EXPRESSION AND LOCALIZATION OF THE LEPTIN RECEPTOR IN ENDOCRINE AND NEUROENDOCRINE TISSUES OF THE RAT

The obese gene (ob) product, leptin, has recently been shown to be pro duced by adipocytes and to circulate in the plasma acting as a hormone to modulate appetite and metabolism. Intriguingly, the ob/ob mutant f emale mouse, which does not produce an active form of leptin due to a mutation of the ob gene, has been shown to be acyclic and sterile. Thi s sterility can be reversed by treatment with recombinant leptin, but not by diet restriction - suggesting that leptin is required for norma l reproductive function. The mechanism(s) whereby leptin modulates rep roductive function are unknown; however, it is possible that leptin co uld directly regulate reproductive tissues. To determine whether endoc rine and neuroendocrine tissues could be targets for leptin action, we examined whether these tissues express the leptin receptor mRNA by ut ilizing reverse-transcription polymerase chain reaction (RT-PCR) analy sis in selected tissues from the male and female rat. The results reve aled that the leptin receptor mRNA transcript is highly expressed in t he ovary, uterus and testis, moderately expressed in the hypothalamus and anterior pituitary, with low to no expression in the adrenal. The RT-PCR results were confirmed by Northern analysis. Furthermore, immor talized GnRH (GT1-7 and NLT) neurons and ovarian granulosa cells were also demonstrated by RT-PCR analysis to express the leptin receptor, s uggesting that GnRH neurons and steroid-producing cells of the ovary c ould be targets for leptin action. Immunohistochemical studies reveale d dense immunolocalization of the leptin receptor in the choroid plexu s, and interestingly, in the arcuate nucleus/median eminence of the fe male rat - a key sit in the control of feeding and reproduction. Final ly, treatment of the ob/ob mouse with recombinant leptin (0.15 mg/kg/d ay x 2 weeks) was found to markedly upregulate side chain cleavage and 17 alpha-hydroxylase mRNA levels in the ovary, demonstrating that lep tin, acting either through a direct or indirect mechanism, can regulat e gene expression in reproductive tissues.