title: Stimulation of ovarian follicle growth after AMPK inhibition.
abstract: Previous studies showed that the protein kinase B (Akt)-mammalian target of rapamycin (mTOR) and Hippo signaling Yes-associated protein (YAP) pathways play important roles in promoting follicle growth. Additionally, other studies demonstrated that 5' adenosine monophosphate-activated protein kinase (AMPK) is an upstream regulatory element of mTOR and YAP. Here, we used AMPK inhibitor (Compound C) toin vitrocultured ovaries from 10-day-old mice followed byin vivografting into adult hosts or toin situtreated ovaries of 3-week-old mice by intrabursal injection followed by gonadotropin stimulation. We found that the phosphorylation of ovarian mTOR and downstream proteins (ribosomal protein S6 (S6) and eukaryotic translation initiation factor 4B (eIF4B)) was upregulated following Compound C administration, whereas tuberous sclerosis complex 2 (TSC2) phosphorylation was downregulated. Additionally, treatment with Compound C increased hypoxia-inducible factor 1-alpha (Hif1a), vascular endothelial growth factor A (Vegfa), VEGF receptor 2 (Vegfr2) and connective tissue growth factor (Ctgf) mRNA levels. Furthermore, treatment of 10-day-old mice with Compound C promoted the growth of preantral and antral follicles accompanied by enhanced angiogenesis.In situintrabursal injection with Compound C, followed by controlled ovarian hyperstimulation, increased the number of ovulated oocytes in 3-week-old mice, and these oocytes could be successfully fertilized, leading to the delivery of healthy pups. Our results demonstrated that treatment with AMPK inhibitor resulted in the activation of the mTOR signaling pathway, increases inCtgfexpression in mouse ovaries, stimulation of follicle development and promotion of ovarian angiogenesis for ovary growth.
authors.affiliation: Department of Obstetrics and GynecologyCenter of Reproductive Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China ssmuirl@163.com artruijinyunfeng@163.com.|Department of Obstetrics and GynecologyStanford University School of Medicine, Stanford University, Stanford, California, USA.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Lu
authors.affiliation: Department of Obstetrics and GynecologyCenter of Reproductive Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China ssmuirl@163.com artruijinyunfeng@163.com.
authors.forename: Song
authors.initials: S
authors.lastname: Guo
authors.affiliation: Department of Obstetrics and GynecologyStanford University School of Medicine, Stanford University, Stanford, California, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Obstetrics and GynecologyStanford University School of Medicine, Stanford University, Stanford, California, USA.
authors.forename: Jae-Hong
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Obstetrics and GynecologyStanford University School of Medicine, Stanford University, Stanford, California, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Department of Obstetrics and GynecologyCenter of Reproductive Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Feng
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D000818:Animals; D002478:Cells, Cultured; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D006080:Ovarian Follicle / Q000166:cytology* / Q000201:enzymology; D010766:Phosphorylation; D015398:Signal Transduction
chemical_list: D055372:AMP-Activated Protein Kinases