Effects of Dietary Advanced Glycation Endproducts on Hypothalamic-Pituitary-Ovarian Axis in vitro and in vivo Study Are Associated with the Development of Polycystic Ovarian Syndrome: The Mechanisms of Action(1/3)

Polycystic ovary syndrome (PCOS) is the most frequent endocrine problem in women of reproductive age and is characterized by hyperandrogenism, hyperinsulinemia and insulin resistance. Women with obesity or diabetes have recently been reported to exhibit significantly higher risk for developing PCOS, implicating a positive association between these disorders and increased PCOS risk. Advanced glycation endproducts (AGEs) are reactive, cross-linking molecules, formed from nonenzymatic reaction of reducing sugars with the amino groups of proteins and lipids. It is known that the presence and accumulation of AGEs in body is able to spark the development of obesity and diabetes; however, the relationship between AGEs and the clinical severity of PCOS is still unknown and need a further study. The primary goal of the proposed study is aimed to assess the role of AGEs in PCOS, with a hope to find promising mechanisms for the prevention of this women disease for further investigation. In the study, human ovarian tissues from women with or without PCOS, AGEs-feeding animal model, and in vitro primary thecal and granulosa cell culture models will be used for the experimental platforms of the study. Three specific aims are proposed as follow: Aim-1. Does the AGEs diet alters the synthesis and secretion of the hypothalamic-pituitary-ovarian (HPO) axis-related hormones or affects the proliferations of thecal and granulosa cells? Aim-2. To investigate which AGEs subtypes play a pathogenetic role mediate AGEs effects on PCOS. In addition, does the specific consequence of AGE-RAGE (receptor for AGEs) interaction is one of the virulence factors in the development of PCOS? This innovative design may highlight the potential implementation of AGEs or RAGE inhibitors as novel therapeutic agents. Aim-3. Would high AGEs diet alter the physiological functions of the ovary, and lead to the severity of PCOS? In the first year’s plan, the effects of AGEs on PCOS were investigated in exogenous AGEs diet administration rats. The study expects to realize whether long-term AGEs diet alters the physiological function of HPO axis. In the second year’s plan, with the availability of cultivated theca and granulosa primary cell cultures, we further assess the effects of several AGEs subtypes on steroid synthesis related hormones release in these cells. Prioritized targets will be knocked down by shRNA and the effect on key hormone enzymes will be evaluated. Finally, to connect AGEs with PCOS pathology, the performed histological studies also reveal differentially expressed AGEs and RAGE localization in HPO axis-related cells as well as patient specimens from PCOS. This project, if successful, will not only enable us to realize the possible role of the AGE-RAGE interaction in PCOS pathology, but also provide a rational basis for developing more refined AGEs to prevent and improve the development of women PCOS.