ROLE OF LEPTIN IN HYPOTHALAMIC-PITUITARY FUNCTION

A defect in the structure of the obese gene is responsible for develop ment of obesity in the ob/ob mouse. The product of expression of the g ene is the protein hormone leptin, Leptin causes weight toss in ob/ob and normal mice, it is secreted by adipocytes, and it is an important controller of the size of fat stores by inhibiting appetite, The ob/ob mouse is infertile and has a pattern of gonadotropin secretion simila r to that of prepubertal animals, Consequently, we hypothesized that l eptin might play a role in the control of gonadotropin secretion and i nitiated studies on its possible acute effects on hypothalamic-pituita ry function. After a preincubation period, hemi-anterior pituitaries o f adult male rats were incubated with leptin for 3 hr, Leptin produced a dose-related increase in follicle-stimulating hormone (FSH) and lut einizing hormone (LH) release, which reached peaks with 10(-9) and 10( -11) M leptin, respectively, Gonadotropin release decreased at higher concentrations of leptin to values indistinguishable from that of cont rol pituitaries, On the other hand, prolactin secretion was greatly in creased in a dose-related manner but only with leptin concentrations ( 10(-7)-10(-5) M), Incubation with leptin of median eminence-arcuate nu clear explants from the same animals produced significant increases in LH-releasing hormone (LHRH) release only at the lowest concentrations tested (10(-12)-10(-10) M). As the leptin concentration was increased , LHRH release decreased and was significantly less than control relea se at the highest concentration tested (10(-6) M), To determine if lep tin can also release gonadotropins in vivo, ovariectomized females bea ring implanted third ventricle cannulae were injected with 10 mu g of estradiol benzoate s.c., followed 72 hr later by microinjection into t he third ventricle of leptin (0.6 nmol in 5 mu l) or an equal volume o f diluent, There was a highly significant increase in plasma LH, which peaked 10-50 min after injection of leptin, Leptin had no effect on p lasma FSH concentrations, and the diluent had no effect on either plas ma FSH or LH, Thus, leptin at very low concentrations stimulated LHRH release from hypothalamic explants and FSH and LH release from anterio r pituitaries of adult male rats in vitro and released LH, but not FSH , in vivo, The results indicate that leptin plays an important role in controlling gonadotropin secretion by stimulatory hypothalamic and pi tuitary actions.