Background:Part of the heterogeneity of the obesity phenotype may originate from genetic differences between obese individuals that may influence energy expenditure (EE).Objective:To examine if common single-nucleotide polymorphisms (SNPs) in genes related to obesity-associated phenotypes are associated with postabsorptive resting energy expenditure (REE) and postprandial REE in obese individuals.Design and methods:Postabsorptive REE and 3-h postprandial REE (liquid test meal containing 95% fat, energy content 50% of estimated REE) were measured in 743 obese individuals from eight clinical centres in seven European countries. The analysis assessed the association of genotypes of 44 SNPs in 28 obesity-related candidate genes with postabsorptive REE and postprandial REE taking into consideration the influence of body composition, habitual physical activity, insulin sensitivity, circulating thermogenic hormones and metabolites.Results:After adjustment for fat-free mass (FFM), age, sex and research centre, SNPs in CART, GAD2, PCSK1, PPARG3, HSD11B1 and LIPC were significantly associated with postabsorptive REE. SNPs in GAD2, HSD11B1 and LIPC remained significantly associated with postabsorptive REE after further adjustment for fat mass (FM). SNPs in CART, PPARG2 and IGF2 were significantly associated with postprandial REE after similar adjustments. These associations with postprandial REE remained significant after further adjustment for FM. FTO, UCP2 and UCP3 variants were not associated with postabsorptive or postprandial REE.Conclusions:Several gene polymorphisms associated with obesity-related phenotypes but not FTO and UCP variants may be responsible for some of the inter-individual variability in postabsorptive REE and fat-induced thermogenesis unaccounted for by FFM, FM, age and sex. The association between FTO and obesity that has been reported earlier may not be mediated directly through modulation of EE in obese individuals.International Journal of Obesity advance online publication, 28 April 2009; doi:10.1038/ijo.2009.59.