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 & setting: Obese subjects recruited among 8 European clinical centers followed 10 weeks 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 24469 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. A 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. AD - INSERM, U858, Laboratoire de Recherches sur les Obesites, Institut de Medecine Moleculaire de Rangueil, Toulouse; Universite Paul Sabatier, Institut Louis Bugnard IFR31, Toulouse; Centre Hospitalier Universitaire de Toulouse, France; Franco-Czech Laboratory for Clinical Research on Obesity, Prague, Czech Republic; INSERM, UMR -870; INRA U-1235; Faculte de Medecine Lyon-Sud universite de Lyon 1; Centre de Recherche en Nutrition Humaine, Hospices civils de Lyon; Lyon, France; Institut de Mathematiques de Toulouse UMR 5219, Universite Paul-Sabatier, Toulouse, France; Department of Medicine, Karolinska Institute, Karolinska University Hospital Huddinge, Stockholm, Sweden; Department of Sports Medicine, Centre of Preventive Medicine, Third Faculty of Medicine, Charles University, Prague, Czech Republic; Franco-Czech Laboratory for Clinical Research on Obesity, Prague, Czech Republic; Department of Physiology and Nutrition, University of Navarra, Pamplona, Spain; Department of Human Biology, Nutrition and Toxicology Research Institute Maastricht (NUTRIM), Maastricht University, Maastricht, The Netherlands; Institute of Preventive Medicine, Centre for Health and Society, Copenhagen University Hospital, Copenhagen, Denmark; School of Biomedical Sciences, Queen's Medical Centre, University of Nottingham Medical School, Nottingham, United Kingdom; INSERM, Nutriomique U872 (Team 7), 75004 Paris, France; Universites Pierre et Marie Curie-Paris6, UMR-S 872, Cordelier Research Center & Paris Descartes, 75006 Paris; and Assistance Publique/Hopitaux de Paris (AP-HP), Pitie Salpetriere Hospital, Nutrition and Endocrinology department, 75013 Paris, France.