Pedersen, O. (Oluf)
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- Allelic variants of melanocortin 3 receptor gene (MC3R) and weight loss in obesity: a randomised trial of hypo-energetic high- versus low-fat diets(Public Library of Sciences, 2011) Santos, J.L. (José Luis); Martinez, J.A. (José Alfredo); Saris, W.H.M. (Wim H. M.); Maiz, A. (Alberto); Sørensen, T.I.A (Thorkild I. A.); Hansen, T. (Torben); Naranjo, C. (C.); Cruz, R. (R.) de la; Astrup, A. (Arne); Grau, K. (K.); Pedersen, O. (Oluf); Holst, C. (C.); Oppert, J.M. (Jean M.); MacDonald, I. (Ian)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.
- TFAP2B influences the effect of dietary fat on weight loss under energy restriction(Public Library of Science, 2012) Martinez, J.A. (José Alfredo); Harder, M.N. (Marie N.); Saris, W.H.M. (Wim H. M.); Rousseau, F. (Francis); Kunesova, M. (Marie); Sørensen, T.I.A (Thorkild I. A.); Hansen, T. (Torben); Ängquist, L. (Lars); Langin, D. (D.); Pfeiffer, A.F. (A.F.); Banasik, K. (Karina); Astrup, A. (Arne); Stocks, T. (Tanja); Rössner, S. (Stephan); Polak, J. (Jan); Arner, P. (P.); Taylor, M. (Moira); Pedersen, O. (Oluf); Kamatani, Y. (Yoichiro); Holst, C. (C.); Hager, J. (Jörg); Oppert, J.M. (Jean M.); MacDonald, I. (Ian)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.
- Genetic polymorphisms and weight loss in obesity: A randomised trial of hypo-energetic high-versus low-fat diets(Public Library of Sciences, 2006) Martinez, J.A. (José Alfredo); Saris, W.H.M. (Wim H. M.); Sørensen, T.I.A (Thorkild I. A.); Boutin, P. (Philippe); Verdich, C. (Camilla); Petersen, M. (Martin); Langin, D. (D.); Dina, C. (Christian); Astrup, A. (Arne); Clement, K. (K.); Petersen, L. (Liselotte); Echwald, S.M. (S.M.); Polak, J. (Jan); Arner, P. (P.); Larsen, L.H. (Lesli H.); Taylor, M. (Moira); Pedersen, O. (Oluf); Stich, V. (Vladimir); Toubro, S. (Soren); Holst, C. (C.); Oppert, J.M. (Jean M.); Froguel, P. (Philippe); MacDonald, I. (Ian)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.
- FTO genotype and weight loss: systematic review and meta-analysis of 9563 individual participant data from eight randomised controlled trials(BMJ, 2016) Martinez, J.A. (José Alfredo); Tuomilehto, J. (Jaakko); Martinez-Gonzalez, M.A. (Miguel Ángel); Rankinen, T. (Tuomo); Saris, W.H.M. (Wim H. M.); Sui, X. (Xuemei); Mathers, J.C. (John C.); Jääskeläinen, T. (Tiina); Uusitupa, M. (Matti); Bray, G.A. (George A.); Svendstrup, M. (Mathilde); Livingstone, K.M. (Katherine M.); Florez, J.C. (Jose C.); Lara, J. (Jose); Erar, B. (Bahar); Sørensen, T.I.A (Thorkild I. A.); Huang, T. (Tao); Hansen, T. (Torben); Church, T.S. (Timothy S.); Jablonski, K.A. (Kathleen A.); Sacks, F.M. (Frank M.); Razquin, C. (Cristina); Astrup, A. (Arne); Celis-Morales, C. (Carlos); Papandonatos, G.D. (George D.); Lindström, J. (Jaana); Qi, L. (Lu); Heianza, Y. (Yoriko); Pedersen, O. (Oluf); Franks, P.W. (Paul W.); Marti-del-Moral, A. (Amelia); McCaffery, J.M. (Jeanne M.)Objective To assess the effect of the FTO genotype on weight loss after dietary, physical activity, or drug based interventions in randomised controlled trials. Design Systematic review and random effects meta-analysis of individual participant data from randomised controlled trials. Data sources Ovid Medline, Scopus, Embase, and Cochrane from inception to November 2015. Eligibility criteria for study selection Randomised controlled trials in overweight or obese adults reporting reduction in body mass index, body weight, or waist circumference by FTO genotype (rs9939609 or a proxy) after dietary, physical activity, or drug based interventions. Gene by treatment interaction models were fitted to individual participant data from all studies included in this review, using allele dose coding for genetic effects and a common set of covariates. Study level interactions were combined using random effect models. Metaregression and subgroup analysis were used to assess sources of study heterogeneity. Results We identified eight eligible randomised controlled trials for the systematic review and meta-analysis (n=9563). Overall, differential changes in body mass index, body weight, and waist circumference in response to weight loss intervention were not significantly different between FTO genotypes. Sensitivity analyses indicated that differential changes in body mass index, body weight, and waist circumference by FTO genotype did not differ by intervention type, intervention length, ethnicity, sample size, sex, and baseline body mass index and age category. Conclusions We have observed that carriage of the FTO minor allele was not associated with differential change in adiposity after weight loss interventions. These findings show that individuals carrying the minor allele respond equally well to dietary, physical activity, or drug based weight loss interventions and thus genetic predisposition to obesity associated with the FTO minor allele can be at least partly counteracted through such interventions. Systematic review registration PROSPERO CRD42015015969.
- TCF7L2 rs7903146-macronutrient interaction in obese individuals' responses to a 10-wk randomized hypoenergetic diet(American Society for Nutrition, 2010) Martinez, J.A. (José Alfredo); Claus, C. (C.); Klimcakova, E. (E.); Sørensen, T.I.A (Thorkild I. A.); Langin, D. (D.); Astrup, A. (Arne); Grau, K. (K.); Pedersen, O. (Oluf); Cauchi, S. (Stephane); Froguel, P. (Philippe); MacDonald, I. (Ian)BACKGROUND: Transcription factor 7-like 2 (TCF7L2) rs7903146 associates with type 2 diabetes and may operate via impaired glucagon-like peptide 1 secretion, which is stimulated more by fat than by carbohydrate ingestion. OBJECTIVE: The objective was to examine the interaction between TCF7L2 rs7903146 and dietary fat and carbohydrate [high-fat, low-carbohydrate: 40-45% of energy as fat (HF); compared with low-fat, high-carbohydrate: 20-25% of energy as fat (LF)] in obese individuals' responses to a 10-wk hypoenergetic diet (-600 kcal/d). DESIGN: European, obese participants (n = 771) were randomly assigned to receive an HF or an LF diet. Body weight, fat mass (FM), fat-free mass (FFM), waist circumference (WC), resting energy expenditure (REE), fasting fat oxidation in percentage of REE (FatOx), homeostasis model assessed insulin release (HOMA-beta), and HOMA-insulin resistance (HOMA-IR) were determined at baseline and after the intervention; 739 individuals were genotyped for rs7903146. RESULTS: Average weight loss was 6.9 kg with the LF and 6.6 kg with the HF (difference between diets, NS) diet. Among individuals who were homozygous for the T-risk allele, those in the HF diet group experienced smaller weight losses (Deltaweight) (2.6 kg; P = 0.009; n = 622), smaller DeltaFFM (1.6 kg; P = 0.027; n = 609), smaller DeltaWC (3.3 cm; P = 0.010; n = 608), and a smaller DeltaHOMA-IR (1.3 units; P = 0.004; n = 615) than did the LF diet group. For C allele carriers, there were no differences between the HF and LF diet groups. For the HF diet group, each additional T allele was associated with a reduced loss of FM (0.67 kg; P = 0.019; n = 609). TCF7L2 rs7903146 was not associated with DeltaREE, DeltaFatOx, DeltaHOMA-beta, or dropout. CONCLUSION: Our results suggest that obese individuals who are homozygous for the TCF7L2 rs7903146 T-risk allele are more sensitive to LF than to HF weight-loss diets.