It is well known that growth hormone (GH) treatment reduces fat mass (FM), which presumably is mediated through stimulation of triglyceride breakdown and inhibition of adipose tissue lipoprotein lipase activity (AT- LPL). However, it is unknown which of the 2 GH-regulated pathways are of most importance for the reduction in FM. We investigated the effect of weight loss together with GH treatment on the activity and gene expression of LPL and hormone-sensitive lipase (HSL) in AT and muscle tissue. A very-low-calorie diet ([VLCD] 740 kcal/d) was given to 18 obese women (body mass index [BMI] > 35 kg/m2) and half of them were treated with GH (0.04 IU/kg) for 4 weeks in a randomized double-blind placebo-controlled study. Subcutaneous fat and muscle biopsies were taken before and after 4 weeks. Weight loss after 4 weeks was similar in the 2 groups, with a reduction of 4.5% (placebo) and 4.6% (GH) and a reduction of FM by 7.4% and 9.0% ([NS] nonsignificant). The weight loss resulted in a small and NS reduction of AT-LPL activity by 20% ± 12% in the placebo group, but in the GH group, AT-LPL was significantly reduced by 65% ± 8% (P < .01). Muscle LPL (M-LPL) activity was not affected by the weight loss alone, but a significant reduction was observed in the GH group (20.4% ± 10%, P < .05). AT-HSL activity was significantly enhanced after weight loss, but GH had no additional effect on this minor increment. This is in accordance with the finding that the incremant in free fatty acid (FFA) after weight loss was similar in the 2 groups. GH treatment was associated with a significant reduction of high-density lipoprotein (HDL) cholesterol (P < .05). In conclusion, GH significantly inhibited AT-LPL activity but had no additional effect on the hypocaloric-induced loss of FM, indicating that under such circumstances, AT-LPL does not directly regulate adipose tissue mass. GH was not found to have opposite effects on the activity of LPL in adipose tissue and muscle, since GH treatment reduced them both (by 65% and 20%, respectively). The VLCD-induced weight loss was associated with a minor enhanced activity of AT-HSL with no independent effect of GH. Thus, concerning body weight, FM, and lipolytic activity, treatment with GH offers no extra benefits during a VLCD for 4 weeks. Copyright (C) 2000 by W.B. Saunders Company.