Plasma leptin and growth hormone (GH) profile and pulsatility have been studied in morbidly obese subjects before and 14 months after bilio-pancreatic diversion (BPD), a bariatric technique producing massive lipid malabsorption. The maximum leptin diurnal variation (acrophase) decreased (10.27+/-1.70 vs. 22.60+/-2.79 ng x ml(-1); P=0.001), while its pulsatility index (PI) increased (1.084+/-0.005 vs. 1.050+/-0.004 ng x ml(-1) x min(-1); P=0.02) after BPD. Plasma GH acrophase increased (P=0.0001) from 0.91+/-0.20 to 4.58+/-0.80 microg x l(-1) x min(-1) after BPD as well as GH PI (1.70+/-0.13 vs. 1.20+/-0.04 microg x l(-1) x min(-1); P=0.024). Whole-body glucose uptake (M), assessed by euglycemic-hyperinsulinemic clamp, almost doubled after BPD (from 0.274+/-0.022 to 0.573+/-0.027 mmol x kgFFM(-1) x min(-1); P<0.0001), while 24 h lipid oxidation was significantly (P<0.0001) reduced (131.94+/-35.58 vs. 44.56+/-15.10 g). However, the average lipid oxidation was 97.2+/-3.1% (P<0.01) of the metabolizable lipid intake after the bariatric operation, while it was 69.2+/-8.5% before. After the operation, skeletal muscle ACC2 mRNA decreased (P<0.0001) from 452.82+/-76.35 to 182.45+/-40.69% of cyclophilin mRNA as did the malonyl-CoA (from 0.28+/-0.02 to 0.16+/-0.01 nmol x g(-1); P<0.0001). Leptin changes negatively correlated with M changes (R2=0.69, P<0.001). In a stepwise regression (R2=0.87, P=0.0055), only changes in 24 h free fatty acids (B=0.105+/-0.018, P=0.002) and glucose/insulin ratio (B=0.247+/-0.081, P=0.029) were the best predictors of leptin variations. In conclusion, the reversion of insulin resistance after BPD might allow reversal of leptin resistance, restoration of leptin pulsatility, and consequent inhibition of ACC2 mRNA expression, translating to a reduced synthesis of malonyl-CoA, which, in turn, results in increased fatty acid oxidation. Finally, since leptin inhibits GH secretion, a reduction of circulating leptin levels might have produced an increase in GH secretion, as observed in our series.