Characterization of a mechanism to inhibit ovarian follicle activation

Capsule:
Foxo3 is induced in cell and organ culture, and a mouse model, by 2-deoxyglucose (2-DG). In mice, 2-DG treatment results in reduced activation of primordial follicles.

Authors:
Sarah J. Barilovits, Ph.D., Kimberly J. Newsom, Ph.D., Justin S. Bickford, Ph.D., Dawn E. Beachy, B.F.A., Alice Rhoton-Vlasak, M.D., Harry S. Nick, Ph.D.

Volume 101, Issue 5, Pages 1450–1457.e4

Abstract:

Objective:
To demonstrate that a small molecule can induce the transcription factor Foxo3 in the ovary and lead to inhibition of follicle activation.

Design:
Cell culture, organ culture, and animal studies.

Setting:
University-based laboratory.

Animal(s):
23 female C57BL/6 mice.

Intervention(s):
Human ovary cells and mouse ovaries in culture treated with 2-deoxyglucose (2-DG) to mimic glucose deprivation, and mice intraperitoneally injected with 100 mg/kg, 300 mg/kg, or 600 mg/kg 2-DG daily for 2 weeks.

Main Outcome Measure(s):
In cell and organ culture, Foxo3 expression analyzed by quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR); in treated animals, expression of genes regulated by nutrient deprivation (Foxo3, ATF4, GRP78, CHOP, ASNS, c-Myc) measured in brain, kidney, and ovary by qRT-PCR; and ovarian follicles histologically classified and counted.

Result(s):
Foxo3 expression is induced by 2-DG at both the mRNA and protein level in human ovarian cell culture, possibly through ATF4-dependent gene regulation. Foxo3 expression is also induced by 2-DG in ovarian organ culture. Treatment of mice with 100 mg/kg 2-DG resulted in a 2.6 fold induction of Foxo3 in the ovary and a 58% decrease in type 3a primary follicles.

Conclusion(s):
Expression of Foxo3 is induced by nutrient deprivation in cell culture, organ culture, and in vivo. In mice, 2-DG treatment results in an inhibition of primordial follicle activation. These data indicate that Foxo3 induction by 2-DG may be useful for fertility preservation.

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