Abstract In order to understand the mechanism of increasing body fat in perimenopausal and postmenopausal women, an ovariectomy-induced obesity model was used to study the role of leptin. In this investigation, a long-term study lasted for 13 weeks was conducted to monitoring the change of serum leptin level in rats after the loss of estrogen, and also to examine the influence of estrogen replacement. The results showed that three weeks after the removal of ovaries the body weight of Ovx rats was already significantly higher than the other two groups, and continued to gain more weight thereafter. Accompanying with the significant weight gain was the changes in the serum leptin levels. The leptin concentration declined gradually during the first half of experimental period, dropping down to an almost undetectable level at week 7 (0.216 ± 0.132 ng/ml). Subsequently, its concentration began to elevate, and by the end of experiment leptin level was significantly higher (3.182 ± 0.936 ng/ml) than the value before the operation (0.818 ± 0.242 ng/ml). This fluctuation of serum leptin level caused by ovariectomy was eliminated by the replacement of estrogen. The present data indicate that ovariectomy-induced weight gain is caused by the early drop in leptin level. The later rise in leptin production is connected to the increased body weight probably originated from a reduced sensitivity in leptin signal.