ABSTRACT: The mRNA profile in ovaries of mouse strain (denoted Y123F) with artificially mutated leptin receptors (LepR), with phenylalanine (F) substitution for all 3 tyrosine (Y) residues within exon 18 of LepR of Tyr985, Tyr1077 and Tyr1138 with wild types of the same litter as the control. Y123F mice also manifested obesity, hyperphagia, hyperleptinemia, hyperinsulinemia and impairment in glucose tolerance, but less pronounced than in db/db mice. Leptin exerts many biological actions, such as on metabolism, reproduction, etc., through binding to and activating LepR, which is expressed mainly in many brain regions. To better understand different roles of downstream signaling pathways, Y123F mice, which expressed mutant leptin receptors with phenylalanine (F) substitution for 3 tyrosines (Y) ---Tyr985, Tyr1077 and Tyr1138, was generated. The body weight and abdominal fat depots of Y123F homozygous mice (HOM) were higher than that of wild mice (WT), and HOM ovaries were atrophic and the follicles developed abnormally, though HOM ovaries did not exhibit polycystic phenotypes. Moreover, Y123F HOM adult had no estrous cycle and blood estrogen concentration remained stable at a low level below detection limit of 5 pg/ml. LepR expression in HOM ovaries was higher than in WT ovaries. Scanned through cDNA microarrays, 41 genes were increased, and 100 genes were decreased in mRNA levels, in HOM vs. WT ovaries; and many signaling pathways were evaluated to be involved significantly. The data of 19 genes were validated by real-time quantitative PCR, most of which were consistent. So Y123F HOM mice were suggested as a new animal model of PCOS when research mainly emphasizes on metabolism disorders and anovulation, but not on the polycystic phenotype. Meanwhile, through the model, we found that JAK-STAT and hormone biosynthesis pathways were involved in the follicular development and ovulation disorders caused by LepR deficiency in ovaries, though not having excluded its indirect actions from brain.
