MON-032 Excessive Ovarian Sympathetic Activity Impairs Embryonic Development and Causes Reproductive and Metabolic Dysfunction

Nerve growth factor is a member of the neurotrophin family and within the ovary, it plays an important role in sympathetic innervation and in the development and maintenance of folliculogenesis. Despite its critical role, excessive levels of ovarian NGF may lead to ovarian pathology and to the development of features of polycystic ovary syndrome (PCOS), which is the most common endocrine disorder among women of reproductive age. Here, using a transgenic mouse model overexpressing NGF selectively in the ovary (17NF mice), we studied how ovarian sympathetic hyperactivity affects embryonic development and reproductive and metabolic function in adulthood. Firstly, we showed that ovarian NGF excess caused growth restriction in the developing female fetuses, which was driven by defects in the placenta function. Moreover, the 17NF fetuses experienced a reduction of germ cell number along with delayed gonocyte and primary oocyte maturation. The adult 17NF mice displayed irregular cyclicity and aberrant ovarian expression of steroidogenic genes and epigenetic markers. The ovarian sympathetic hyperactivity also led to increased systemic sympathetic outflow, indicated by increased circulating dopamine levels, and to metabolic dysfunction in adulthood. The 17NF mice had increased adiposity, impaired glucose metabolism and decreased energy expenditure. The subcutaneous and parametrial fat depots displayed impaired function due to ovarian NGF excess, wherein the subcutaneous fat increased mass by enhanced preadipocyte differentiation and enlarged adipocyte size, while the parametrial fat had smaller adipocyte size and a modest increase in stimulated lipolysis. These defects also led to hepatic steatosis. Overall, our findings indicate that ovarian sympathetic hyperactivity has deleterious effects on whole-body homeostasis and leads to impaired embryonic development and to reproductive and metabolic defects in adult life.