We recently showed that male rats exhibit lower hypophagia and body weight loss compared to female rats following central leptin delivery, suggesting a role for oestradiol in leptin responsiveness. Accordingly, we delivered Ob (leptin) or GFP (control) gene into the brain of male rats that were simultaneously treated with oestradiol or vehicle. In a reciprocal approach, we compared oestradiol-deficient (OVX) with intact females (sham) that received leptin or control vector. Changes in food intake), body weight and body composition were examined. In males, oestradiol and leptin resulted in lower cumulative food intake (15%) and endpoint body weight (5%), although rats receiving dual treatment (oestradiol-leptin) ate 28% less and weighed 22% less than vehicle-control. Changes in food intake were unique to each treatment, with a rapid decrease in vehicle-leptin followed by gradual renormalisation. By contrast, hypophagia in oestradiol-control was of lower amplitude and sporadic. Leptin selectively targeted fat mass and endpoint abdominal fat mass was 65%-80% lower compared to their respective control groups. In females, both leptin groups had lower body weight (endpoint values 20% lower than control groups) with the highest extent in sham animals (endpoint value was 28% less in sham-leptin than in sham-control). OVX rats rapidly started regaining their lost body weight reminiscent of the pattern in males. Leptin rapidly and robustly reduced fat mass with endpoint values 30%-35% less than control treated animals. It appears that leptin and oestradiol decreased food intake and body weight via different mechanisms, with the pattern of oestradiol-leptin being reminiscent of that observed in females and the pattern of OVX-leptin reminiscent of that observed in males. Oestrogen status did not influence initial fat mass loss by leptin. It can be concluded that oestradiol modulates the long-term response to central leptin overexpression, although its actions on energy homeostasis are additive and independent of those of leptin.