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 (IP) infusion of the amylin homolog salmon calcitonin (sCT) that produces a sustained reduction in daily food intake and adiposity in diet-induced obese rats. Rats (646±10 g, 27±1% body fat) with IP catheters tethered to infusion swivels had free access to a 45% fat diet. Vehicle-treated rats (n=16) had relatively stable food intake, body weight and adiposity during the 7-wk test period. None of 10 sCT dosing regimens administered in succession to a second group of rats (n=18) produced a sustained 25-35% reduction in daily food intake for >5 days, although body weight and adiposity were reduced across the 7-wk period by 9% (587±12 vs. 651±14g) and 22% (20.6±1.2 vs. 26.5±1.1%), respectively. The declining inhibitory effect of sCT on daily food intake when inter-infusion interval was 6h appeared to be due in part to an increase in food intake between infusions. The declining inhibitory effect of sCT on food intake when inter-infusion interval was 2-3h suggested possible receptor down-regulation and tolerance to sCT administration; however, food intake increased dramatically when sCT treatments were discontinued for 1 day following apparent loss in treatment efficacies. These results demonstrate the activation of a potent homeostatic response to increase food intake when sCT treatments reduce food intake and energy reserves in diet-induced obese rats.