Effect of high-fat diet-induced obesity on the Akt/FoxO/Smad signaling pathway and the follicular development of the mouse ovary.

Obesity has a negative effect on ovarian functions, which is reported to increase the risk of infertility. The mechanism underlying obesity‑induced infertility is not yet clear. The present study established a high‑fat diet (HFD)‑induced obesity mouse model to elucidate the mechanisms underlying the effect of HFD‑induced obesity on follicular development in the mouse ovary. The 4‑week‑old female mice were fed with HFD or normal control (NC) diet for 15 or 20 weeks. Body mass index was used to demonstrate that the mice were obese following HFD treatment. The follicular development of the ovaries from the HFD group mice was retarded in a time‑dependent manner, as demonstrated by morphological and histological examination of the ovaries. Further investigation via western blot analysis demonstrated that the activity of the transcription factor, forkhead box O3a (FoxO3a), was increased by HFD through downregulated FoxO3a phosphorylation, which may contribute to the inhibited development of ovarian follicles. To determine the regulatory mechanism of FoxO3 on the follicular development, the expression levels of FoxO3a target protein, Smad1/5/8, were also determined and there was significant decrease in phosphorylated Smad1/5/8 in the ovaries from the HFD group compared with the NC group, indicating that FoxO3a/Smad1/5/8 may be important in the regulation of follicular development. The expression levels of the upstream regulator of FoxO3a, Akt, were also examined and it was demonstrated that Akt phosphorylation was significantly reduced in the HFD group compared with the NC group, indicating that Akt/FoxO3a may be also involved in follicular development. Together, the experiments demonstrated that HFD‑induced obesity affected the activity of the Akt/FoxO3a/Smad1/5/8 signaling pathway in a time‑dependent manner during the follicular development of the mouse ovary, leading to abnormal follicular development. These findings may provide part of a theoretical basis for the clinical prevention and treatment of obesity-associated female infertility.