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The association between vitamin D receptor polymorphisms and tissue-specific insulin resistance in human obesity.
Pramono, A, Jocken, JWE, Adriaens, ME, Hjorth, MF, Astrup, A, Saris, WHM, Blaak, EE
International journal of obesity (2005). 2021;(4):818-827
Abstract
BACKGROUND/OBJECTIVES To investigate (1) the association of four VDR polymorphisms (TaqI/rs731236, ApaI/rs7975232, FokI/rs10735810, and Bsml/rs1544410) with markers of adiposity and tissue-specific insulin resistance at baseline, after weight loss and weight maintenance; (2) the effect of the VDR polymorphisms in the SAT transcriptome in overweight/obese Caucasians of the DiOGenes cohort. METHODS We included 553 adult obese individuals (mean BMI 34.8 kg/m2), men (n = 197) and women (n = 356) at baseline, following an 8-week weight loss intervention and 26 weeks weight maintenance. Genotyping was performed using an Illumina 660W-Quad SNP chip on the Illumina iScan Genotyping System. Tissue-specific IR was determined using Hepatic Insulin Resistance Index (HIRI), Muscle Insulin Sensitivity Index (MISI), and Adipose Tissue Insulin Resistance Index (Adipo-IR). Expression quantitative trait loci (eQTL) analysis was performed to determine the effect of SNPs on SAT gene expression. RESULTS None of the VDR polymorphisms were associated with HIRI or MISI. Interestingly, carriers of the G allele of VDR FokI showed higher Adipo-IR (GG + GA 7.8 ± 0.4 vs. AA 5.6 ± 0.5, P = 0.010) and higher systemic FFA (GG + GA: 637.8 ± 13.4 vs. AA: 547.9 ± 24.7 µmol/L, P = 0.011), even after adjustment with age, sex, center, and FM. However, eQTL analysis showed minor to no effect of these genotypes on the transcriptional level in SAT. Also, VDR polymorphisms were not related to changes in body weight and IR as result of dietary intervention (P > 0.05 for all parameters). CONCLUSIONS The VDR Fokl variant is associated with elevated circulating FFA and Adipo-IR at baseline. Nevertheless, minor to no effect of VDR SNPs on the transcriptional level in SAT, indicating that putative mechanisms of action remain to be determined. Finally, VDR SNPs did not affect dietary intervention outcome in the present cohort.
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A Randomized, Double-Blind, Placebo-Controlled Study of Gelesis100: A Novel Nonsystemic Oral Hydrogel for Weight Loss.
Greenway, FL, Aronne, LJ, Raben, A, Astrup, A, Apovian, CM, Hill, JO, Kaplan, LM, Fujioka, K, Matejkova, E, Svacina, S, et al
Obesity (Silver Spring, Md.). 2019;(2):205-216
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Abstract
OBJECTIVE This study aims to assess the efficacy and safety of Gelesis100, a novel, nonsystemic, superabsorbent hydrogel to treat overweight or obesity. METHODS The Gelesis Loss Of Weight (GLOW) study was a 24-week, multicenter, randomized, double-blind, placebo-controlled study in patients with BMI ≥ 27 and ≤ 40 kg/m2 and fasting plasma glucose ≥ 90 and ≤ 145 mg/dL. The co-primary end points were placebo-adjusted weight loss (superiority and 3% margin super-superiority) and at least 35% of patients in the Gelesis100 group achieving ≥ 5% weight loss. RESULTS Gelesis100 treatment caused greater weight loss over placebo (6.4% vs. 4.4%, P = 0.0007), achieving 2.1% superiority but not 3% super-superiority. Importantly, 59% of Gelesis100-treated patients achieved weight loss of ≥ 5%, and 27% achieved ≥ 10% versus 42% and 15% in the placebo group, respectively. Gelesis100-treated patients had twice the odds of achieving ≥ 5% and ≥ 10% weight loss versus placebo (adjusted OR: 2.0, P = 0.0008; OR: 2.1, P = 0.0107, respectively), with 5% responders having a mean weight loss of 10.2%. Patients with prediabetes or drug-naive type 2 diabetes had six times the odds of achieving ≥ 10% weight loss. Gelesis100 treatment had no apparent increased safety risks. CONCLUSIONS Gelesis100 is a promising new nonsystemic therapy for overweight and obesity with a highly desirable safety and tolerability profile.
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Subcutaneous Adipose Tissue and Systemic Inflammation Are Associated With Peripheral but Not Hepatic Insulin Resistance in Humans.
van der Kolk, BW, Kalafati, M, Adriaens, M, van Greevenbroek, MMJ, Vogelzangs, N, Saris, WHM, Astrup, A, Valsesia, A, Langin, D, van der Kallen, CJH, et al
Diabetes. 2019;(12):2247-2258
Abstract
Obesity-related insulin resistance (IR) may develop in multiple organs, representing various etiologies for cardiometabolic diseases. We identified abdominal subcutaneous adipose tissue (ScAT) transcriptome profiles in liver or muscle IR by means of RNA sequencing in overweight or obese participants of the Diet, Obesity, and Genes (DiOGenes) (NCT00390637, ClinicalTrials.gov) cohort (n = 368). Tissue-specific IR phenotypes were derived from a 5-point oral glucose tolerance test. Hepatic and muscle IR were characterized by distinct abdominal ScAT transcriptome profiles. Genes related to extracellular remodeling were upregulated in individuals with primarily hepatic IR, while genes related to inflammation were upregulated in individuals with primarily muscle IR. In line with this, in two independent cohorts, the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) (n = 325) and the Maastricht Study (n = 685), an increased systemic low-grade inflammation profile was specifically related to muscle IR but not to liver IR. We propose that increased ScAT inflammatory gene expression may translate into an increased systemic inflammatory profile, linking ScAT inflammation to the muscle IR phenotype. These distinct IR phenotypes may provide leads for more personalized prevention of cardiometabolic diseases.
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The effectiveness of breakfast recommendations on weight loss: a randomized controlled trial.
Dhurandhar, EJ, Dawson, J, Alcorn, A, Larsen, LH, Thomas, EA, Cardel, M, Bourland, AC, Astrup, A, St-Onge, MP, Hill, JO, et al
The American journal of clinical nutrition. 2014;(2):507-13
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BACKGROUND Breakfast is associated with lower body weight in observational studies. Public health authorities commonly recommend breakfast consumption to reduce obesity, but the effectiveness of adopting these recommendations for reducing body weight is unknown. OBJECTIVE We tested the relative effectiveness of a recommendation to eat or skip breakfast on weight loss in adults trying to lose weight in a free-living setting. DESIGN We conducted a multisite, 16-wk, 3-parallel-arm randomized controlled trial in otherwise healthy overweight and obese adults [body mass index (in kg/m²) between 25 and 40] aged 20-65 y. Our primary outcome was weight change. We compared weight change in a control group with weight loss in experimental groups told to eat breakfast or to skip breakfast [no breakfast (NB)]. Randomization was stratified by prerandomization breakfast eating habits. A total of 309 participants were randomly assigned. RESULTS A total of 283 of the 309 participants who were randomly assigned completed the intervention. Treatment assignment did not have a significant effect on weight loss, and there was no interaction between initial breakfast eating status and treatment. Among skippers, mean (±SD) baseline weight-, age-, sex-, site-, and race-adjusted weight changes were -0.71 ± 1.16, -0.76 ± 1.26, and -0.61 ± 1.18 kg for the control, breakfast, and NB groups, respectively. Among breakfast consumers, mean (±SD) baseline weight-, age-, sex-, site-, and race-adjusted weight changes were -0.53 ± 1.16, -0.59 ± 1.06, and -0.71 ± 1.17 kg for the control, breakfast, and NB groups, respectively. Self-reported compliance with the recommendation was 93.6% for the breakfast group and 92.4% for the NB group. CONCLUSIONS A recommendation to eat or skip breakfast for weight loss was effective at changing self-reported breakfast eating habits, but contrary to widely espoused views this had no discernable effect on weight loss in free-living adults who were attempting to lose weight.
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A multicentre weight loss study using a low-calorie diet over 8 weeks: regional differences in efficacy across eight European cities.
Papadaki, A, Linardakis, M, Plada, M, Larsen, TM, van Baak, MA, Lindroos, AK, Pfeiffer, AF, Martinez, JA, Handjieva-Darlenska, T, Kunešová, M, et al
Swiss medical weekly. 2013;:w13721
Abstract
PRINCIPLES The efficacy of low-calorie diets (LCDs) has not been investigated in large-scale studies or among people from different regions, who are perhaps unaccustomed to such methods of losing weight. The aim of the present study was to investigate changes in obesity measures among overweight/obese adults from eight European cities (from Northern, Central and Southern Europe) during the 8-week LCD phase of the DiOGenes study (2006-2007), a family-based, randomised, controlled dietary intervention. METHODS 938 overweight/obese adults completed baseline examinations and underwent an 8-week LCD, providing 3.3-4.2 MJ/day to replace all meals. Anthropometric measurements and body composition were assessed at baseline and post-LCD. RESULTS 773 (82.4%) adults (mean age, 43.1 y) completed the LCD successfully. The highest drop-out rate was observed in Southern (24.9%) and the lowest in Northern (13.3%) European cities. Overall, the LCD induced favourable changes in all outcomes, including an approximate 11.0% reduction in body weight and body fat percentage. Changes in outcomes differed significantly between regions, with North- and Central-European cities generally achieving higher percentage reductions in most anthropometric measurements assessed. Nonetheless, participants in Southern Europe reduced their body fat percentage significantly more than participants in Northern Europe (-11.8 vs. -9.5%, P = 0.017). CONCLUSIONS The LCD significantly improved anthropometric and body composition measurements in all cities participating in DiOGenes.
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Circulating ACE is a predictor of weight loss maintenance not only in overweight and obese women, but also in men.
Wang, P, Holst, C, Wodzig, WK, Andersen, MR, Astrup, A, van Baak, MA, Larsen, TM, Jebb, SA, Kafatos, A, Pfeiffer, AF, et al
International journal of obesity (2005). 2012;(12):1545-51
Abstract
BACKGROUND Circulating angiotensin-converting enzyme (ACE) was identified as a predictor of weight loss maintenance in overweight/obese women of the Diogenes project. OBJECTIVE To investigate whether ACE acted also as a predictor in men of the Diogenes study and to compare it with that in women. DESIGN Subjects, who lost ≥ 8% of body weight induced by low-caloric diet in an 8-week weight loss period, were assigned to weight loss maintenance with dietary intervention for 6 months. SUBJECTS 125 overweight/obese healthy men from eight European countries who completed whole intervention. MEASUREMENTS Concentrations and activity of serum ACE at baseline and after the 8-week weight loss, in addition to anthropometric and physiological parameters. RESULTS Serum ACE concentration decreased by 11.3 ± 10.6% during the weight loss period in men. A greater reduction is associated with less body weight regain during the maintenance period (r=0.227, P=0.012). ACE change was able to predict a weight regain ≤ 20% after 6 months, with an odds ratio of 1.59 (95% confidence interval (CI): 1.09-2.33, P=0.016) for every 10% reduction, which was independent of body mass index and weight loss. The prediction power was weaker in men than in women, but without a significant sex difference (P=0.137). In pooled subjects (N=218), the odds ratio was 1.96 (95% CI: 1.46-2.64, P<0.001). CONCLUSIONS A greater reduction of ACE during weight loss is favorable for weight maintenance in both men and women. This can offer useful information for personalized advice to improve weight loss maintenance. It also confirms the role of ACE in the metabolic pathways of weight regulation.
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Clinical correlates of weight loss and attrition during a 10-week dietary intervention study: results from the NUGENOB project.
Handjieva-Darlenska, T, Holst, C, Grau, K, Blaak, E, Martinez, JA, Oppert, JM, Taylor, MA, Sørensen, TI, Astrup, A
Obesity facts. 2012;(6):928-36
Abstract
OBJECTIVE The aim of this study was to identify the pre-treatment subject characteristics and weight loss changes as determinants of weight loss and attrition during a 10-week dietary intervention study. METHODS A total of 771 obese subjects (BMI 35.6 kg/m(2)) of both genders were included from 8 clinical centres in 7 European countries, who underwent a 10-week dietary intervention study comparing two hypo-energetic (-600 kcal/day) diets varying in fat content. RESULTS The multiple regression model showed that weight loss at week 10 was predicted by: 6.55 + 1.27 × early weight loss (kg) at week 1 + 1.35 × gender (R(2) = 0.28, p < 0.001). When performing the corresponding model with half-way weight loss (week 5) as covariate, the regression equation was: weight loss (kg) at week 10 = 1.88 + 1.38 × half-way weight loss (kg) (week 5) + 0.42 × gender (R(2) = 0.77, p < 0.001). A cut-off target of ≥ 4 kg weight loss at week 5 emerged as an optimal predictor for reaching at least 10% weight loss at week 10. Greater attrition likelihood was predicted by high-fat diet, decreased early and half-way weight losses. CONCLUSION Early and half-way weight losses are associated with and could contribute to prediction of the final weight loss and attrition.
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The effect of tesofensine on appetite sensations.
Gilbert, JA, Gasteyger, C, Raben, A, Meier, DH, Astrup, A, Sjödin, A
Obesity (Silver Spring, Md.). 2012;(3):553-61
Abstract
Tesofensine (TE), an inhibitor of monoamine presynaptic reuptake, has produced twice the weight loss seen with currently marketed drugs. However, its long term effect on appetite in humans has not been studied. A multicentre phase II trial was divided into two parts (24 weeks each). Part 1 had a randomized, double-blind, placebo-controlled design and Part 2, an open-labeled, single-group, uncontrolled design. A drug-free period (12 ± 3 weeks) separated them. In Part 1, participants (n = 158) were assigned to 0.25, 0.5 or 1.0 mg TE, or placebo. Completers of Part 1 were invited to participate in Part 2 (n = 113), during which they all received 0.5 or 1.0 mg TE. Appetite sensations and a composite satiety score (CSS = satiety + fullness + (100 - hunger) + (100 - prospective food consumption) were assessed. In Part 1 TE induced a dose-dependent increase in CSS at week 12 that correlated with weight loss during the 24 weeks (r = 0.36, P < 0.0001). However, CSS diminished over time as weight loss progressed (e.g., for 1.0 mg; 52 ± 17 mm; 64 ± 13 mm; 55 ± 13 mm at baseline, week 12 and week 24, respectively). After drug withdrawal CSS returned to baseline values (50 ± 17 mm, in the whole sample.), despite the participants' reduced-weight state (-7.2 ± 6.7 kg, P < 0.0001). The reintroduction of TE in Part 2 increased CSS again (56 ± 17 mm at week 60), regardless of initial treatment/weight loss. We postulate that enhanced satiety is involved in early weight loss. Whether the attenuated effect on appetite seen after 24 weeks is due to a counteracting effect in the weight reduced state or whether the appetite suppressing effect of TE per se diminishes over time is, however, still unclear.
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Dietary strategy to manipulate ad libitum macronutrient intake, and glycaemic index, across eight European countries in the Diogenes Study.
Moore, CS, Lindroos, AK, Kreutzer, M, Larsen, TM, Astrup, A, van Baak, MA, Handjieva-Darlenska, T, Hlavaty, P, Kafatos, A, Kohl, A, et al
Obesity reviews : an official journal of the International Association for the Study of Obesity. 2010;(1):67-75
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The aim of this study was to describe the development and implementation of a multifaceted, low-fat, weight-loss strategy for a Pan-European randomized controlled dietary intervention study, Diogenes. There were 891 families with at least one overweight/obese parent who underwent screening. Eligible, overweight/obese adults followed an 8-week weight-loss phase with a fixed low-energy diet (800 kcal). On attaining weight loss of > or = 8%, families were randomized to a 6- or 12-month low-fat (25-30%E) diet either based on national dietary guidelines or one of four interventions: low protein (LP)/low glycaemic index (LGI), LP/high GI (HGI), high protein (HP)/LGI and HP/HGI. The impact of each diet in preventing weight (re)gain was tested. A points-based system was used to manipulate dietary protein and carbohydrate. Manipulating carbohydrate composition involved substituting foods with a relatively high or low GI. A questionnaire was designed and completed by study investigators, providing feedback on the dietary intervention methods used to inform future interventions. The points system allowed macronutrient manipulations without compromising dietary flexibility or enforcing energy restrictions. Reported centre/participant differences in the ease of implementing the intervention may reflect dietary diversity and personal preferences for specific weight-management strategies. The points system provides a useful starting point for designing improved experimental paradigms for the manipulation of dietary intake in future trials.
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The Diet, Obesity and Genes (Diogenes) Dietary Study in eight European countries - a comprehensive design for long-term intervention.
Larsen, TM, Dalskov, S, van Baak, M, Jebb, S, Kafatos, A, Pfeiffer, A, Martinez, JA, Handjieva-Darlenska, T, Kunesová, M, Holst, C, et al
Obesity reviews : an official journal of the International Association for the Study of Obesity. 2010;(1):76-91
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Diogenes is a Pan-European, randomized, controlled dietary intervention study investigating the effects of dietary protein and glycaemic index on weight (re)gain, metabolic and cardiovascular risk factors in obese and overweight families in eight European centres. The article is methodological in character, and the presentation of 'results' will be limited to baseline characteristics of the study populations included. A total of 891 families with at least one overweight/obese parent underwent screening. The parents started an initial 8-week low-calorie diet and families with minimum one parent attaining a weight loss of > or = 8%, were randomized to one of five energy ad libitum, low-fat (25-30 E%) diets for 6 or 12 months: low protein/low glycaemic index, low protein/high glycaemic index, high protein/low glycaemic index, high protein/high glycaemic index or control (national dietary guidelines). At two centres the families were provided dietary instruction plus free foods for 6 months followed by 6-month dietary instruction only. At the remaining six centres the families received dietary instruction only for 6 months. The median weight loss during the low-calorie diet was 10.3 kg (inter-quartile range: 8.7-12.8 kg, n = 775). A total of 773 adults and 784 children were randomized to the 6-month weight (re)gain prevention phase. Despite major cultural and dietary regional differences in Europe, interventions addressing effects of dietary factors are feasible with a reasonable attrition.