Human obesity is associated with increased leptin levels, related to body composition and fat mass (FM). Insulin has been suggested to be a regulator of in vivo leptin secretion. To further investigate the relationships between insulin and leptin levels in human obesity, we have studied 10 obese females, aged 26-57 yr [body mass index (BMI), 42.9+/-6.3], successfully treated by biliopancreatic (BPD) diversion, in an early postoperative period (2 months after surgery, post-BPD I; BMI, 37.2+/-7.5) and a late postoperative period (16-24 months after surgery; BMI, 27.6+/-3.96). Fourteen normal female subjects (18-59 yr; BMI, 27.9+/-1.4 kg/m2) were studied as controls. In pre-BPD obese subjects, leptin levels were higher than those in controls (60.5+/-18.8 vs. 28.7+/-4.8 ng/mL; P<0.001). BMI and insulin levels were also significantly greater (P<0.0001 and P<0.03, respectively). After surgery, the three parameters considered significantly decreased (P = 0.0007 for BMI, P<0.0001 for leptin, and P = 0.038 for insulin, using Friedman's test for repeated data). Concerning the correlation between leptin and FM in our patients, control subjects and pre-BPD subjects confirmed the correlation found in the general population (r = 0.78; P<0.01). On the contrary, post-BPD patients at 2 months lay outside the general correlation between FM and leptin; in fact, patients with low leptin levels still had a high FM. Moreover, in the post-BPD patients there was no longer a significant correlation between FM and leptin. Concerning the correlation between insulin and leptin levels, a significant correlation was present in control subjects and pre-BPD patients (r = 0.46; P<0.05). Using correlation analysis for repeated measures in surgically treated obese patients, a significant correlation within the subjects was present (r = 0.91; P<0.0001). After operation, BMI and leptin levels had a different pattern of decrease; leptin decreased rapidly, without correlation with BMI, indicating that body composition is not the only factor regulating leptin levels. The consistent correlation with insulin levels suggests an important interaction between these two hormones in post-BPD obese subjects.