Abstract
BackgroundThe complex regulatory mechanism involved in ovarian follicular development is not completely understood. Neuronal neuropeptide Y (NPY) is involved in the regulation of feeding behavior, energy homeostasis, and reproduction behavior, while its function in ovarian follicular development is not clear. The objective of this study was to investigate if and how NPY regulates follicle development in the ovary.MethodsAll experiments were performed using Sprague Dawley rats. To understand NPY expression pattern at different stages of follicular development, NPY content was assessed using immunohistochemistry in individual follicles. NPY and its receptors expression pattern were evaluated in granulosa cells isolated from preantral (PA), early antral (EA) and late antral follicles (LAF). The influence of NPY on granulosa cell proliferation and apoptosis were further assessed in vitro, using Ki67- and TUNEL-positivity assays. To investigate whether NPY induced-proliferation in EA granulosa cells is mediated through the activation of NPY receptor Y5 (NPY5R) and Mitogen-activated protein kinase (MEK) signal pathway, EA granulosa cells were treated with NPY5R antagonist (CGP71683) and MEK inhibitors (PD98059 and U0126), and Ki67-positive cells were assessed.ResultsNPY protein expression was follicular stage-dependent and cell type-specific. NPY signal intensity in EA was higher than those in PA and LAF. Antral granulosa cells showed the highest signal intensity compared to mural granulosa cells, cumulus cells and theca cells. Granulosa cells NPY protein content and mRNA abundance were higher in EA than in LAF. NPY receptor contents in granulosa cells were follicular stage-dependent. While NPY reduced apoptosis of EA granulosa cells, it increased the proliferation through NPY5R and MEK pathway. In contrast, in LAF granulosa cells, NPY reduced proliferation and increased the number of apoptotic cells, with no significant effects on PA granulosa cells.ConclusionThis study is the first to evaluate the intraovarian role of NPY in granulosa cells at various stage of follicular development. These results indicate that NPY regulates granulosa cells proliferation and apoptosis in a follicular stage-dependent and autocrine manner. NPY may play a role in pathogenesis of ovarian follicular disorders.
Highlights
The complex regulatory mechanism involved in ovarian follicular development is not completely understood
Ovarian neuropeptide Y (NPY) mRNA and protein content is cell type- and follicular stage-specific To determine if the granulosa cell is the primary follicular source of NPY, and whether its expression is follicular stage-specific, NPY signal intensity and localization were assessed by immunofluorescence in 21-day-old Sprague Dawley (SD) rat ovaries
NPY signals were evident in granulosa cells in primordial, preantral (PA), early antral (EA) and late antral follicles (LAF), but could not be demonstrated in atretic follicles due to nonspecific binding
Summary
The complex regulatory mechanism involved in ovarian follicular development is not completely understood. Neuronal neuropeptide Y (NPY) is involved in the regulation of feeding behavior, energy homeostasis, and reproduction behavior, while its function in ovarian follicular development is not clear. Neuronal NPY is involved in the regulation of feeding behavior [3], energy homeostasis [4], memory retention [5] and reproductive behavior [6]. It has been reported that NPY regulates proliferation [7, 8], apoptosis [9], immune [10] and reproductive functions as it is expressed by leydig cells [7, 11]. NPY acts on the luteal vascular system regulating corpus luteum function [8]. It is not clear whether and how NPY regulates follicle development
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