Hyperleptinaemia is observed in obese animals and humans, suggesting that leptin resistance rather than leptin deficiency is a characteristic feature of obesity. This study was designed to determine whether peripherally or centrally administered leptin is effective on the short-term food intake and expression of Fos protein in the hypothalamus in the Otsuka Long-Evans Tokushima Fatty (OLETF) or Long-Evans Tokushima Otsuka (LETO) rat, as a control. The OLETF rat exhibits a polygenic syndrome of hyperphagia, obesity, hyperinsulinaemia, and hyperglycaemia. Male OLETF rats of 5, 8, and 14 weeks of age became heavier than LETO rats. Serum leptin concentrations were not significantly different between LETO and OLETF rats at the age of 5 weeks, but in 8- and 14-week-old OLETF rats were increased to 3.4 and 2.9 times those of LETO rats, respectively. The 8-week-old OLETF and LETO rats were given intraperitoneal (i.p.) injections with recombinant mouse leptin to measure the kinetics. There was a dramatic increase in plasma leptin concentration at 1 h, a decline by 3 h, and the concentrations 6 h after injection were similar to the basal levels. There were no significant difference between OLETF and LETO rats. In LETO rats at 5, 8 and 14 weeks of age, i.p. injection of leptin significantly decreased food intake. Whereas 5-week-old OLETF rats responded to leptin with a decrease in food intake, 8- and 14-week-old OLETF rats became resistant to peripherally administered leptin. In contrast, intracerebroventricular (i.c.v.) injections of leptin were very effective in inhibiting food intake in both OLETF and LETO rats at 14 weeks of age. Intraperitoneal injection of leptin in the LETO rats at each age increased the number of Fos-positive nuclei detected in the ventromedial hypothalamic (VMH), the dorsomedial hypothalamic (DMH) and arcuate nuclei, whereas there was no significant increase in the number of cells expressing c-fos protein in the hypothalamus of the 8- and 14 week-old OLETF rats with hyperleptinaemia. On the other hand, increased expression of c-fos protein in the VMH, DMH and arcuate nuclei following i.c.v. injection of leptin was observed in both OLETF and LETO rats at 5, 8 and 14 weeks of age. These data demonstrated that obese OLETF rats are peripherally leptin resistant, while they retain sensitivity to centrally administered leptin.