Enhanced glycolysis in granulosa cells promotes the activation of primordial follicles through mTOR signaling

Xiaodan Zhang,Feifei Yuan,Wenbo Zhang,Biao Li,Xuelan Li,Zhijuan Wang,Min Lin,Ling Deng,Meijia Zhang,Nana Zheng,Xin Chen

doi:10.1038/s41419-022-04541-1

Abstract

In mammals, nonrenewable primordial follicles are activated in an orderly manner to maintain the longevity of reproductive life. Mammalian target of rapamycin (mTOR)-KIT ligand (KITL) signaling in pre-granulosa cells and phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt)-forkhead Box O3a (FOXO3a) signaling in oocytes are important for primordial follicle activation. The activation process is accompanied by the enhancement of energy metabolism, but the causal relationship is unclear. In the present study, the levels of glycolysis-related proteins GLUT4, HK1, PFKL, and PKM2 were significantly increased in granulosa cells but were decreased in oocytes during the mouse primordial-to-primary follicle transition. Both short-term pyruvate deprivation in vitro and acute fasting in vivo increased the glycolysis-related gene and protein levels, decreased AMPK activity, and increased mTOR activity in mouse ovaries. The downstream pathways Akt and FOXO3a were phosphorylated, resulting in mouse primordial follicle activation. The blockade of glycolysis by 2-deoxyglucose (2-DG), but not the blockade of the communication network between pre-granulosa cells and oocyte by KIT inhibitor ISCK03, decreased short-term pyruvate deprivation-promoted mTOR activity. Glycolysis was also increased in human granulosa cells during the primordial-to-primary follicle transition, and short-term pyruvate deprivation promoted the activation of human primordial follicles by increasing the glycolysis-related protein levels and mTOR activity in ovarian tissues. Taken together, the enhanced glycolysis in granulosa cells promotes the activation of primordial follicles through mTOR signaling. These findings provide new insight into the relationship between glycolytic disorders and POI/PCOS.

Highlights

IntroductionThe nonrenewable primordial follicle pool is established around the time of birth [1]
In mammals, the nonrenewable primordial follicle pool is established around the time of birth [1]
These results suggest that glycolysis is increased in granulosa cells but is decreased in oocytes during mouse primordial follicle activation

Summary

Introduction

The nonrenewable primordial follicle pool is established around the time of birth [1]. A limited number of primordial follicles are activated into the growing stage, while the remaining follicles are maintained in the quiescent state [2]. Activation of primordial follicles is critical to maintain the longevity of reproductive life [3]. In POI patients, the altered recruitment of primordial follicles causes a decrease in ovarian reserve [4]. In PCOS patients, the accumulation of preantral small follicles may be caused by an increase in primordial follicle activation and the inability of antral follicle growth [5]. Elucidation of the molecular mechanism of primordial follicle activation is crucial for the diagnosis and treatment of ovarian diseases

Methods

Results

Conclusion