Pancreatic polypeptide (PP) is released from the pancreas in response to a meal. In humans, low-circulating PP levels have been observed in obesity, and administration of pharmacological doses of PP has been shown to decrease food intake. The aim of the present study was to investigate whether low circulating PP is associated with weight gain in Pima Indians. Plasma PP concentrations were measured after an overnight fast and 30 min after a standardized mixed meal in 33 nondiabetic male subjects who had a follow-up visit 4.9 +/- 2.5 years later. Cross-sectionally, fasting and postprandial PP levels were negatively associated with body size and adiposity. Prospectively, the change in PP response to the meal was negatively associated with the change in body weight (r = -0.53, P = 0.002). In contrast, a high fasting PP level was positively associated with change in body weight (r = 0.45, P = 0.009). In conclusion, our results provide evidence that, even within the physiological range, PP contributes to the regulation of energy balance in humans. However this contribution appears to be more complex than anticipated because of the opposite effect of fasting and postprandial PP on the risk of future weight gain.