D-Psicose, a rare sugar, not only has very low caloric value but possesses anti-adipogenic properties. Here, we identified target genes in adipose tissue affected by D-psicose by transcriptomic analysis and provided mechanistic explanations for the anti-adipogenic effect. C57BL/6J ob/ob mice were fed with a control or 5% D-psicose diet for 12 weeks. D-Psicose decreased final body weight, adipose tissue mass, adipocyte size, and serum total cholesterol levels. We identified 103 differentially expressed genes involved in inflammatory response, molecular transport, and lipid metabolism consequent to D-psicose administration. Genes related to inflammation and adipo/lipogenesis were significantly down-regulated, whereas those associated with beta-oxidation were up-regulated by D-psicose. Our data suggest that Fos, Mmp3, Fgf21, and Abcd2 might be key target genes associated with D-psicose-induced changes in lipid metabolism and subsequent chronic inflammatory responses. D-Psicose is thus a promising sugar substitute possessing a direct gene-regulatory function related to the suppression of body fat deposition. (C) 2016 Elsevier Ltd. All rights reserved.