AIMS/HYPOTHESIS: Adaptation to energy restriction is associated with changes in gene expression in adipose tissue. However, it is unknown to what extent these changes are dependent on the energy restriction as such or on the macronutrient composition of the diet. METHODS: We determined the levels of transcripts for 38 genes that are expressed in adipose tissue and encode transcription factors, enzymes, transporters and receptors known to play critical roles in the regulation of adipogenesis, mitochondrial respiration, and lipid and carbohydrate metabolism. Two groups of 25 obese subjects following 10-week hypocaloric diet programmes with either 20-25 or 40-45% of total energy derived from fat were investigated. Levels of mRNA were measured by performing real-time RT-PCR on subcutaneous fat samples obtained from the subjects before and after the diets. RESULTS: The two groups of subjects lost 7 kg over the duration of the diets. Ten genes were regulated by energy restriction; however, none of the genes showed a significantly different response to the diets. Levels of peroxisome proliferator-activated receptor gamma co-activator 1alpha mRNA were increased, while the expression of the genes encoding leptin, osteonectin, phosphodiesterase 3B, hormone-sensitive lipase, receptor A for natriuretic peptide, fatty acid translocase, lipoprotein lipase, uncoupling protein 2 and peroxisome proliferator-activated receptor gamma was decreased. Clustering analysis revealed new potential coregulation of genes. For example, the expression of the genes encoding the adiponectin receptors may be regulated by liver X receptor alpha. CONCLUSIONS/INTERPRETATION: In accordance with the comparable loss of fat mass produced by the two diets, this study shows that energy restriction and/or weight loss rather than the ratio of fat: carbohydrate in a low-energy diet is of importance in modifying the expression of genes in the human adipose tissue.