System model network for adipose tissue signatures related to weight changes in response to calorie restriction and subsequent weight maintenance.

Nutrigenomics investigates relationships between nutrients and all genome-encoded molecular entities. This holistic approach requires systems biology to scrutinize the effects of diet on tissue biology. To decipher the adipose tissue (AT) response to diet induced weight changes we focused on key molecular (lipids and transcripts) AT species during a longitudinal dietary intervention. To obtain a systems model, a network approach was used to combine all sets of variables (bio-clinical, fatty acids and mRNA levels) and get an overview of their interactions. AT fatty acids and mRNA levels were quantified in 135 obese women at baseline, after an 8-week low calorie diet (LCD) and after 6 months of ad libitum weight maintenance diet (WMD). After LCD, individuals were stratified a posteriori according to weight change during WMD. A 3 steps approach was used to infer a global model involving the 3 sets of variables. It consisted in inferring intra-omic networks with sparse partial correlations and inter-omic networks with regularized canonical correlation analysis and finally combining the obtained omic-specific network in a single global model. The resulting networks were analyzed using node clustering, systematic important node extraction and cluster comparisons. Overall, AT showed both constant and phase-specific biological signatures in response to dietary intervention. AT from women regaining weight displayed growth factors, angiogenesis and proliferation signaling signatures, suggesting unfavorable tissue hyperplasia. By contrast, after LCD a strong positive relationship between AT myristoleic acid (a fatty acid with low AT level) content and de novo lipogenesis mRNAs was found. This relationship was also observed, after WMD, in the group of women that continued to lose weight. This original system biology approach provides novel insight in the AT response to weight control by highlighting the central role of myristoleic acid that may account for the beneficial effects of weight loss.

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.

Higher protein diets consumed ad libitum improve cardiovascular risk markers in children of overweight parents from eight European countries.

Dietary strategies to improve early cardiovascular markers in overweight children are needed. We investigated the effect of dietary protein and glycemic index (GI) on cardiovascular markers and metabolic syndrome (MetS) scores in 5- to 18-y-old children of overweight/obese parents from 8 European centers. Families were randomized to 1 of 5 diets consumed ad libitum: high protein (HP) or low protein (LP) combined with high GI (HGI) or low GI (LGI), or a control diet. At 6 centers, families received dietary instruction (instruction centers); at 2 centers, free foods were also provided (supermarket centers). Diet, anthropometry, blood pressure, and serum cardiovascular markers (lipid profile, glucose regulation, and inflammation) were measured in 253 children at baseline, 1 mo, and/or 6 mo. Protein intake was higher in the HP groups (19.9 ± 1.3% energy) than in the LP groups at 6 mo (16.8 ± 1.2% energy) (P = 0.001). The GI was 4.0 points lower (95% CI: 2.1, 6.1) in the LGI compared with the HGI groups (P < 0.001). In the supermarket centers, the HP and LP groups differed more in protein intake than did the groups in the instruction centers (P = 0.009), indicating better compliance. The HP diets evoked a 2.7-cm (95% CI: 0.9, 5.1) smaller waist circumference and a 0.25-mmol/L (95% CI: 0.09, 0.41) lower serum LDL cholesterol compared with the LP diets at 6 mo (P < 0.007). In a separate supermarket center analysis, the HP compared with LP diets reduced waist circumference (P = 0.004), blood pressure (P < 0.01), serum insulin (P = 0.013), and homeostasis model of assessment-insulin resistance (P = 0.016). In the instruction centers, the HP compared with the LP diets reduced LDL cholesterol (P = 0.004). No consistent effect of GI was seen and the MetS scores were not affected. In conclusion, increased protein intake improved cardiovascular markers in high-risk children, particularly in those undergoing most intensive intervention.

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.

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.

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.

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.

[Reduction of abdominal obesity and cardiometabolic health risks in obese adolescents in response to a short-term spa weight management program]. / Redukce abdominální obezity a kardiometabolických rizik u obézních adolescentu krátkodobým lázenským redukcním programem.

BACKGROUND: Overweight and obesity is associated with metabolic and cardiovascular complications even in children and adolescents. Obesity in childhood represents a serious health problem, as an obese child frequently remains obese subject in adulthood. Obesity is also an important early risk factor for morbidity and mortality in adulthood. The aim of this study was to follow changes in selected anthropometric parameters and cardiometabolic risks in overweight and obese adolescents in response to a 4-week spa weight management program. METHODS AND RESULTS: The studied cohort included 342 adolescents (boys, n = 121, girls, n = 221); mean age (+/- SD) 14.9 +/- 1.4 years (range 13.0 to 17.9 years) with overweight or obesity, mean BMI (+/- SD) 30.1 +/- 4.4 kg/m2 who underwent a 4-week spa weight management program. Anthropometric (body height and weight, waist circumference, sagittal abdominal diameter, total body fat and intra-abdominal fat), clinical (blood pressure) and biochemical (total cholesterol, HDL and LDL cholesterol, triglycerides, glucose, insulin) parameters were studied. All examinations were conducted before and after a 4-week weight management program. Statistical evaluation of the data was performed by ANOVA. The data are expressed as means +/- SD. In response to treatment all subjects demonstrated significant decreases in initial body weight (-6.3 +/- 2.3 %), percent of total fat (-2.7 +/- 2.5 %), percent of trunk fat (-2.5 +/- 1.5 %), degree of enlargement in visceral fat stores (-2.1 +/- 2.8), as well as reductions in waist circumference (-4.7 +/- 3.2 cm) and sagittal abdominal diameter (-1.0 +/- 1.8 cm). Positive changes in lipid profile and decrease in insulin resistance as measured by HOMA-IR were also recorded together with significant reductions in both systolic and diastolic blood pressures. CONCLUSIONS: Short-term weight management program in adolescents led to significant reductions in body weight, trunk and visceral fat and cardiometabolic health risks.

[A new simple method for estimating trunk and visceral fat by bioelectrical impedance: comparison with magnetic resonance imaging and dual X-ray absorptiometry in Czech adolescents]. / Nová jednoduchá metoda stanovení viscerálního a trunkálního tuku pomocí bioelektrické impedance: srovnání s magnetickou rezonancí a duální rentgenovou absorpciometrií u ceských adolescentu.

BACKGROUND: The enlargement of visceral fat (VF) in abdominal obesity is associated with increased cardiometabolic health risks in both adults and adolescents. A precise measurement of VF by sophisticated methods as computed tomography (CT) and magnetic resonance imaging (MRI) cannot be applied in routine clinical practice. The aim of our study was to compare estimates on visceral and trunk fat in adolescents obtained by a new bioimpedance analysis instrument (BIA)--Tanita AB-140 ViScan--with those obtained by MRI, dual X-ray absorptiometry (DEXA) and anthropometry. METHODS AND RESULTS: Investigated cohort: 39 adolescent secondary school students; median (lower quartile; upper quartile)--age: 16.4 (15.4; 17.4) years; body weight: 63.8 (54.1; 79.0) kg; BMI: 21.4 (19.5; 27.4) kg/m2. Investigated parameters: BMI, body circumferences and sagittal abdominal diameter (SAD), trunk, visceral and subcutaneous fat determined by BIA, MRI and DEXA. STATISTICS: Spearman's correlations. The assessment of trunk fat by BIA correlated with DEXA estimates (r = 0.979, p < 0.0001) and with abdominal fat measured by MRI (r = 0.930, p < 0.0001). The visceral fat amount derived from abdominal BIA exhibited lower, however significant correlation with visceral fat determined by MRI (r = 0.791, p < 0.001). The visceral fat area presumed by abdominal BIA significantly correlated with anthropometric parameters as abdominal circumference (r = 0.923, p < 0.0001), waist circumference (r = 0.913, p < 0.0001) and SAD (r= 0.891, p < 0.0001). CONCLUSIONS: The new method estimating abdominal fat by BIA represents a reliable tool for clinical evaluation of the trunk fat in adolescents. However, its advantages over anthropometric measurements in evaluation of VF require further validation studies.

A common variant near BDNF is associated with dietary calcium intake in adolescents.

Specific targets for most obesity candidate genes discovered by genomewide association studies remain unknown. Such genes are often highly expressed in the hypothalamus, indicating their role in energy homeostasis. We aimed to evaluate the associations of selected gene variants with adiposity and dietary traits. Anthropometric parameters, fat mass, dietary intake (total energy, fat, protein, carbohydrate, fiber, and calcium) and 10 gene variants (in/near TMEM18, SH2B1, KCTD15, PCSK1, BDNF, SEC16B, MC4R and FTO) were analyzed in 1953 Czech individuals aged 10.0 to 18.0 years (1035 nonoverweight and 918 overweight: body mass index [BMI] ≥90th percentile). Obesity risk alleles of TMEM18 rs7561317, SEC16B rs10913469, and FTO rs9939609 were related to increased body weight and BMI (P < .005). The FTO variant also showed a significant positive association with waist circumference and fat mass (P < .001). Overweight adolescents had a lower total energy intake (P < .001) but a higher percentage of fat (P = .009) and protein intake (P < .001) than the nonoverweight subjects. There was also a lower calcium intake in the overweight group (P < .001). An association with at least one component of dietary intake was found in 3 of 10 studied gene variants. The MC4R rs17782313 was associated negatively with protein (P = .012) and positively associated with fiber (P = .032) intakes. The obesity risk alleles of BDNF rs925946 and FTO rs9939609 were related to a lower calcium intake (P = .001 and .037). The effects of FTO and MC4R variants, however, disappeared after corrections for multiple testing. Our results suggest that the common BDNF variant may influence dietary calcium intake independent of BMI.

Glucose homeostasis and insulin resistance: prevalence, gender differences and predictors in adolescents.

BACKGROUND: Adolescence, due to transient pubertal insulin resistance (IR), is associated with a higher risk for disturbances of glucose metabolism. The aim of our study was 1) to investigate the prevalence of disturbances of glucose metabolism, 2) to define gender specific homeostasis model assessment of insulin resistance (HOMA-IR) thresholds associated with increased cardiometabolic risks and 3) to provide predictors of HOMA-IR. METHODS: The studied cohort consisted of Czech adolescents aged 13.0-17.9 years: 1,518 individuals of general population and three studied groups according weight category (615 normal weight, 230 overweight and 683 obese). The prevalence of IR, impaired fasting glucose (IFG) and type 2 diabetes was assessed. Risky HOMA-IR thresholds based on components of metabolic syndrome were investigated. HOMA-IR prediction was calculated taking into account age, blood pressure, multiple anthropometric, biochemical and hormonal parameters. RESULTS: In general population cohort, the prevalence of IFG and type 2 diabetes was 7.0% and <0.5%, respectively. Boys regardless of weight presented significantly higher levels of blood glucose and higher prevalence of IFG than girls. Obese boys were found more insulin resistant than obese girls. HOMA-IR thresholds of 3.6 for girls and 4.4 for boys were associated with increased cardiometabolic risks. For both genders, the model of HOMA-IR prediction was composed of age, BMI, ratio of free triiodthyronine to free thyroxine, gamma-glutamyltransferase activity and levels of triglycerides and sex hormone-binding globulin. CONCLUSIONS: The type 2 diabetes in adolescents, including those who were obese, was rarely diagnosed. Obese adolescent boys were at greater risk for IR and for IFG than obese girls. In adolescence, thresholds of HOMA-IR in contrast to predictors were found gender specific.

Metabolic syndrome, circulating RBP4, testosterone, and SHBG predict weight regain at 6 months after weight loss in men.

OBJECTIVE: Weight loss helps reduce the symptoms of the metabolic syndrome (MetS) in the obese, but weight regain after active weight loss is common. The changes and predictive role of circulating adipokines and sex hormones for weight regain in men during dietary intervention, and also the effect of basal MetS status on weight regain, were investigated. DESIGN AND METHODS: Twenty-four men who continued to lose weight (WL) and 24 men who regained weight (WR) during the 6-month follow-up period after weight loss were selected from the Diogenes Study. Their circulating concentrations of leptin, adiponectin, retinol-binding protein 4 (RBP4), luteinizing hormone, prolactin, progesterone, total and free testosterone, and sex hormone-binding globulin (SHBG) were measured at baseline, after 8-week low-calorie diet-induced active weight loss, and after a subsequent 26-week ad libitum weight maintenance diet, and analyzed together with anthropometrical and physiological parameters. RESULTS: Overweight and obese men with MetS at baseline had higher risk to regain weight (odds ratio = 2.8, P = 0.015). High baseline RBP4, low total testosterone, and low SHBG are predictors of weight loss regain (different between WR and WL with P = 0.001, 0.038, and 0.044, respectively). CONCLUSIONS: These variables may play roles in the link between MetS and weight loss regain.