An experiment was conducted to examine whether a potent, orally active and highly selective neuropeptide Y Y1 receptor antagonist attenuates hyperphagia and obesity in genetically obese Zucker fatty rats.Oral administration of the Y1 antagonist (30 and 100 mg kg−1, once daily for 2 weeks) significantly suppressed the daily food intake and body weight gain in Zucker fatty rats accompanied with a reduction of fat cell size and plasma corticosterone levels.Despite the fact that food intake was gradually returned to near the control level, the body weight of the treated animals remained significantly less when compared to that of the controls for the duration of the treatment.These results suggest that the Y1 receptor, at least in part, participate in pathophysiological feeding and/or fat accumulation observed in Zucker fatty rats. Y1 antagonists might be useful for the treatment of obesity.