OBJECTIVE: To evaluate the impact of moderate body weight loss on both adipose tissue lipoprotein lipase (AT-LPL) activity and expression and to verify whether variation in AT-LPL could be related to changes in lipid ± lipoprotein metabolism. DESIGN: Intervention study of a 15-week weight reducing program (energy de®cit: 500 ± 800 kcalad below the subjects' estimated sedentary energy expenditure). SUBJECTS: Thirty two obese subjects (14 men and 18 premenopausal women; aged 36 ± 50 y) whose body fatness ranged from 34 to 54% fat. MEASUREMENTS: Adipose tissue biopsies from the abdominal and femoral depots, various fatness and fat distribution parameters (computed tomography and anthropometry), fasting plasma concentrations of high-and low-density lipoprotein cholesterol (HDL-C, LDL-C), and triglycerides at baseline and 4 ± 6 weeks after the 15-week weight reducing program, when subjects were weight stable. RESULTS: In response to weight loss, AT-LPL activity of both regions did not change in men, but decreased in women. Regarding AT-LPL expression, no interaction between time and sex was observed in response to the treatment. In both genders, the higher was the basal AT-LPL activity, the greater was the reduction of this enzyme activity in response to weight loss, in both the abdominal and femoral depots ( 7 0.53`r`7 0.84, P values ranging from 0.0001 to 0.05). Body weight loss promoted a signi®cant reduction in plasma triglyceride (TG), insulin and LDL-cholesterol (C) concentrations in men whereas only plasma TG and LDL-C levels were decreased in women (P`0.05). Although the average reduction in HDL-C levels in response to weight loss was not signi®cant, the higher was the decrease in femoral AT-LPL activity, the greater was the reduction in plasma HDL-C levels (r 0.50, P`0.05) in response to weight loss, in women. An inverse relationship was observed between changes in femoral AT-LPL activity and HDL-C levels variation in men (r 7 0.64, P`0.05). CONCLUSION: (1) variation in AT-LPL activity differs between men and women in response to moderate body weight loss although the corresponding enzyme mRNA levels remain unchanged; and (2) changes in femoral AT-LPL activity are related to weight loss induced variation in plasma HDL-C concentrations.