Cross-Talk Between FSH and Endoplasmic Reticulum Stress: A Mutually Suppressive Relationship

Abstract

Suboptimal cellular conditions result in the accumulation of unfolded proteins in the endoplasmic reticulum (ER) and trigger ER stress. In this study, we investigated the effects of follicle stimulating hormone (FSH) on ER stress in granulosa cells (GCs) obtained from 3-week-old female C57BL6 mice 24 or 48 hours after intraperitoneal injection of 5 IU pregnant mare's serum gonadotropin (PMSG), and in primary mouse GCs in culture treated with FSH (10-100 mIU/mL) for 24 or 48 hours. Moreover, mouse GCs in culture were treated with tunicamycin (Tm) or thapsigargin (Tp), which induce ER stress by inhibiting N-glycosylation of ER proteins and ER calcium adenosine triphosphatase, respectively, and their response to FSH was evaluated. We found that FSH attenuated ER stress in mouse GCs in vivo and in vitro; messenger RNA levels of ER stress-associated genes Xbp1s, Atf6, Chop, and Casp12 were decreased upon exposure to FSH/PMSG. Activating transcription factor 4 protein levels also demonstrated consistent decrease following FSH stimulation. Both Tm and Tp treatments inhibited FSH response, ER stressinduced cells did not show any change in estradiol levels in response to FSH, whereas in untreated GCs, estradiol production increased 3-fold after incubation with FSH for 60 hours. Furthermore, ER stress-induced cells failed to demonstrate aromatase (Cyp19a1) expression upon exposure to FSH. Importantly, under high-ER stress conditions FSH stimulation was unable to downregulate the expression of ER stress-associated genes. Our findings suggest that FSH decreases ER stress in GCs under physiologic conditions. However, under conditions that cause a significant increase in ER stress, FSH response is attenuated.

Impact of delipidated estrous sheep serum supplementation on in vitro maturation, cryotolerance and endoplasmic reticulum stress gene expression of sheep oocytes

“…No significant differences were found in the expression levels of ATF4 , ATF6 , GRP78 , and CHOP10 in COCs that were matured in vitro —either in whole serum or in delipidated serum. Attenuation in the expression levels of GRP78 in in vitro matured COCs could be a consequence of FSH supplementation in the IVM media as reported previously for mice [ 52 ]. COCs that were matured in vitro in IVM media supplemented with delipidated serum and vitrification upregulated the expression of ATF4 , ATF6 , CHOP10 , and GRP78.…”

Reduction in FSH Throughout the Menstrual Cycle After Omega-3 Fatty Acid Supplementation in Young Normal Weight but not Obese Women

“…Evidence suggests that ER stress, a critical pathway in the pathogenesis of obesity, 28 may impact both the pituitary and ovary to modulate gonadotropin secretion, folliculogenesis, and oocyte quality. 19,[29][30][31] Induction of ER stress in pituitary gonadotropes suppresses LH and FSH secretion and may underlie the hypogonadotropism of obesity. 30 In the ovary, ER stress impairs ovarian function and reduces FSH responses, potentially resulting in an increase in FSH, characteristic of ovarian aging.…”

Dual role for the unfolded protein response in the ovary: adaption and apoptosis

“…Follicle-stimulating hormone (FSH) is the major stimulator of follicle growth and development in the final and preantral stages (Oktay et al, 1997; Hsueh et al, 2015; Babayev et al, 2016). FSH attenuates ER stress in mouse GCs in vivo and in vitro (Babayev et al, 2016).…”

“…FSH attenuates ER stress in mouse GCs in vivo and in vitro (Babayev et al, 2016). Conversely, induction of severe ER stress inhibits the FSH response and negates the effects of FSH on GCs expressed ER stress-associated gene (Babayev et al, 2016). …”