Overweight and obesity lead to higher morbidity risks, which are alleviated even by mild weight loss. To gain insight in the molecular effects of weight loss in adipose tissue, we analyzed the effects of short-term dietary restriction (DR) on mice fed a low-fat diet (lean mice) or a high-fat diet (obese mice). Female C57B16/J mice on both diets were on DR until an average body weight loss of 20%, which was achieved in 8 to 12 days depending on body weight at the start of DR. Plasma free fatty acids and blood glucose levels decreased significantly on DR. In the (restricted) low-fat diet groups, gene expression analysis using adipose-enriched cDNA microarrays revealed only two transcripts to be significant differentially expressed by DR: up-regulation of malic enzyme (Modi) and down-regulation of major urinary protein 1 (Mup1). Real-time polymerase chain reaction analysis confirmed these findings and showed, for the high-fat diet groups, an identical expression pattern for Mup1, whereas Mod1 showed an opposed gene expression pattern for the high-fat diet groups. In conclusion, initial weight loss induces transcriptional changes only in a very small number of adipose genes, which also depends on the (restricted) diet used.