Clement, K. (K.)
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- A distinct adipose tissue gene expression response to caloric restriction predicts 6-mo weight maintenance in obese subjects(American Society for Nutrition, 2011) Martinez, J.A. (José Alfredo); Pelloux, V. (Véronique); Saris, W.H.M. (Wim H. M.); Viguerie, N. (N.); Mutch, D.M. (David M.); Walker, C.G. (C.G.); Langin, D. (D.); Handjieva-Darlenska, T. (Teodora); Babalis, D. (D.); Van-Baak, M.A. (M.A.); Astrup, A. (Arne); Clement, K. (K.); Pers, T.H. (T.H.); Zucker, J.D. (J.D.); Temanni, M.R. (M. Ramzi); Holst, C. (C.); Marquez-Quiñones, A. (A.)BACKGROUND: Weight loss has been shown to reduce risk factors associated with cardiovascular disease and diabetes; however, successful maintenance of weight loss continues to pose a challenge. OBJECTIVE: The present study was designed to assess whether changes in subcutaneous adipose tissue (scAT) gene expression during a low-calorie diet (LCD) could be used to differentiate and predict subjects who experience successful short-term weight maintenance from subjects who experience weight regain. DESIGN: Forty white women followed a dietary protocol consisting of an 8-wk LCD phase followed by a 6-mo weight-maintenance phase. Participants were classified as weight maintainers (WMs; 0-10% weight regain) and weight regainers (WRs; 50-100% weight regain) by considering changes in body weight during the 2 phases. Anthropometric measurements, bioclinical variables, and scAT gene expression were studied in all individuals before and after the LCD. Energy intake was estimated by using 3-d dietary records. RESULTS: No differences in body weight and fasting insulin were observed between WMs and WRs at baseline or after the LCD period. The LCD resulted in significant decreases in body weight and in several plasma variables in both groups. WMs experienced a significant reduction in insulin secretion in response to an oral-glucose-tolerance test after the LCD; in contrast, no changes in insulin secretion were observed in WRs after the LCD. An ANOVA of scAT gene expression showed that genes regulating fatty acid metabolism, citric acid cycle, oxidative phosphorylation, and apoptosis were regulated differently by the LCD in WM and WR subjects. CONCLUSION: This study suggests that LCD-induced changes in insulin secretion and scAT gene expression may have the potential to predict successful short-term weight maintenance
- Adipose tissue transcriptome reflects variations between subjects with continued weight loss and subjects regaining weight 6 mo after caloric restriction independent of energy intake(American Society for Nutrition, 2010) Martinez, J.A. (José Alfredo); Saris, W.H.M. (Wim H. M.); Viguerie, N. (N.); Wang, P. (Ping); Vidal, H. (Hubert); Mutch, D.M. (David M.); Jebb, S.A. (Susan A.); Larsen, T.M. (Thomas M.); Langin, D. (D.); Handjieva-Darlenska, T. (Teodora); Babalis, D. (D.); Pfeiffer, A.F. (A.F.); Astrup, A. (Arne); Clement, K. (K.); Roussel, B. (B.); Debard, C. (C.); Holst, C. (C.); Kalouskova, P. (P.); Combes, M. (M.); Marquez-Quiñones, A. (A.); Mariman, E.C. (E.C.)BACKGROUND: The mechanisms underlying body weight evolution after diet-induced weight loss are poorly understood. OBJECTIVE: We aimed to identify and characterize differences in the subcutaneous adipose tissue (SAT) transcriptome of subjects with different weight changes after energy restriction-induced weight loss during 6 mo on 4 different diets. DESIGN: After an 8-wk low-calorie diet (800 kcal/d), we randomly assigned weight-reduced obese subjects from 8 European countries to receive 4 diets that differed in protein and glycemic index content. In addition to anthropometric and plasma markers, SAT biopsies were taken at the beginning [clinical investigation day (CID) 2] and end (CID3) of the weight follow-up period. Microarray analysis was used to define SAT gene expression profiles at CID2 and CID3 in 22 women with continued weight loss (successful group) and in 22 women with weight regain (unsuccessful group) across the 4 dietary arms. RESULTS: Differences in SAT gene expression patterns between successful and unsuccessful groups were mainly due to weight variations rather than to differences in dietary macronutrient content. An analysis of covariance with total energy intake as a covariate identified 1338 differentially expressed genes. Cellular growth and proliferation, cell death, cellular function, and maintenance were the main biological processes represented in SAT from subjects who regained weight. Mitochondrial oxidative phosphorylation was the major pattern associated with continued weight loss. CONCLUSIONS: The ability to control body weight loss independent of energy intake or diet composition is reflected in the SAT transcriptome. Although cell proliferation may be detrimental, a greater mitochondrial energy gene expression is suggested as being beneficial for weight control.
- 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.
- Contribution of energy restriction and macronutrient composition to changes in adipose tissue gene expression during dietary weight-loss programs in obese women.(Endocrine Society, 2008) Martinez, J.A. (José Alfredo); Saris, W.H.M. (Wim H. M.); Viguerie, N. (N.); Vidal, H. (Hubert); Klimcakova, E. (E.); Sørensen, T.I.A (Thorkild I. A.); Langin, D. (D.); Clement, K. (K.); Arner, P. (P.); Taylor, M. (Moira); Capel, F. (F.); Vega, N. (Nathalie); Holst, C. (C.); Oppert, J.M. (Jean M.); Dejean, S. (S.)CONTEXT: Hypoenergetic diets are used to reduce body fat mass and metabolic risk factors in obese subjects. The molecular changes in adipose tissue associated with weight loss and specifically related to the dietary composition are poorly understood. OBJECTIVE: We investigated adipose tissue gene expression from human obese women according to energy deficit and the fat and carbohydrate content of the diet. DESIGN AND SETTING: Obese subjects recruited among eight European clinical centers were followed up 10 wk of either a low-fat (high carbohydrate) or a moderate-fat (low carbohydrate) hypoenergetic diet. SUBJECTS: Two sets of 47 women in each dietary arm were selected among 648 subjects matched for anthropometric and biological parameters. MAIN OUTCOME MEASURE: We measured adipose tissue gene expression changes in one set using a candidate gene approach. The other set was used to survey 24,469 transcripts using DNA microarrays. Results were analyzed using dedicated statistical methods. Diet-sensitive regulations were confirmed on the other set of subjects. RESULTS: The two diets induced similar weight loss and similar changes for most of the biological variables except for components of the blood lipid profile. One thousand genes were regulated by energy restriction. We validated an effect of the fat to carbohydrate ratio for five genes (FABP4, NR3C1, SIRT3, FNTA, and GABARAPL2) with increased expression during the moderate-fat diet. CONCLUSIONS: Energy restriction had a more pronounced impact on variations in human adipose tissue gene expression than macronutrient composition. The macronutrient-sensitive regulation of a subset of genes may influence adipose tissue function and metabolic response.
- Determinants of human adipose tissue gene expression: impact of diet, sex, metabolic status, and cis genetic regulation(Public Library of Science, 2012) Martinez, J.A. (José Alfredo); Saris, W.H.M. (Wim H. M.); Valle, C. (Carine); Montastier, E. (E.); Viguerie, N. (N.); Vidal, H. (Hubert); Maoret, J.J. (J.J.); Villa-Vialaneix, N. (N.); Langin, D. (D.); Astrup, A. (Arne); Clement, K. (K.); Roussel, B. (B.); Iacovoni, J.S. (J. S.); Holst, C. (C.); Hager, J. (Jörg); Combes, M. (M.)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.
- OBEDIS core variables project: European expert guidelines on a minimal core set of variables to include in randomized, controlled clinical trials of obesity interventions(Karger, 2020) Yki-Järvinen, H. (Hannele); Farpour-Lambert, N. (Nathalie); Sadaf-Farooqi, I. (I.); Natali, A. (Andrea); Roche, H. (Helen); Alligier, M. (Maud); Boirie, Y. (Yves); Ziegler, O. (Olivier); Jacobi, D. (David); Sørensen, T.I.A (Thorkild I. A.); Tappy, L. (Luc); Scheen, A.J. (André J.); Palmeira, A.L. (Antonio L.); Frühbeck, G. (Gema); Halford, J.C.G. (Jason C. G.); Brunault, P. (Paul); Bouwman, J. (Jildau); Barrès, R. (Romain); Langin, D. (D.); Julia, C. (Chantal); Clement, K. (K.); Blaak, E.E. (Ellen E.); Pagotto, U. (Uberto); Simon, C. (Chantal); Hager, J. (Jörg); Hauner, H. (Hans); Goossens, G.H. (Gijs H.); Oppert, J.M. (Jean M.); Laville, M. (Martine); Campbell, K. (Kristina); Neovius, M. (Martin); Rydén, M. (Mikael)Heterogeneity of interindividual and intraindividual responses to interventions is often observed in randomized, controlled trials for obesity. To address the global epidemic of obesity and move toward more personalized treatment regimens, the global research community must come together to identify factors that may drive these heterogeneous responses to interventions. This project, called OBEDIS (OBEsity Diverse Interventions Sharing – focusing on dietary and other interventions), provides a set of European guidelines for a minimal set of variables to include in future clinical trials on obesity, regardless of the specific endpoints. Broad adoption of these guidelines will enable researchers to harmonize and merge data from multiple intervention studies, allowing stratification of patients according to precise phenotyping criteria which are measured using standardized methods. In this way, studies across Europe may be pooled for better prediction of individuals’ responses to an intervention for obesity – ultimately leading to better patient care and improved obesity outcomes.
- Adipose gene expression prior to weight loss can differentiate and weakly predict dietary responders(Public Library of Science, 2007) Martinez, J.A. (José Alfredo); Pelloux, V. (Véronique); Saris, W.H.M. (Wim H. M.); Viguerie, N. (N.); Combes, F. (Florence); Mutch, D.M. (David M.); Sørensen, T.I.A (Thorkild I. A.); Langin, D. (D.); Astrup, A. (Arne); Clement, K. (K.); Zucker, J.D. (J.D.); Temanni, M.R. (M. Ramzi); Holst, C. (C.); Henegar, C. (Corneliu)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.
- Contemporary medical, device, and surgical therapies for obesity in adults(Elsevier, 2023) Perdomo-Zelaya, C.M. (Carolina M.); Cohen, R.V. (Ricardo V.); Frühbeck, G. (Gema); Clement, K. (K.); Sumithran, P. (Priya)The goal of obesity management is to improve health. Sustained weight loss of more than 10% overall bodyweight improves many of the complications associated with obesity (eg, prevention and control of type 2 diabetes, hypertension, fatty liver disease, and obstructive sleep apnoea), as well as quality of life. Maintenance of weight loss is the major challenge of obesity management. Like all chronic diseases, managing obesity requires a long-term, multimodal approach, taking into account each individual's treatment goals, and the benefit and risk of different therapies. In conjunction with lifestyle interventions, anti-obesity medications and bariatric surgery improve the maintenance of weight loss and associated health gains. Most available anti-obesity medications act on central appetite pathways to reduce hunger and food reward. In the past 5 years, therapeutic advances have seen the development of targeted treatments for monogenic obesities and a new generation of anti-obesity medications. These highly effective anti-obesity medications are associated with weight losses of more than 10% of overall bodyweight in more than two-thirds of clinical trial participants. Long-term data on safety, efficacy, and cardiovascular outcomes are awaited. Long-term studies have shown that bariatric surgical procedures typically lead to a durable weight loss of 25% and rapid, sustained improvements in complications of obesity, although they have not yet been compared with new-generation highly effective anti-obesity medications. Further work is required to determine optimal patient-specific treatment strategies, including combinations of lifestyle interventions, anti-obesity medications, endoscopic and bariatric surgical procedures, and to ensure equitable access to effective treatments.