Chronic administration of anorexigenic substances to experimental animals by injections or continuous infusion typically produces either no effect or a transient reduction in food intake and body weight. Our aim here was to identify an intermittent dosing strategy for intraperitoneal infusion of peptide YY(3-36) [PYY(3-36)] that produces a sustained reduction in daily food intake and adiposity in diet-induced obese rats. Rats (665±10g body weight, 166±7g body fat) with intraperitoneal catheters tethered to infusion swivels had free access to a 45% fat diet. Vehicle-treated rats (n=23) had relatively stable food intake, body weight and adiposity during the 9-week test period. None of 15 PYY(3-36) dosing regimens administered in succession to a second group of rats (n=22) produced a sustained 15-25% reduction in daily food intake for >5 days, although body weight and adiposity were reduced across the 9-week period by 12% (594±15 vs. 672±15g) and 43% (96±7 vs. 169±9g), respectively. The declining inhibitory effect of PYY(3-36) on daily food intake when inter-infusion interval was 3h appeared to be due in part to an increase in food intake between infusions. The declining inhibitory effect of PYY(3-36) on daily food intake when inter-infusion interval was <3h suggested possible receptor down-regulation and tolerance to frequent PYY(3-36) administration; however, food intake significantly increased when PYY(3-36) treatments were discontinued for 1 day following apparent loss in treatment efficacies. Together, these results demonstrate the development of a potent homeostatic response to increase food intake when PYY(3-36) reduces food intake and energy reserves in diet-induced obese rats.