To help understand the mechanisms by which weight loss is maintained after Roux-en-Y gastric bypass (RYGBP), we measured circulating concentrations of total and bioactive octanoylated ghrelin, peptide YY (PYY), glucose, and insulin in the fasted state and in response to a liquid test meal in three groups of adult women: lean (n = 8); weight-stable 35 +/- 5 months after RYGBP (n = 12; mean body mass index, 33 kg/m(2)); and matched to the surgical group for body mass index and age (n = 12). Fasting plasma total ghrelin levels were nearly identical between RYGBP (425 +/- 54 pg/ml) and the matched controls (424 +/- 28 pg/ml) and highest in lean controls (564 +/- 103 pg/ml). The response to the test meal was comparable between lean and RYGBP groups, with 27% and 20% maximal suppression, respectively, whereas the magnitude of suppression was significantly diminished in the matched controls (17%) compared with the lean group. Fasting levels of octanoylated ghrelin were highest in the lean controls, 220 +/- 36 pg/ml vs. 143 +/- 27 in the RYGBP group (P = 0.05) and 127 +/- 12 pg/ml in the matched controls (P < 0.05). The magnitude of maximal postmeal suppression of octanoylated ghrelin was more marked than with total ghrelin, but similar among groups, ranging from 44-47%. In response to the test meal, there was an early exaggerated rise in PYY in the RYGBP group, such that the peak PYY concentration was 163 +/- 24 pg/ml compared with 58 +/- 17 (P < 0.01) and 77 +/- 23 (P < 0.05) in the matched and lean controls, respectively; area under the curve at 90 min was significantly greater compared with both control groups. Leptin and fasting insulin concentrations and homeostasis model of assessment insulin resistance indices were nearly identical between lean and RYGBP subjects and significantly higher in the body mass index-matched controls. In summary, the absence of a compensatory increase in ghrelin concentrations that usually occurs with diet-induced weight loss, and the exaggerated postprandial PYY response after RYGBP, may contribute to weight loss and to the ability of an individual to maintain weight loss after this surgical procedure.