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1.  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
2.  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
3.  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
4.  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
5.  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
6.  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
8.  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
9.  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
10.  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
11.  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
12.  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
13.  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
14.  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
15.  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
16.  Adipose Gene Expression Prior to Weight Loss Can Differentiate and Weakly Predict Dietary Responders 
PLoS ONE  2007;2(12):e1344.
Background
The ability to identify obese individuals who will successfully lose weight in response to dietary intervention will revolutionize disease management. Therefore, we asked whether it is possible to identify subjects who will lose weight during dietary intervention using only a single gene expression snapshot.
Methodology/Principal Findings
The present study involved 54 female subjects from the Nutrient-Gene Interactions in Human Obesity-Implications for Dietary Guidelines (NUGENOB) trial to determine whether subcutaneous adipose tissue gene expression could be used to predict weight loss prior to the 10-week consumption of a low-fat hypocaloric diet. Using several statistical tests revealed that the gene expression profiles of responders (8–12 kgs weight loss) could always be differentiated from non-responders (<4 kgs weight loss). We also assessed whether this differentiation was sufficient for prediction. Using a bottom-up (i.e. black-box) approach, standard class prediction algorithms were able to predict dietary responders with up to 61.1%±8.1% accuracy. Using a top-down approach (i.e. using differentially expressed genes to build a classifier) improved prediction accuracy to 80.9%±2.2%.
Conclusion
Adipose gene expression profiling prior to the consumption of a low-fat diet is able to differentiate responders from non-responders as well as serve as a weak predictor of subjects destined to lose weight. While the degree of prediction accuracy currently achieved with a gene expression snapshot is perhaps insufficient for clinical use, this work reveals that the comprehensive molecular signature of adipose tissue paves the way for the future of personalized nutrition.
doi:10.1371/journal.pone.0001344
PMCID: PMC2147074  PMID: 18094752
18.  Genetic Polymorphisms and Weight Loss in Obesity: A Randomised Trial of Hypo-Energetic High- versus Low-Fat Diets  
PLoS Clinical Trials  2006;1(2):e12.
Objectives:
To study if genes with common single nucleotide polymorphisms (SNPs) associated with obesity-related phenotypes influence weight loss (WL) in obese individuals treated by a hypo-energetic low-fat or high-fat diet.
Design:
Randomised, parallel, two-arm, open-label multi-centre trial.
Setting:
Eight clinical centres in seven European countries.
Participants:
771 obese adult individuals.
Interventions:
10-wk dietary intervention to hypo-energetic (−600 kcal/d) diets with a targeted fat energy of 20%–25% or 40%–45%, completed in 648 participants.
Outcome Measures:
WL during the 10 wk in relation to genotypes of 42 SNPs in 26 candidate genes, probably associated with hypothalamic regulation of appetite, efficiency of energy expenditure, regulation of adipocyte differentiation and function, lipid and glucose metabolism, or production of adipocytokines, determined in 642 participants.
Results:
Compared with the noncarriers of each of the SNPs, and after adjusting for gender, age, baseline weight and centre, heterozygotes showed WL differences that ranged from −0.6 to 0.8 kg, and homozygotes, from −0.7 to 3.1 kg. Genotype-dependent additional WL on low-fat diet ranged from 1.9 to −1.6 kg in heterozygotes, and from 3.8 kg to −2.1 kg in homozygotes relative to the noncarriers. Considering the multiple testing conducted, none of the associations was statistically significant.
Conclusions:
Polymorphisms in a panel of obesity-related candidate genes play a minor role, if any, in modulating weight changes induced by a moderate hypo-energetic low-fat or high-fat diet.
Editorial Commentary
Background: Obesity is an important cause of death and disease, particularly in the developed world. It is understood that both environmental and genetic factors contribute towards obesity. Numerous studies have associated particular gene variants with a tendency towards obesity, but it is not known whether such gene variants affect the degree to which obese individuals will lose weight when dieting.
What this trial shows: As part of a randomised trial, 771 participants were assigned to one of two different low-energy diets for 10 weeks: one low in fat or one high in fat. The researchers then did a genetic analysis of 642 participants completing the intervention, to find out whether any of 42 distinct genetic variations in 26 genes were associated with weight loss in the trial. The genetic variants were chosen for study as they were known or already thought to be associated with appetite regulation or various aspects of metabolism and fat tissue development and function. The investigators found that none of the genetic variants studied had a significant association with weight loss in the trial. It was also seen that the majority of genetic variants were not associated with efficacy of one dietary intervention over another.
Strengths and limitations: Although a large number of participants was recruited into the trial, the genetic analysis involved multiple comparisons—168 tests of 42 genetic variants. This increases the likelihood that any significant associations found could have resulted from chance alone. Significant associations from this study will require additional confirmation in larger studies.
Contribution to the evidence: This study adds data indicating that variation in the genes studied did not have an important influence on weight loss.
doi:10.1371/journal.pctr.0010012
PMCID: PMC1488899  PMID: 16871334
19.  Increased uncoupling protein 3 content does not affect mitochondrial function in human skeletal muscle in vivo 
Journal of Clinical Investigation  2003;111(4):479-486.
Phosphocreatine (PCr) resynthesis rate following intense anoxic contraction can be used as a sensitive index of in vivo mitochondrial function. We examined the effect of a diet-induced increase in uncoupling protein 3 (UCP3) expression on postexercise PCr resynthesis in skeletal muscle. Nine healthy male volunteers undertook 20 one-legged maximal voluntary contractions with limb blood flow occluded to deplete muscle PCr stores. Exercise was performed following 7 days consumption of low-fat (LF) or high-fat (HF) diets. Immediately following exercise, blood flow was reinstated, and muscle was sampled after 20, 60, and 120 seconds of recovery. Mitochondrial coupling was assessed by determining the rate of PCr resynthesis during recovery. The HF diet increased UCP3 protein content by approximately 44% compared with the LF diet. However, this HF diet–induced increase in UCP3 expression was not associated with any changes in the rate of muscle PCr resynthesis during conditions of maximal flux through oxidative phosphorylation. Muscle acetylcarnitine, free-creatine, and lactate concentrations during recovery were unaffected by the HF diet. Taken together, our findings demonstrate that increasing muscle UCP3 expression does not diminish the rate of PCr resynthesis, allowing us to conclude that the primary role of UCP3 in humans is not uncoupling.
doi:10.1172/JCI200316653
PMCID: PMC152374  PMID: 12588886

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