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1.  Objectively Measured Physical Activity in European Adults: Cross-Sectional Findings from the Food4Me Study 
PLoS ONE  2016;11(3):e0150902.
Background
Comparisons of objectively measured physical activity (PA) between residents of European countries measured concurrently with the same protocol are lacking. We aimed to compare PA between the seven European countries involved in the Food4Me Study, using accelerometer data collected remotely via the Internet.
Methods
Of the 1607 participants recruited, 1287 (539 men and 748 women) provided at least 3 weekdays and 2 weekend days of valid accelerometer data (TracmorD) at baseline and were included in the present analyses.
Results
Men were significantly more active than women (physical activity level = 1.74 vs. 1.70, p < 0.001). Time spent in light PA and moderate PA differed significantly between countries but only for women. Adherence to the World Health Organization recommendation to accumulate at least 150 min of moderate-equivalent PA weekly was similar between countries for men (range: 54–65%) but differed significantly between countries for women (range: 26–49%). Prevalence estimates decreased substantially for men and women in all seven countries when PA guidelines were defined as achieving 30 min of moderate and vigorous PA per day.
Conclusions
We were able to obtain valid accelerometer data in real time via the Internet from 80% of participants. Although our estimates are higher compared with data from Sweden, Norway, Portugal and the US, there is room for improvement in PA for all countries involved in the Food4Me Study.
doi:10.1371/journal.pone.0150902
PMCID: PMC4801355  PMID: 26999053
2.  Network Analysis of Metabolite GWAS Hits: Implication of CPS1 and the Urea Cycle in Weight Maintenance 
PLoS ONE  2016;11(3):e0150495.
Background and Scope
Weight loss success is dependent on the ability to refrain from regaining the lost weight in time. This feature was shown to be largely variable among individuals, and these differences, with their underlying molecular processes, are diverse and not completely elucidated. Altered plasma metabolites concentration could partly explain weight loss maintenance mechanisms. In the present work, a systems biology approach has been applied to investigate the potential mechanisms involved in weight loss maintenance within the Diogenes weight-loss intervention study.
Methods and Results
A genome wide association study identified SNPs associated with plasma glycine levels within the CPS1 (Carbamoyl-Phosphate Synthase 1) gene (rs10206976, p-value = 4.709e-11 and rs12613336, p-value = 1.368e-08). Furthermore, gene expression in the adipose tissue showed that CPS1 expression levels were associated with successful weight maintenance and with several SNPs within CPS1 (cis-eQTL). In order to contextualize these results, a gene-metabolite interaction network of CPS1 and glycine has been built and analyzed, showing functional enrichment in genes involved in lipid metabolism and one carbon pool by folate pathways.
Conclusions
CPS1 is the rate-limiting enzyme for the urea cycle, catalyzing carbamoyl phosphate from ammonia and bicarbonate in the mitochondria. Glycine and CPS1 are connected through the one-carbon pool by the folate pathway and the urea cycle. Furthermore, glycine could be linked to metabolic health and insulin sensitivity through the betaine osmolyte. These considerations, and the results from the present study, highlight a possible role of CPS1 and related pathways in weight loss maintenance, suggesting that it might be partly genetically determined in humans.
doi:10.1371/journal.pone.0150495
PMCID: PMC4777532  PMID: 26938218
3.  Nutrient Status Assessment in Individuals and Populations for Healthy Aging—Statement from an Expert Workshop 
Nutrients  2015;7(12):10491-10500.
A workshop organized by the University Medical Center Groningen addressed various current issues regarding nutrient status of individuals and populations, tools and strategies for its assessment, and opportunities to intervene. The importance of nutrient deficiencies and information on nutrient status for health has been illustrated, in particular for elderly and specific patient groups. The nutrient profile of individuals can be connected to phenotypes, like hypertension or obesity, as well as to socio-economic data. This approach provides information on the relationship between nutrition (nutrient intake and status) and health outcomes and, for instance, allows us to use the findings to communicate and advocate a healthy lifestyle. Nutrition is complex: a broader profile of nutrients should be considered rather than focusing solely on a single nutrient. Evaluating food patterns instead of intake of individual nutrients provides better insight into relationships between nutrition and health and disease. This approach would allow us to provide feedback to individuals about their status and ways to improve their nutritional habits. In addition, it would provide tools for scientists and health authorities to update and develop public health recommendations.
doi:10.3390/nu7125547
PMCID: PMC4690099  PMID: 26694458
nutrient; status; aging; patients
4.  Analysis of Dietary Pattern Impact on Weight Status for Personalised Nutrition through On-Line Advice: The Food4Me Spanish Cohort 
Nutrients  2015;7(11):9523-9537.
Obesity prevalence is increasing. The management of this condition requires a detailed analysis of the global risk factors in order to develop personalised advice. This study is aimed to identify current dietary patterns and habits in Spanish population interested in personalised nutrition and investigate associations with weight status. Self-reported dietary and anthropometrical data from the Spanish participants in the Food4Me study, were used in a multidimensional exploratory analysis to define specific dietary profiles. Two opposing factors were obtained according to food groups’ intake: Factor 1 characterised by a more frequent consumption of traditionally considered unhealthy foods; and Factor 2, where the consumption of “Mediterranean diet” foods was prevalent. Factor 1 showed a direct relationship with BMI (β = 0.226; r2 = 0.259; p < 0.001), while the association with Factor 2 was inverse (β = −0.037; r2 = 0.230; p = 0.348). A total of four categories were defined (Prudent, Healthy, Western, and Compensatory) through classification of the sample in higher or lower adherence to each factor and combining the possibilities. Western and Compensatory dietary patterns, which were characterized by high-density foods consumption, showed positive associations with overweight prevalence. Further analysis showed that prevention of overweight must focus on limiting the intake of known deleterious foods rather than exclusively enhance healthy products.
doi:10.3390/nu7115482
PMCID: PMC4663610  PMID: 26593942
dietary pattern; dietary habits; obesity; personalised nutrition
5.  Diets with High or Low Protein Content and Glycemic Index for Weight-Loss Maintenance 
The New England journal of medicine  2010;363(22):2102-2113.
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.)
doi:10.1056/NEJMoa1007137
PMCID: PMC3359496  PMID: 21105792
6.  How reliable is internet-based self-reported identity, socio-demographic and obesity measures in European adults? 
Genes & Nutrition  2015;10(5):28.
In e-health intervention studies, there are concerns about the reliability of internet-based, self-reported (SR) data and about the potential for identity fraud. This study introduced and tested a novel procedure for assessing the validity of internet-based, SR identity and validated anthropometric and demographic data via measurements performed face-to-face in a validation study (VS). Participants (n = 140) from seven European countries, participating in the Food4Me intervention study which aimed to test the efficacy of personalised nutrition approaches delivered via the internet, were invited to take part in the VS. Participants visited a research centre in each country within 2 weeks of providing SR data via the internet. Participants received detailed instructions on how to perform each measurement. Individual’s identity was checked visually and by repeated collection and analysis of buccal cell DNA for 33 genetic variants. Validation of identity using genomic information showed perfect concordance between SR and VS. Similar results were found for demographic data (age and sex verification). We observed strong intra-class correlation coefficients between SR and VS for anthropometric data (height 0.990, weight 0.994 and BMI 0.983). However, internet-based SR weight was under-reported (Δ −0.70 kg [−3.6 to 2.1], p < 0.0001) and, therefore, BMI was lower for SR data (Δ −0.29 kg m−2 [−1.5 to 1.0], p < 0.0001). BMI classification was correct in 93 % of cases. We demonstrate the utility of genotype information for detection of possible identity fraud in e-health studies and confirm the reliability of internet-based, SR anthropometric and demographic data collected in the Food4Me study.
Trial registration: NCT01530139 (http://clinicaltrials.gov/show/NCT01530139).
Electronic supplementary material
The online version of this article (doi:10.1007/s12263-015-0476-0) contains supplementary material, which is available to authorized users.
doi:10.1007/s12263-015-0476-0
PMCID: PMC4491331  PMID: 26143178
Internet-based; Validation; Identity; Anthropometrics; Personalised nutrition; Randomised controlled trial
7.  Increased Intake of Foods with High Nutrient Density Can Help to Break the Intergenerational Cycle of Malnutrition and Obesity 
Nutrients  2015;7(7):6016-6037.
A workshop held at the University Medical Center in Groningen, The Netherlands, aimed at discussing the nutritional situation of the population in general and the role diet plays during critical windows in the life course, during which the body is programmed for the development of non-communicable diseases (NCDs). NCDs are increasingly prevalent as our society ages, and nutrition is well known to play an important role in determining the risk and the time of onset of many common NCDs. Even in affluent countries, people have difficulties to achieve adequate intakes for a range of nutrients: Economic constraints as well as modern lifestyles lead people to consume diets with a positive energy balance, but low in micronutrients, resulting in increasing prevalence of obesity and suboptimal nutritional status. Information about nutrient density, which refers to the content of micronutrients relative to energy in food or diets, can help identify foods that have a low calorie to nutrient ratio. It thus allows the consumption of diets that cover nutritional needs without increasing the risk of becoming obese. Given the impact a nutrient dense, low energy diet can have on health, researchers, food industry and governments jointly should develop options for affordable, appealing nutrient-rich food products, which, in combination with physical activity, allow for optimal health throughout the life-course.
doi:10.3390/nu7075266
PMCID: PMC4517043  PMID: 26197337
nutrient density; vitamin; PUFA; life cycle; non-communicable diseases; obesity
8.  System Model Network for Adipose Tissue Signatures Related to Weight Changes in Response to Calorie Restriction and Subsequent Weight Maintenance 
PLoS Computational Biology  2015;11(1):e1004047.
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.
Author Summary
Obesity is an excess fat mass leading to metabolic diseases. Dietary management is a conventional strategy to promote weight loss. As energy buffering, in the form of esterified fatty acids, and secretory organ, the adipose tissue has a pivotal role in obesity and its related complications. A comprehensive insight of adipose tissue response during and after calorie restriction might improve obesity management. Modern nutrition research study the impact of diet on health by combining multiple datasets to provide an holistic view of tissue physiopathology. To identify significant clusters of fatty acids, transcripts or bio-clinical parameters related to weight change along calorie restriction and subsequent weight follow-up in obese individuals, the issue of different datasets integration must be resolved. Here, we implemented an innovative multistep approach to infer multi-data networks and compare clusters of network components. This original strategy highlighted an unexpected central role of a minor adipose tissue fatty acid, myristoleic acid, which is not provided by food. Its link to transcripts encoding enzymes from a pathway converting glucose into fat that mediates favorable metabolic effects makes myristoleic acid a key factor of the positive impact of fat mass reduction.
doi:10.1371/journal.pcbi.1004047
PMCID: PMC4295881  PMID: 25590576
9.  Design and baseline characteristics of the Food4Me study: a web-based randomised controlled trial of personalised nutrition in seven European countries 
Genes & Nutrition  2014;10(1):450.
Improving lifestyle behaviours has considerable potential for reducing the global burden of non-communicable diseases, promoting better health across the life-course and increasing well-being. However, realising this potential will require the development, testing and implementation of much more effective behaviour change interventions than are used conventionally. Therefore, the aim of this study was to conduct a multi-centre, web-based, proof-of-principle study of personalised nutrition (PN) to determine whether providing more personalised dietary advice leads to greater improvements in eating patterns and health outcomes compared to conventional population-based advice. A total of 5,562 volunteers were screened across seven European countries; the first 1,607 participants who fulfilled the inclusion criteria were recruited into the trial. Participants were randomly assigned to one of the following intervention groups for a 6-month period: Level 0—control group—receiving conventional, non-PN advice; Level 1—receiving PN advice based on dietary intake data alone; Level 2—receiving PN advice based on dietary intake and phenotypic data; and Level 3—receiving PN advice based on dietary intake, phenotypic and genotypic data. A total of 1,607 participants had a mean age of 39.8 years (ranging from 18 to 79 years). Of these participants, 60.9 % were women and 96.7 % were from white-European background. The mean BMI for all randomised participants was 25.5 kg m−2, and 44.8 % of the participants had a BMI ≥ 25.0 kg m−2. Food4Me is the first large multi-centre RCT of web-based PN. The main outcomes from the Food4Me study will be submitted for publication during 2015.
Electronic supplementary material
The online version of this article (doi:10.1007/s12263-014-0450-2) contains supplementary material, which is available to authorized users.
doi:10.1007/s12263-014-0450-2
PMCID: PMC4261071  PMID: 25491748
Personalised nutrition; Web-based; Phenotype; Genotype; Randomised controlled trial
10.  Body Characteristics, Dietary Protein and Body Weight Regulation. Reconciling Conflicting Results from Intervention and Observational Studies? 
PLoS ONE  2014;9(7):e101134.
Background/Objectives
Physiological evidence indicates that high-protein diets reduce caloric intake and increase thermogenic response, which may prevent weight gain and regain after weight loss. Clinical trials have shown such effects, whereas observational cohort studies suggest an association between greater protein intake and weight gain. In both types of studies the results are based on average weight changes, and show considerable diversity in both directions. This study investigates whether the discrepancy in the evidence could be due to recruitment of overweight and obese individuals into clinical trials.
Subjects/Methods
Data were available from the European Diet, Obesity and Genes (DiOGenes) post-weight-loss weight-maintenance trial and the Danish Diet, Cancer and Health (DCH) cohort. Participants of the DCH cohort were matched with participants from the DiOGenes trial on gender, diet, and body characteristics. Different subsets of the DCH-participants, comparable with the trial participants, were analyzed for weight maintenance according to the randomization status (high or low protein) of the matched trial participants.
Results
Trial participants were generally heavier, had larger waist circumference and larger fat mass than the participants in the entire DCH cohort. A better weight maintenance in the high-protein group compared to the low protein group was observed in the subgroups of the DCH cohort matching body characteristics of the trial participants.
Conclusion
This modified observational study, minimized the differences between the RCT and observational data with regard to dietary intake, participant characteristics and statistical analysis. Compared with low protein diet the high protein diet was associated with better weight maintenance when individuals with greater body mass index and waist circumference were analyzed. Selecting subsets of large-scale observational cohort studies with similar characteristics as participants in clinical trials may reconcile the otherwise conflicting results.
doi:10.1371/journal.pone.0101134
PMCID: PMC4081118  PMID: 24992329
11.  Adipose Tissue CIDEA Is Associated, Independently of Weight Variation, to Change in Insulin Resistance during a Longitudinal Weight Control Dietary Program in Obese Individuals 
PLoS ONE  2014;9(7):e98707.
Aim
Weight loss reduces risk factors associated with obesity. However, long-term metabolic improvement remains a challenge. We investigated quantitative gene expression of subcutaneous adipose tissue in obese individuals and its relationship with low calorie diet and long term weight maintenance induced changes in insulin resistance.
Research Design
Three hundred eleven overweight and obese individuals followed a dietary protocol consisting of an 8-week low calorie diet followed by a 6-month ad libitum weight-maintenance diet. Individuals were clustered according to insulin resistance trajectories assessed using homeostasis model assessment of insulin resistance (HOMA-IR) index. Adipose tissue mRNA levels of 267 genes selected for regulation according to obesity, metabolic status and response to dieting was assessed using high throughput RT-qPCR. A combination of discriminant analyses was used to identify genes with regulation according to insulin resistance trajectories. Partial correlation was used to control for change in body mass index.
Results
Three different HOMA-IR profile groups were determined. HOMA-IR improved during low calorie diet in the 3 groups. At the end of the 6-month follow-up, groups A and B had reduced HOMA-IR by 50%. In group C, HOMA-IR had returned to baseline values. Genes were differentially expressed in the adipose tissue of individuals according to groups but a single gene, CIDEA, was common to all phases of the dietary intervention. Changes in adipose tissue CIDEA mRNA levels paralleled variations in insulin sensitivity independently of change in body mass index. Overall, CIDEA was up-regulated in adipose tissue of individuals with successful long term insulin resistance relapse and not in adipose tissue of unsuccessful individuals.
Conclusion
The concomitant change in adipose tissue CIDEA mRNA levels and insulin sensitivity suggests a beneficial role of adipose tissue CIDEA in long term glucose homeostasis, independently of weight variation.
Trial Registration
ClinicalTrials.gov NCT00390637
doi:10.1371/journal.pone.0098707
PMCID: PMC4077708  PMID: 24983748
12.  Determinants of Human Adipose Tissue Gene Expression: Impact of Diet, Sex, Metabolic Status, and Cis Genetic Regulation 
PLoS Genetics  2012;8(9):e1002959.
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.
Author Summary
In obesity, an excess of adipose tissue is associated with dyslipidemia and diabetic complications. Gene expression is under the control of various genetic and environmental factors. As a central organ for the control of metabolic disturbances in conditions of both weight gain and loss, a comprehensive understanding of the control of adipose tissue gene expression is of paramount interest. We analyzed adipose tissue gene expression in obese individuals from the DiOGenes protocol, one of the largest dietary interventions worldwide. We found evidence for composite control of adipose tissue gene expression by nutrition, metabolic syndrome, body mass index, sex, and genotype with two main novel features. First, we observed a preeminent effect of sex on adipose tissue gene expression, which was independent of nutritional status, fat mass, and sex chromosomes. Second, the control of gene expression by cis genetic factors was unaffected by sex and nutritional status. Altogether, the effects of the investigated factors were most often independent of each other. Comprehension of the relative importance of environmental and individual factors that control the expression of human adipose tissue genes may help deciphering strategies aimed at controlling adipose tissue function during metabolic disorders.
doi:10.1371/journal.pgen.1002959
PMCID: PMC3459935  PMID: 23028366
13.  TFAP2B Influences the Effect of Dietary Fat on Weight Loss under Energy Restriction 
PLoS ONE  2012;7(8):e43212.
Background
Numerous gene loci are related to single measures of body weight and shape. We investigated if 55 SNPs previously associated with BMI or waist measures, modify the effects of fat intake on weight loss and waist reduction under energy restriction.
Methods and Findings
Randomized controlled trial of 771 obese adults. (Registration: ISRCTN25867281.) One SNP was selected for replication in another weight loss intervention study of 934 obese adults. The original trial was a 10-week 600 kcal/d energy-deficient diet with energy percentage from fat (fat%) in range of 20–25 or 40–45. The replication study used an 8-weeks diet of 880 kcal/d and 20 fat%; change in fat% intake was used for estimation of interaction effects. The main outcomes were intervention weight loss and waist reduction. In the trial, mean change in fat% intake was −12/+4 in the low/high-fat groups. In the replication study, it was −23/−12 among those reducing fat% more/less than the median. TFAP2B-rs987237 genotype AA was associated with 1.0 kg (95% CI, 0.4; 1.6) greater weight loss on the low-fat, and GG genotype with 2.6 kg (1.1; 4.1) greater weight loss on the high-fat (interaction p-value; p = 0.00007). The replication study showed a similar (non-significant) interaction pattern. Waist reduction results generally were similar. Study-strengths include (i) the discovery study randomised trial design combined with the replication opportunity (ii) the strict dietary intake control in both studies (iii) the large sample sizes of both studies. Limitations are (i) the low minor allele frequency of the TFAP2B polymorphism, making it hard to investigate non-additive genetic effects (ii) the different interventions preventing identical replication-discovery study designs (iii) some missing data for non-completers and dietary intake. No adverse effects/outcomes or side-effects were observed.
Conclusions
Under energy restriction, TFAP2B may modify the effect of dietary fat intake on weight loss and waist reduction.
doi:10.1371/journal.pone.0043212
PMCID: PMC3428346  PMID: 22952648
14.  Caloric Restriction Induces Changes in Insulin and Body Weight Measurements That Are Inversely Associated with Subsequent Weight Regain 
PLoS ONE  2012;7(8):e42858.
Background
Successful weight maintenance following weight loss is challenging for many people. Identifying predictors of longer-term success will help target clinical resources more effectively. To date, focus has been predominantly on the identification of predictors of weight loss. The goal of the current study was to determine if changes in anthropometric and clinical parameters during acute weight loss are associated with subsequent weight regain.
Methodology
The study consisted of an 8-week low calorie diet (LCD) followed by a 6-month weight maintenance phase. Anthropometric and clinical parameters were analyzed before and after the LCD in the 285 participants (112 men, 173 women) who regained weight during the weight maintenance phase. Mixed model ANOVA, Spearman correlation, and linear regression were used to study the relationships between clinical measurements and weight regain.
Principal Findings
Gender differences were observed for body weight and several clinical parameters at both baseline and during the LCD-induced weight loss phase. LCD-induced changes in BMI (Spearman’s ρ = 0.22, p = 0.0002) were inversely associated with weight regain in both men and women. LCD-induced changes in fasting insulin (ρ = 0.18, p = 0.0043) and HOMA-IR (ρ = 0.19, p = 0.0023) were also associated independently with weight regain in both genders. The aforementioned associations remained statistically significant in regression models taking account of variables known to independently influence body weight.
Conclusions/Significance
LCD-induced changes in BMI, fasting insulin, and HOMA-IR are inversely associated with weight regain in the 6-month period following weight loss.
doi:10.1371/journal.pone.0042858
PMCID: PMC3414506  PMID: 22905179
15.  Effects of Meal Frequency on Metabolic Profiles and Substrate Partitioning in Lean Healthy Males 
PLoS ONE  2012;7(6):e38632.
Introduction
The daily number of meals has an effect on postprandial glucose and insulin responses, which may affect substrate partitioning and thus weight control. This study investigated the effects of meal frequency on 24 h profiles of metabolic markers and substrate partitioning.
Methods
Twelve (BMI:21.6±0.6 kg/m2) healthy male subjects stayed after 3 days of food intake and physical activity standardization 2×36 hours in a respiration chamber to measure substrate partitioning. All subjects randomly received two isoenergetic diets with a Low meal Frequency (3×; LFr) or a High meal Frequency (14×; HFr) consisting of 15 En% protein, 30 En% fat, and 55 En% carbohydrates. Blood was sampled at fixed time points during the day to measure metabolic markers and satiety hormones.
Results
Glucose and insulin profiles showed greater fluctuations, but a lower AUC of glucose in the LFr diet compared with the HFr diet. No differences between the frequency diets were observed on fat and carbohydrate oxidation. Though, protein oxidation and RMR (in this case SMR + DIT) were significantly increased in the LFr diet compared with the HFr diet. The LFr diet increased satiety and reduced hunger ratings compared with the HFr diet during the day.
Conclusion
The higher rise and subsequently fall of insulin in the LFr diet did not lead to a higher fat oxidation as hypothesized. The LFr diet decreased glucose levels throughout the day (AUC) indicating glycemic improvements. RMR and appetite control increased in the LFr diet, which can be relevant for body weight control on the long term.
Trial Registration
ClinicalTrails.gov NCT01034293
doi:10.1371/journal.pone.0038632
PMCID: PMC3374835  PMID: 22719910
16.  Intraduodenal Administration of Intact Pea Protein Effectively Reduces Food Intake in Both Lean and Obese Male Subjects 
PLoS ONE  2011;6(9):e24878.
Background
Human duodenal mucosa secretes increased levels of satiety signals upon exposure to intact protein. However, after oral protein ingestion, gastric digestion leaves little intact proteins to enter the duodenum. This study investigated whether bypassing the stomach, through intraduodenal administration, affects hormone release and food-intake to a larger extent than orally administered protein in both lean and obese subjects.
Methods
Ten lean (BMI:23.0±0.7 kg/m2) and ten obese (BMI:33.4±1.4 kg/m2) healthy male subjects were included. All subjects randomly received either pea protein solutions (250 mg/kg bodyweight in 0.4 ml/kg bodyweight of water) or placebo (0.4 ml/kg bodyweight of water), either orally or intraduodenally via a naso-duodenal tube. Appetite-profile, plasma GLP-1, CCK, and PYY concentrations were determined over a 2 h period. After 2 h, subjects received an ad-libitum meal and food-intake was recorded.
Results
CCK levels were increased at 10(p<0.02) and 20(p<0.01) minutes after intraduodenal protein administration (IPA), in obese subjects, compared to lean subjects, but also compared to oral protein administration (OPA)(p<0.04). GLP-1 levels increased after IPA in obese subjects after 90(p<0.02) to 120(p<0.01) minutes, compared to OPA. Food-intake was reduced after IPA both in lean and obese subjects (-168.9±40 kcal (p<0.01) and −298.2±44 kcal (p<0.01), respectively), compared to placebo. Also, in obese subjects, food-intake was decreased after IPA (−132.6±42 kcal; p<0.01), compared to OPA.
Conclusions
Prevention of gastric proteolysis through bypassing the stomach effectively reduces food intake, and seems to affect obese subjects to a greater extent than lean subjects. Enteric coating of intact protein supplements may provide an effective dietary strategy in the prevention/treatment of obesity.
doi:10.1371/journal.pone.0024878
PMCID: PMC3172308  PMID: 21931864
18.  Allelic Variants of Melanocortin 3 Receptor Gene (MC3R) and Weight Loss in Obesity: A Randomised Trial of Hypo-Energetic High- versus Low-Fat Diets 
PLoS ONE  2011;6(6):e19934.
Introduction
The melanocortin system plays an important role in energy homeostasis. Mice genetically deficient in the melanocortin-3 receptor gene have a normal body weight with increased body fat, mild hypophagia compared to wild-type mice. In humans, Thr6Lys and Val81Ile variants of the melanocortin-3 receptor gene (MC3R) have been associated with childhood obesity, higher BMI Z-score and elevated body fat percentage compared to non-carriers. The aim of this study is to assess the association in adults between allelic variants of MC3R with weight loss induced by energy-restricted diets.
Subjects and Methods
This research is based on the NUGENOB study, a trial conducted to assess weight loss during a 10-week dietary intervention involving two different hypo-energetic (high-fat and low-fat) diets. A total of 760 obese patients were genotyped for 10 single nucleotide polymorphisms covering the single exon of MC3R gene and its flanking regions, including the missense variants Thr6Lys and Val81Ile. Linear mixed models and haplotype-based analysis were carried out to assess the potential association between genetic polymorphisms and differential weight loss, fat mass loss, waist change and resting energy expenditure changes.
Results
No differences in drop-out rate were found by MC3R genotypes. The rs6014646 polymorphism was significantly associated with weight loss using co-dominant (p = 0.04) and dominant models (p = 0.03). These p-values were not statistically significant after strict control for multiple testing. Haplotype-based multivariate analysis using permutations showed that rs3827103–rs1543873 (p = 0.06), rs6014646–rs6024730 (p = 0.05) and rs3746619–rs3827103 (p = 0.10) displayed near-statistical significant results in relation to weight loss. No other significant associations or gene*diet interactions were detected for weight loss, fat mass loss, waist change and resting energy expenditure changes.
Conclusion
The study provided overall sufficient evidence to support that there is no major effect of genetic variants of MC3R and differential weight loss after a 10-week dietary intervention with hypo-energetic diets in obese Europeans.
doi:10.1371/journal.pone.0019934
PMCID: PMC3114803  PMID: 21695122
19.  Glucokinase Regulatory Protein Genetic Variant Interacts with Omega-3 PUFA to Influence Insulin Resistance and Inflammation in Metabolic Syndrome 
PLoS ONE  2011;6(6):e20555.
Glucokinase Regulatory Protein (GCKR) plays a central role regulating both hepatic triglyceride and glucose metabolism. Fatty acids are key metabolic regulators, which interact with genetic factors and influence glucose metabolism and other metabolic traits. Omega-3 polyunsaturated fatty acids (n-3 PUFA) have been of considerable interest, due to their potential to reduce metabolic syndrome (MetS) risk.
Objective
To examine whether genetic variability at the GCKR gene locus was associated with the degree of insulin resistance, plasma concentrations of C-reactive protein (CRP) and n-3 PUFA in MetS subjects.
Design
Homeostasis model assessment of insulin resistance (HOMA-IR), HOMA-B, plasma concentrations of C-peptide, CRP, fatty acid composition and the GCKR rs1260326-P446L polymorphism, were determined in a cross-sectional analysis of 379 subjects with MetS participating in the LIPGENE dietary cohort.
Results
Among subjects with n-3 PUFA levels below the population median, carriers of the common C/C genotype had higher plasma concentrations of fasting insulin (P = 0.019), C-peptide (P = 0.004), HOMA-IR (P = 0.008) and CRP (P = 0.032) as compared with subjects carrying the minor T-allele (Leu446). In contrast, homozygous C/C carriers with n-3 PUFA levels above the median showed lower plasma concentrations of fasting insulin, peptide C, HOMA-IR and CRP, as compared with individuals with the T-allele.
Conclusions
We have demonstrated a significant interaction between the GCKR rs1260326-P446L polymorphism and plasma n-3 PUFA levels modulating insulin resistance and inflammatory markers in MetS subjects. Further studies are needed to confirm this gene-diet interaction in the general population and whether targeted dietary recommendations can prevent MetS in genetically susceptible individuals.
Trial Registration
ClinicalTrials.gov NCT00429195
doi:10.1371/journal.pone.0020555
PMCID: PMC3108949  PMID: 21674002
20.  Genetic Polymorphisms in the Hypothalamic Pathway in Relation to Subsequent Weight Change – The DiOGenes Study 
PLoS ONE  2011;6(2):e17436.
Background
Single nucleotide polymorphisms (SNPs) in genes encoding the components involved in the hypothalamic pathway may influence weight gain and dietary factors may modify their effects.
Aim
We conducted a case-cohort study to investigate the associations of SNPs in candidate genes with weight change during an average of 6.8 years of follow-up and to examine the potential effect modification by glycemic index (GI) and protein intake.
Methods and Findings
Participants, aged 20–60 years at baseline, came from five European countries. Cases (‘weight gainers’) were selected from the total eligible cohort (n = 50,293) as those with the greatest unexplained annual weight gain (n = 5,584). A random subcohort (n = 6,566) was drawn with the intention to obtain an equal number of cases and noncases (n = 5,507). We genotyped 134 SNPs that captured all common genetic variation across the 15 candidate genes; 123 met the quality control criteria. Each SNP was tested for association with the risk of being a ‘weight gainer’ (logistic regression models) in the case-noncase data and with weight gain (linear regression models) in the random subcohort data. After accounting for multiple testing, none of the SNPs was significantly associated with weight change. Furthermore, we observed no significant effect modification by dietary factors, except for SNP rs7180849 in the neuromedin β gene (NMB). Carriers of the minor allele had a more pronounced weight gain at a higher GI (P = 2×10−7).
Conclusions
We found no evidence of association between SNPs in the studied hypothalamic genes with weight change. The interaction between GI and NMB SNP rs7180849 needs further confirmation.
doi:10.1371/journal.pone.0017436
PMCID: PMC3044761  PMID: 21390334
21.  Blood Profile of Proteins and Steroid Hormones Predicts Weight Change after Weight Loss with Interactions of Dietary Protein Level and Glycemic Index 
PLoS ONE  2011;6(2):e16773.
Background
Weight regain after weight loss is common. In the Diogenes dietary intervention study, high protein and low glycemic index (GI) diet improved weight maintenance.
Objective
To identify blood predictors for weight change after weight loss following the dietary intervention within the Diogenes study.
Design
Blood samples were collected at baseline and after 8-week low caloric diet-induced weight loss from 48 women who continued to lose weight and 48 women who regained weight during subsequent 6-month dietary intervention period with 4 diets varying in protein and GI levels. Thirty-one proteins and 3 steroid hormones were measured.
Results
Angiotensin I converting enzyme (ACE) was the most important predictor. Its greater reduction during the 8-week weight loss was related to continued weight loss during the subsequent 6 months, identified by both Logistic Regression and Random Forests analyses. The prediction power of ACE was influenced by immunoproteins, particularly fibrinogen. Leptin, luteinizing hormone and some immunoproteins showed interactions with dietary protein level, while interleukin 8 showed interaction with GI level on the prediction of weight maintenance. A predictor panel of 15 variables enabled an optimal classification by Random Forests with an error rate of 24±1%. A logistic regression model with independent variables from 9 blood analytes had a prediction accuracy of 92%.
Conclusions
A selected panel of blood proteins/steroids can predict the weight change after weight loss. ACE may play an important role in weight maintenance. The interactions of blood factors with dietary components are important for personalized dietary advice after weight loss.
Registration
ClinicalTrials.gov NCT00390637
doi:10.1371/journal.pone.0016773
PMCID: PMC3038864  PMID: 21340022
22.  Hormone-Sensitive Lipase Serine Phosphorylation and Glycerol Exchange Across Skeletal Muscle in Lean and Obese Subjects  
Diabetes  2008;57(7):1834-1841.
OBJECTIVE—Increased intramuscular triacylglycerol (IMTG) storage is a characteristic of the obese insulin-resistant state. We aimed to investigate whether a blunted fasting or β-adrenergically mediated lipolysis contributes to this increased IMTG storage in obesity.
RESEARCH DESIGN AND METHODS—Forearm skeletal muscle lipolysis was investigated in 13 lean and 10 obese men using [2H5]glycerol combined with the measurement of arteriovenous differences before and during β-adrenergic stimulation using the nonselective β-agonist isoprenaline (ISO). Muscle biopsies were taken from the vastus lateralis muscle before and during ISO to investigate hormone-sensitive lipase (HSL) protein expression and serine phosphorylation.
RESULTS—Baseline total glycerol release across the forearm was significantly blunted in obese compared with lean subjects (P = 0.045). This was accompanied by lower HSL protein expression (P = 0.004), HSL phosphorylation on PKA sites Ser563 (P = 0.041) and Ser659 (P = 0.09), and HSL phosphorylation on the AMPK site Ser565 (P = 0.007), suggesting a blunted skeletal muscle lipolysis in obesity. Total forearm glycerol uptake during baseline did not differ significantly between groups, whereas higher net fatty acid uptake across the forearm was observed in the obese (P = 0.064). ISO induced an increase in total glycerol release from skeletal muscle, which was not significantly different between groups. Interestingly, this was accompanied by an increase in HSL Ser659 phosphorylation in obese subjects during ISO compared with baseline (P = 0.008).
CONCLUSIONS—Obesity is accompanied by impaired fasting glycerol release, lower HSL protein expression, and serine phosphorylation. It remains to be determined whether this is a primary factor or an adaptation to the obese insulin-resistant state.
doi:10.2337/db07-0857
PMCID: PMC2453623  PMID: 18398140
23.  Dietary Energy Density in Relation to Subsequent Changes of Weight and Waist Circumference in European Men and Women 
PLoS ONE  2009;4(4):e5339.
Background
Experimental studies show that a reduction in dietary energy density (ED) is associated with reduced energy intake and body weight. However, few observational studies have investigated the role of ED on long-term weight and waist circumference change.
Methods and Principal Findings
This population-based prospective cohort study included 89,432 participants from five European countries with mean age 53 years (range: 20–78 years) at baseline and were followed for an average of 6.5 years (range: 1.9–12.5 years). Participants were free of cancer, cardiovascular diseases and diabetes at baseline. ED was calculated as the energy intake (kcal) from foods divided by the weight (g) of foods. Multiple linear regression analyses were performed to investigate the associations of ED with annual weight and waist circumference change.
Mean ED was 1.7 kcal/g and differed across study centers. After adjusting for baseline anthropometrics, demographic and lifestyle factors, follow-up duration and energy from beverages, ED was not associated with weight change, but significantly associated with waist circumference change overall. For 1 kcal/g ED, the annual weight change was −42 g/year [95% confidence interval (CI): −112, 28] and annual waist circumference change was 0.09 cm/year [95% CI: 0.01, 0.18]. In participants with baseline BMI<25 kg/m2, 1 kcal/g ED was associated with a waist circumference change of 0.17 cm/year [95% CI: 0.09, 0.25].
Conclusion
Our results suggest that lower ED diets do not prevent weight gain but have a weak yet potentially beneficial effect on the prevention of abdominal obesity as measured by waist circumference.
doi:10.1371/journal.pone.0005339
PMCID: PMC2669499  PMID: 19396357
24.  Adipose triglyceride lipase (ATGL) expression in human skeletal muscle is type I (oxidative) fiber specific 
Histochemistry and Cell Biology  2008;129(4):535-538.
Accumulation of triacylglycerol (TAG) and lipid intermediates in skeletal muscle plays an important role in the etiology of insulin resistance and type 2 diabetes mellitus. Disturbances in skeletal muscle lipid turnover and lipolysis may contribute significantly to this. So far, knowledge on the regulation of muscle lipolysis is limited. Recently the identification of a new lipase was reported: adipose triglyceride lipase (ATGL). ATGL deficient animals show significant lipid accumulation in skeletal muscle, which may indicate that ATGL plays a pivotal role in skeletal muscle lipolysis. However, until now, it is still unknown whether ATGL protein is expressed in human skeletal muscle. Therefore, the aim of the present study was to investigate whether ATGL is expressed at the protein level in human skeletal muscle, and to examine whether its expression is fiber-type specific. To accomplish this, we established an imunohistochemical and immunofluorescent staining procedure to study ATGL protein expression in relation to fiber type in human vastus lateralis muscle of eight male subjects (BMI range: 21.0–34.5 kg/m2 and age: 38–59 years). In the present paper we report for the first time that ATGL protein is indeed expressed in human skeletal muscle. Moreover, ATGL is exclusively expressed in type I (oxidative) muscle fibers, suggesting a pivotal role for ATGL in intramuscular fatty acid handling, lipid storage and breakdown.
doi:10.1007/s00418-008-0386-y
PMCID: PMC2668625  PMID: 18224330
ATGL;  Skeletal muscle; Fiber type; Obesity; Protein
25.  Human Skeletal Muscle Mitochondrial Uncoupling Is Associated with Cold Induced Adaptive Thermogenesis 
PLoS ONE  2008;3(3):e1777.
Background
Mild cold exposure and overfeeding are known to elevate energy expenditure in mammals, including humans. This process is called adaptive thermogenesis. In small animals, adaptive thermogenesis is mainly caused by mitochondrial uncoupling in brown adipose tissue and regulated via the sympathetic nervous system. In humans, skeletal muscle is a candidate tissue, known to account for a large part of the epinephrine-induced increase in energy expenditure. However, mitochondrial uncoupling in skeletal muscle has not extensively been studied in relation to adaptive thermogenesis in humans. Therefore we hypothesized that cold-induced adaptive thermogenesis in humans is accompanied by an increase in mitochondrial uncoupling in skeletal muscle.
Methodology/Principal Findings
The metabolic response to mild cold exposure in 11 lean, male subjects was measured in a respiration chamber at baseline and mild cold exposure. Skeletal muscle mitochondrial uncoupling (state 4) was measured in muscle biopsies taken at the end of the respiration chamber stays. Mild cold exposure caused a significant increase in 24h energy expenditure of 2.8% (0.32 MJ/day, range of −0.21 to 1.66 MJ/day, p<0.05). The individual increases in energy expenditure correlated to state 4 respiration (p<0.02, R2 = 0.50).
Conclusions/Significance
This study for the first time shows that in humans, skeletal muscle has the intrinsic capacity for cold induced adaptive thermogenesis via mitochondrial uncoupling under physiological conditions. This opens possibilities for mitochondrial uncoupling as an alternative therapeutic target in the treatment of obesity.
doi:10.1371/journal.pone.0001777
PMCID: PMC2258415  PMID: 18335051

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