Estradiol and leptin have separate but additive anorexigenic effects and differentially target fat mass in rats

We recently showed that male compared to female rats exhibit lower hypophagia and body weight (BW) loss following central leptin delivery, suggesting a role for estradiol in leptin responsiveness. Addressing this, we delivered Ob (Leptin) or GFP (Control) gene into the brain of male rats that were simultaneously treated with estradiol or Vehicle. In a reciprocal approach, we compared estradiol-deficient (Ovx) to intact females (Sham) that received Leptin or Control vector. Changes in food intake (FI), BW, and body composition were examined. In males, estradiol and Leptin resulted in lower cumulative food intake (15%) and endpoint body weight (5%) but rats receiving dual treatment (Estradiol-Leptin) ate 28% less and weighed 22% less than Vehicle-Control. Changes in FI were unique to each treatment, with a rapid decrease in Vehicle-Leptin followed by gradual renormalization. In contrast, hypophagia in Estradiol-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 BW 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 estradiol decreased FI and BW through different mechanisms, with the pattern of Estradiol-Leptin reminiscent of that observed in females and with the pattern of Ovx-Leptin, reminiscent of that observed in males. Estrogen status did not influence initial fat mass loss by Leptin. It can be concluded that estradiol modulates long-term response to central leptin overexpression but its actions on energy homeostasis are additive and independent of those of leptin.