Chronic administration of leptin into the lateral ventricle induces sexual maturation in severely food-restricted female rats

In many species, delayed sexual maturation occurs when metabolic conditions are not satisfactory. Recently, leptin was shown to be involved in the regulation of food intake and body mass. Furthermore, leptin administration was shown to advance sexual maturation in mice and to rescue sexual function in adverse metabolic conditions, We examined plasma leptin levels in female rats during development and evaluated the role of leptin on sexual maturation in rats subjected to food restriction. In normal rats, plasma leptin levels were low at day 24 of life, then steadily increased during the juvenile period, reaching 740 +/- 56 pg/ml at 40 days at time of vaginal opening (VO) and further increasing by day 60 (957 +/- 73 pg/ml). Food restriction initiated at day 25 strongly impaired this increase, in proportion to the severity of the restriction. With a daily food intake reduced to 7-8 g/day, that permanently prevented VO, plasma leptin levels were very low at day 53 (169 +/- 67 pg/ml). Following switch to ad libitum feeding, plasma leptin reached high levels within 2 days (1577 +/- 123 pg/ml), and VO occurred 4 days later. If the severe food restriction was maintained and a central infusion of leptin (10 mu g/day) was initiated, a significant decrease in body weight compared with vehicle-infused controls was observed. In these conditions, VO occurred in eight out of the nine leptin-treated rats, representing induction of the process of sexual maturation confirmed by increases in ovarian and uterine weights. This induction of sexual maturation exclusively results from a central effect of leptin because no leak of the icy administered leptin to the general circulation was observed. These data suggest that the rising plasma levels of leptin in the prepubertal period represent a signal to the brain indicating that the young animal is metabolically ready to go through the process of sexual maturation.