenance with diets varying in protein and glycemic index on cardiovascular risk factors: the diet, obesity, and genes (DiOGenes) study: a randomized, controlled trial.

BACKGROUND: We sought to separately examine the effects of either weight loss or diets varying in protein content and glycemic index without further changes in body weight on cardiovascular risk factors within the Diet, Obesity, and Genes study (DiOGenes). METHODS AND RESULTS: DiOGenes is a pan-European controlled dietary intervention study in 932 overweight adults who first lost body weight on an 8-week low-calorie diet and were then randomized to 1 of 5 ad libitum diets for 26 weeks. The diets were either high or low protein or high or low glycemic index in 4 combinations or control. Weight loss (-11.23 kg; 95% confidence interval, -11.54 to -10.92; P<0.001) reduced high-sensitivity C-reactive protein (-1.15 mg/L; 95% confidence interval, -1.30 to -0.41; P<0.001), low- and high-density lipoprotein cholesterol, triglycerides, and blood pressure. During the 26-week weight maintenance period in the intention-to-treat analysis, the further decrease of high-sensitivity C-reactive protein blood levels was -0.46 mg/L greater (95% confidence interval, -0.79 to -0.13) in the groups assigned to low-glycemic-index diets than in those on high-glycemic-index diets (P<0.001). Groups on low-protein diets achieved a -0.25 mg/L greater reduction in high-sensitivity C-reactive protein (95% confidence interval, -0.59 to -0.17) than those on high-protein diets (P<0.001), whereas lipid profiles and blood pressure were not differently affected. CONCLUSIONS: This large-scale intervention study clearly separates weight loss from dietary composition-related effects. Low-glycemic-index carbohydrates and, to a lesser extent, low-protein intake may specifically reduce low-grade inflammation and associated comorbidities in overweight/obese adults. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT00390637.

Fish consumption does not prevent increase in waist circumference in European women and men.

Fish consumption is the major dietary source of EPA and DHA, which according to rodent experiments may reduce body fat mass and prevent obesity. However, human studies have suggested that fish consumption has no appreciable association with body-weight gain. We investigated the associations between fish consumption and subsequent change in waist circumference. Sex, age and waist circumference at enrolment were considered as potential effect modifiers. Women and men (n 89 432) participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) were followed for a median of 5·5 years. Mixed-effect linear regression was used to investigate the associations between fish consumption and subsequent change in waist circumference. Among all participants, the average annual change in waist circumference was - 0·01 cm/10 g higher total fish consumption per d (95 % CI - 0·01, 0·00) and - 0·01 cm/10 g higher fatty fish consumption per d (95 % CI - 0·02, - 0·01), after adjustment for potential confounders. Lean fish consumption was not associated with change in waist circumference. Adjustment for potential over- or underestimation of fish consumption measurements did not systematically change the observed associations, but the 95 % CI became slightly wider. The results in subgroups from analyses stratified by sex, age or waist circumference at enrolment were not systematically different. In conclusion, the present study suggests that fish consumption does not prevent increase in waist circumference.

Blood profiling of proteins and steroids during weight maintenance with manipulation of dietary protein level and glycaemic index.

Weight regain after weight loss is common. In the Diogenes dietary intervention study, a high-protein and low-glycaemic index (GI) diet improved weight maintenance. The objective of the present study was to identify (1) blood profiles associated with continued weight loss and weight regain (2) blood biomarkers of dietary protein and GI levels during the weight-maintenance phase. Blood samples were collected at baseline, after 8 weeks of low-energy diet-induced weight loss and after a 6-month dietary intervention period from female continued weight losers (n 48) and weight regainers (n 48), evenly selected from four dietary groups that varied in protein and GI levels. The blood concentrations of twenty-nine proteins and three steroid hormones were measured. The changes in analytes during weight maintenance largely correlated negatively with the changes during weight loss, with some differences between continued weight losers and weight regainers. Increases in leptin (LEP) and C-reactive protein (CRP) were significantly associated with weight regain (P < 0·001 and P = 0·005, respectively), and these relationships were influenced by the diet. Consuming a high-protein and high-GI diet dissociated the positive relationship between the change in LEP concentration and weight regain. CRP increased during the weight-maintenance period only in weight regainers with a high-protein diet (P < 0·001). In addition, testosterone, luteinising hormone, angiotensinogen, plasminogen activator inhibitor-1, resistin, retinol-binding protein 4, insulin, glucagon, haptoglobin and growth hormone were also affected by the dietary intervention. The blood profile reflects not only the weight change during the maintenance period, but also the macronutrient composition of the dietary intervention, especially the protein level.

The Healthy Start project: a randomized, controlled intervention to prevent overweight among normal weight, preschool children at high risk of future overweight.

BACKGROUND: Research shows that obesity prevention has to start early. Targeting interventions towards subgroups of individuals who are predisposed, but yet normal weight, may prove more effective in preventing overweight than interventions towards unselected normal weight subsets. Finally, interventions focused on other factors than diet and activity are lacking. The objectives were to perform a randomized, controlled intervention aiming at preventing overweight in children aged 2-6 years, who are yet normal weight, but have high predisposition for future overweight, and to intervene not only by improving diet and physical activity, but also reduce stress and improve sleep quality and quantity. METHODS/DESIGN: Based on information from the Danish National Birth Registry and administrative birth forms, children were selected based on having either a high birth weight, a mother who was overweight prior to pregnancy, or a familial low socioeconomic status. Selected children (n = 5,902) were randomized into three groups; an intervention group, a shadow control group followed in registers exclusively, and a control group examined at the beginning and at the end of the intervention. Approximately 21% agreed to participate. Children who presented as overweight prior to the intervention were excluded from this study (n = 92). In the intervention group, 271 children were included, and in the control group 272 were included. Information obtained from the shadow control group is on-going, but it is estimated that 394 children will be included. The intervention took place over on average 1½ year between 2009 and 2011, and consisted of optional individual guidance in optimizing diet and physical activity habits, reducing chronic stress and stressful events and improving sleep quality and quantity. The intervention also included participation in cooking classes and play arrangements. Information on dietary intake, meal habits, physical activity, sleep habits, and overall stress level was obtained by 4-7 day questionnaire diaries and objective measurements. DISCUSSION: If the Healthy Start project is effective in preventing excessive weight gain, it will provide valuable information on new determinants of obesity which should be considered in future interventions, and on new strategies to prevent development of overweight and obesity at an early age.

Effects of different protein content and glycaemic index of ad libitum diets on diabetes risk factors in overweight adults: the DIOGenes multicentre, randomized, dietary intervention trial.

BACKGROUND: Dietary regimens providing different levels of protein and glycemic index (GI) foods when prescribed for weight management may also influence insulin sensitivity. PROCEDURES AND OUTCOMES: Overweight/obese adults in 8 European countries who lost ≥ 8% of initial body-weight (BW) after following a low calorie diet (LCD) were later randomly assigned with a 2x2 factorial design into 4 ad libitum dietary groups with two different protein content levels and dissimilar glycemic index, which were compared to a healthy reference diet. Specific markers assessing insulin resistance were measured. The LCD was initially applied to 932 adults and 773 were randomised to the 5 ad libitum diets. The 6-months programme was completed by 548 participants. The assignment to the Low Protein /High Glycemic Index diet induced a statistically higher HOMA-IR increase during the 6 months period as compared to the control. Contrariwise, the insulin response was lower in the High Protein/Low Glycemic Index diet after 60 and 90 min of an Oral Glucose Tolerance test subsequently carried out after the 6-months intervention. The Low Glycemic Index diets (either with high or low protein content) also lead to a decrease in fructosamine levels during the trial. CONCLUSION/INTERPRETATION: After a weight loss period, an increase in the dietary protein proportions and a decrease in the consumption of foods with a high Glycemic Index within an ad libitum dietary intervention aiming to weight maintenance produced favorable effects on glycaemic control and insulin sensitivity in overweight/obese subjects.

A cross-sectional study on trans-fatty acids and risk markers of CHD among middle-aged men representing a broad range of BMI.

Intake of trans-fatty acids (TFA), especially industrially produced TFA (I-TFA), has been associated with the risk of CHD through influence on serum lipid levels. Other causal pathways remain less investigated. In the present cross-sectional study of middle-aged men representing a broad range of BMI, the association between intake of TFA, I-TFA and ruminant TFA (R-TFA) and obesity-associated risk markers of CHD was assessed. The study comprised 393 Danish men (median age 49 years) with a median BMI of 28·4 kg/m(2). Intake of TFA was estimated based on 7 d dietary records, whereas outcomes of interest (waist circumference, sagittal abdominal diameter, percentage of truncal fat, C-reactive protein, IL-6, blood lipids, blood pressure, HbA1c and insulin sensitivity index) were obtained through clinical examination. The associations were assessed by linear regression analysis. The median intake of total TFA among the 393 men was 1·3 g/d, covering a daily I-TFA intake of 0·4 g (10-90th percentile 0·0-1·0) and R-TFA intake of 0·9 g (10-90th percentile 0·4-1·8). Intake of these amounts of TFA showed no significant associations with abdominal fatness, inflammatory markers, blood lipids, blood pressure and insulin homeostasis. Among middle-aged men with a generally low intake of TFA, neither I-TFA nor R-TFA was significantly related to obesity-associated risk markers of CHD. The decreased average intake of I-TFA in Denmark since 1995 is suggested to effectively prevent occurrence of the adverse metabolic changes and health consequences, which have formerly been observed in relation to, especially, I-TFA intake.

Danish patients with chronic pancreatitis have a four-fold higher mortality rate than the Danish population.

BACKGROUND & AIMS: We investigated mortality of patients with chronic pancreatitis (CP), compared with the Danish population and sought to determine whether clinical presentations of CP can be used in prognosis. We also investigated clinical factors associated with mortality and causes of death among these patients. METHODS: The Copenhagen Pancreatitis Study is a prospective study of patients admitted from 1977 to 1982 to the 5 main hospitals in Copenhagen with a diagnosis of acute pancreatitis or CP. In 2008, follow-up data were collected from these patients from the Danish Registries; this subcohort comprised 290 patients with probable (n = 41) or definite CP (n = 249). RESULTS: The mortality of patients with definite CP was 4-fold that of the Danish population and significantly higher than that of patients with probable CP (P = .003; 95% confidence interval [CI], 1.21-2.57); patients with probable CP had a 2- to 3-fold higher mortality rate than the population. In patients with definite CP, factors significantly associated with mortality included non-employment (P = .015; 95% CI, 0.53-0.93), and being underweight (P = .020; 95% CI, 0.52-0.95). Sex, alcohol use, smoking, single versus co-living, exocrine insufficiency, diabetes, pancreatic calcification, CP inheritance, painless CP, acute exacerbation of CP, or surgery for CP had no impact on survival. The most frequent causes of death were digestive diseases (19.5%), malignancies (19.5%), and cardiovascular diseases (11.3%). CONCLUSIONS: Danish patients with definite CP had a 4-fold higher mortality rate compared with the background population and a higher mortality rate than patients with probable CP. Being nonemployed or underweight had significant impact on survival.

Contribution of energy restriction and macronutrient composition to changes in adipose tissue gene expression during dietary weight-loss programs in obese women.

CONTEXT: Hypoenergetic diets are used to reduce body fat mass and metabolic risk factors in obese subjects. The molecular changes in adipose tissue associated with weight loss and specifically related to the dietary composition are poorly understood. OBJECTIVE: We investigated adipose tissue gene expression from human obese women according to energy deficit and the fat and carbohydrate content of the diet. DESIGN AND SETTING: Obese subjects recruited among eight European clinical centers were followed up 10 wk of either a low-fat (high carbohydrate) or a moderate-fat (low carbohydrate) hypoenergetic diet. SUBJECTS: Two sets of 47 women in each dietary arm were selected among 648 subjects matched for anthropometric and biological parameters. MAIN OUTCOME MEASURE: We measured adipose tissue gene expression changes in one set using a candidate gene approach. The other set was used to survey 24,469 transcripts using DNA microarrays. Results were analyzed using dedicated statistical methods. Diet-sensitive regulations were confirmed on the other set of subjects. RESULTS: The two diets induced similar weight loss and similar changes for most of the biological variables except for components of the blood lipid profile. One thousand genes were regulated by energy restriction. We validated an effect of the fat to carbohydrate ratio for five genes (FABP4, NR3C1, SIRT3, FNTA, and GABARAPL2) with increased expression during the moderate-fat diet. CONCLUSIONS: Energy restriction had a more pronounced impact on variations in human adipose tissue gene expression than macronutrient composition. The macronutrient-sensitive regulation of a subset of genes may influence adipose tissue function and metabolic response.

Fat oxidation before and after a high fat load in the obese insulin-resistant state.

BACKGROUND: Obesity may be associated with a lowered use of fat as a fuel, which may contribute to the enlarged adipose tissue stores. AIM: The aim of the present study was to study fatty acid use in the fasting state and in response to a high fat load in a large cohort of obese subjects (n = 701) and a lean reference group (n = 113). METHODS: Subjects from eight European centers underwent a test meal challenge containing 95 en% fat [energy content 50% of estimated resting energy expenditure (EE)]. Fasting and postprandial fat oxidation and circulating metabolites and hormones were determined over a 3-h period. RESULTS: Postprandial fat oxidation (as percent of postprandial EE, adjusted for fat mass, age, gender, center, and energy content of the meal) decreased with increasing body mass index (BMI) category (P < 0.01), an effect present only in those obese subjects with a relatively low fasting fat oxidation (below median, interaction BMI category x fasting fat oxidation, P < 0.001). Fasting fat oxidation increased with increasing BMI category (P < 0.001), which was normalized after adjustment for fat-free mass and fat mass. Furthermore, insulin resistance was positively associated with postprandial fat oxidation (P < 0.05) and negatively associated with fasting fat oxidation (expressed as percent of EE), independent of body composition. CONCLUSIONS: The present data indicate an impaired capacity to regulate fat oxidation in the obese insulin-resistant state, which is hypothesized to play a role in the etiology of both obesity and insulin resistance.

Body mass index in school-aged children and the risk of routinely diagnosed non-alcoholic fatty liver disease in adulthood: a prospective study based on the Copenhagen School Health Records Register.

OBJECTIVE: The relation between childhood overweight and adult non-alcoholic fatty liver disease (NAFLD) is largely unknown. We investigated if weight and weight gain in childhood increases the risk of being diagnosed with NAFLD in routine clinical settings in adulthood. PARTICIPANTS: We studied 244,464 boys and girls, born between 1930 and 1989, who attended school in Copenhagen, Denmark. Their heights and weights were measured by physicians or nurses at mandatory school health examinations at ages 7-13 years. Body mass index (BMI) z-scores were calculated from an internal age-specific and sex-specific reference. OUTCOME MEASURES: NAFLD reported in the National Patient Register and the National Register of Pathology at 18 years of age or older. HRs with 95% CIs were estimated. RESULTS: During follow-up, 1264 and 1106 NAFLD cases, respectively, occurred in men and women. In both sexes, childhood BMI z-score was not consistently associated with adult NAFLD. Change in BMI z-score between 7 and 13 years of age was positively associated with NAFLD in both sexes. When adjusted for BMI z-score at age 7 years, the HRs of adult NAFLD were 1.15 (95% CI 1.05 to 1.26) and 1.12 (95% CI 1.02 to 1.23) per 1-unit gain in BMI z-score in men and women, respectively. Associations were similar when adjusted for BMI z-score at age 13 years, and were consistent across birth years. CONCLUSIONS: A BMI gain in school-aged children is associated with adult NAFLD. Intriguingly, BMI gain appears to have an effect on adult NAFLD irrespective of either the initial or the attained BMI. Taken together, our results suggest that BMI gain in childhood, rather than the level of BMI per se, is important in the development of adult NAFLD.

Variation in extracellular matrix genes is associated with weight regain after weight loss in a sex-specific manner.

The extracellular matrix (ECM) of adipocytes is important for body weight regulation. Here, we investigated whether genetic variation in ECM-related genes is associated with weight regain among participants of the European DiOGenes study. Overweight and obese subjects (n = 469, 310 females, 159 males) were on an 8-week low-calorie diet with a 6-month follow-up. Body weight was measured before and after the diet, and after follow-up. Weight maintenance scores (WMS, regained weight as percentage of lost weight) were calculated based on the weight data. Genotype data were retrieved for 2903 SNPs corresponding to 124 ECM-related genes. Regression analyses provided us with six significant SNPs associated with the WMS in males: 3 SNPs in the POSTN gene and a SNP in the LAMB1, COL23A1, and FBLN5 genes. For females, 1 SNP was found in the FN1 gene. The risk of weight regain was increased by: the C/C genotype for POSTN in a co-dominant model (OR 8.25, 95 % CI 2.85-23.88) and the T/C-C/C genotype in a dominant model (OR 4.88, 95 % CI 2.35-10.16); the A/A genotype for LAMB1 both in a co-dominant model (OR 18.43, 95 % CI 2.35-144.63) and in a recessive model (OR 16.36, 95 % CI 2.14-124.9); the G/A genotype for COL23A1 in a co-dominant model (OR 3.94, 95 % CI 1.28-12.10), or the A-allele in a dominant model (OR 2.86, 95 % CI 1.10-7.49); the A/A genotype for FBLN5 in a co-dominant model (OR 13.00, 95 % CI 1.61-104.81); and the A/A genotype for FN1 in a recessive model (OR 2.81, 95 % CI 1.40-5.63). Concluding, variants of ECM genes are associated with weight regain after weight loss in a sex-specific manner.

Vital exhaustion as a risk factor for ischaemic heart disease and all-cause mortality in a community sample. A prospective study of 4084 men and 5479 women in the Copenhagen City Heart Study.

BACKGROUND: Vital exhaustion, a psychological measure characterized by fatigue and depressive symptoms, has been suggested to be an independent risk factor for ischaemic heart disease (IHD) but the generality of the phenomenon remains in question. The aim of this study is to describe prevalence of these symptoms in a community sample and determine whether they prospectively predict increased risk of IHD and all-cause mortality in men and women. METHODS: The study base was 4084 men and 5479 women aged 20-98 free of IHD examined in 1991-1993 in the Copenhagen City Heart Study. Events were ascertained through record linkage until 1998 for IHD and September 2000 for all-cause mortality. There were 483 first hospital admissions and deaths caused by IHD and 1559 deaths from all causes during follow-up. RESULTS: The 17 items on the vital exhaustion questionnaire were frequently endorsed with prevalence ranging from 6 to 47 per cent, higher in women. All but 4 of the 17 items were significantly associated with IHD with significant relative risks (RR) ranging between 1.36 (95% CI: 1.08, 1.72) and 2.10 (95% CI: 1.63, 2.71). Associations with all-cause mortality were also observed, but were weaker. RR of both IHD and all-cause mortality increased with increasing item sum score and were similar in men and women. For IHD, RR reached a maximum of 2.57 (95% CI: 1.65, 4.00) for subjects endorsing >9 items. The similar RR for all-cause mortality was 2.50 (95% CI: 2.09, 2.99). Multivariate adjustment for biological, behavioural, and socioeconomic risk factors did not substantially affect the association for IHD but attenuated the association with all-cause mortality. CONCLUSIONS: Measures of fatigue and depression were common symptoms in this population sample and convey increased risk of IHD and of all-cause mortality. We propose this knowledge begin to be implemented in risk assessment in clinical practice.