p62 Deficiency Leads to Hypogonadism and Infertility via Pituitary Functions Loss in Young Female Mice before Metabolic Disorders Onset

p62/SQSTM1 is an essential protein adaptor that fine-tunes numerous biological processes by autophagy or related cell signaling pathway. Previous studies have proved that p62 loss lead to mature-onset metabolic disorders including obesity, diabetes and fatty liver in adult mice; and in younger human being those metabolic diseases are close to reproductive dysfunctions, such as PCOS. Here, the metabolism and reproductive function of younger (8 weeks) p62 deficient female mice was observed, and hypothalamus-pituitary-ovary axis was evaluated to explore the possible upstream mechanisms. We found that although p62 deficiency rarely exposes obvious metabolic influences during younger stage of female mice, the deteriorative reproductive function has exhibited, such as attenuated breeding success rate and number of pups per litter. In particular, genetic deletion of p62 causes impaired estrous cycle, thread-like atrophied uteri and low-weight ovary with the lack of corpus luteum, failure of folliculogenesis and ovulation. Next, the low levels of plasma sex steroid hormone estradiol and gonadotropic luteinizing hormone (LH) have also been detected. Furthermore, defected steroidogenesis signaling including decreased StAR and P450scc in p62 KO ovary reveals reduced cholesterol-to-pregnenolone transition, meanwhile, increased Lhcgr mRNA expression in ovarian suggests a compensatory reaction. Consistent with lower serum LH level, significantly decreased mRNA expression of Lhb as well as slightly reduced Fshb also were found in the pituitary of p62 KO female mice. In addition, the elevated expression of Kiss1 mRNA in hypothalamus might discover the compensatory for pituitary function loss. Our findings support the vital role p62 of pituitary on reproductive function in younger individuals, and this effect might be the direct consequence rather than by metabolic disorders induced by p62 deficiency. Disclosure M. Long: None. H. Zheng: None. X. Li: None.