Objective:As the peroxisome proliferator-activated receptor gamma (PPARgamma) plays a central role in fat mass regulation, we investigated whether initial subcutaneous PPARgamma activity is related to fat mass generation during overfeeding.Subjects:Fourteen healthy female subjects (age 25+/-4 years, BMI 22.1+/-2.3 kg/m(2)).Design and measurements:Subjects were overfed with a diet supplying 50% more energy than baseline energy requirements for 14 days. Fasting blood samples were analyzed for leptin, insulin and glucose. Fasting subcutaneous abdominal fat biopsies were obtained for analysis of PPARgamma1, PPARgamma2, aP2 and UCP2 mRNAs.Results:Initial PPARgamma1 and 2, aP2 and UCP2 mRNAs were not related to fat gain (P>0.12). However, PPARgamma1, PPARgamma2 and aP2 mRNA changes were positively related to changes in plasma leptin (P<0.05) and, except aP2 (P=0.06), to fat gain (P<0.05). PPARgamma and aP2 mRNA changes were positively related (P<0.01), indicating that PPARgamma mRNA levels reflected PPARgamma activity.Conclusion:These data suggest that the ability to increase PPARgamma activity might be involved in the susceptibility to gain weight during a positive energy balance.International Journal of Obesity advance online publication, 25 October 2005; doi:10.1038/sj.ijo.0803146.