Leptin directly stimulates aromatase activity in human luteinized granulosa cells

Leptin, the obese (ob) gene product, is secreted by adipocytes and regulate s appetite through interaction with hypothalamic leptin receptors. Leptin m ay also have a stimulatory effect on reproductive function. Furthermore, le ptin receptor mRNA is expressed in the ovary, suggesting a direct effect on its function. The present study examines the direct role of leptin on the oestrogen-producing activity in human luteinized granulosa cells. The cells were obtained from in-vitro fertilization pre-ovulatory follicles, precult ured for 24 h in the presence of 5% charcoal-treated serum, and incubated f or 48-96 h in a serum-free medium containing recombinant human leptin, foll icle stimulating hormone (FSH), and/or insulin-like growth factor-I (IGF-I) . A single addition of leptin (0.5-10 ng/ml) stimulated aromatase activity with the incubation time of up to 96 h. The addition of leptin (1 ng/ml) fu rther augmented the stimulation by a single addition of FSH (100 ng/ml) or IGF-I (100 ng/ml), or a combination of both. A single addition of leptin (1 ng/ml) or a combination of leptin (1 ng/ml), FSH (100 ng/ml), and IGF-I (1 00 ng/ml) gave rise to an increase in each parameter of oestrogen-producing activity measured, i.e. P450arom mRNA level, P450arom protein level, aroma tase specific activity, and the oestradiol concentration in the culture sup ernatant. However, the production of progesterone did not change. These res ults indicate that leptin stimulates oestrogen production by increasing P45 0arom mRNA and P450arom protein expression and, consequently, aromatase act ivity by its direct action on the human luteinized granulosa cells.