Weight loss in obese patients, even if moderate, is clearly beneficial for health and implies a reduction in either adipocyte number or volume. This can be regulated by the key adipose transcription factors, sterol-regulatory-element binding protein-1c/adipocyte differentiation and determination factor-1 (SREBP1c/ADD1), peroxisome proliferator-activated receptor-gamma2 (PPARgamma2) and CCAAT-enhancer binding protein-alpha (C/EBPalpha). which regulate the adipocyte metabolism and differentiation process. The present study was undertaken to obtain insights into the expression of these transcription factors during moderate weight loss in humans. In addition, the adipose depot-related differences and the relation to adipose lipoprotein lipase (LPL) expression and plasma lipids were studied. Using quantitative reverse transcription polymerase chain reaction (RT-PCR), the total amount of each adipose transcription factor messenger ribonucleic acid (mRNA) was determined in the subcutaneous or omental adipose tissue after a controlled, 2-month, bodyweight-reduction trial in 11 obese middle-aged women and 17 comparable obese controls. Weight loss (6% of body weight) was associated with reduced serum insulin and plasma triacylglycerols. Adipose tissue PPARgamma2 and SREBP1c/ADD1 mRNA were lower in the weight-loss group than in controls (by 30% and 28%, respectively), whereas the C/EBPalpha mRNA level did not change. Moreover, PPARgamma2 mRNA was lower only in the subcutaneous adipose depot and was related to both adipose tissue lipoprotein lipase (LPL) mRNA and improvement in plasma triacylglycerols in the weight-loss group. Our results suggest a functional role for SREBP1c/ADD1 and PPARgamma2 in the control of energy metabolism in human adipose tissue.