Knockdown of regulatory associated protein of TOR (raptor) in hypothalamus-stimulated folliculogenesis and induced ovarian cysts.

Context: Mammalian target of rapamycin complex 1 (mTORC1) is an essential sensor that regulates fundamental biological processes like cell growth, proliferation and energy metabolism. The treatment of disease by sirolimus, a mTORC1 inhibitor, causes adverse effects, such as female fertility disorders. Aims: The objective of the study was to decipher the reproductive consequences of a downregulation of mTORC1 in the hypothalamus. Methods: The reduced expression of mTORC1 was induced after intracerebroventricular injection of lentivirus expressing a short hairpin RNA (shRNA) against regulatory associated protein of TOR (raptor) in adult female mice (ShRaptor mice). Key results: The ShRaptor mice were fertile and exhibited a 15% increase in the litter size compared with control mice. The histological analysis showed an increase in antral, preovulatory follicles and ovarian cysts. In the hypothalamus, the GnRH mRNA and FSH levels in ShRaptor mice were significantly elevated. Conclusions: These results support the hypothesis that mTORC1 in the central nervous system participates in the regulation of female fertility and ovarian function by influencing the GnRH neuronal activity. Implications: These results suggest that a lower mTORC1 activity directly the central nervous system leads to a deregulation in the oestrous cycle and an induction of ovarian cyst development. Sirolimus is a selective immunosuppressant targeting the protein Raptor, but induces adverse effect such as female fertility disorders. We have deciphered the reproductive consequences of lowering the expression of Raptor in the central nervous system in mice. Female mice exhibited a 15% increase in the litter size, elevated expression of hypothalamic and pituitary hormones GnRH and FSH leading to a change in ovarian activity and the development of cysts. [ABSTRACT FROM AUTHOR]