A ketogenic diet alleviates the apoptosis of granulosa cells by inhibiting the activation of cGAS-STING signaling pathway in PCOS mice
Abstract Background Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility. The ketogenic diet (KD), a diet high in fat and low in carbohydrates, has been applied clinically for the treatment of obese women with PCOS. We have previously demonstrated that KD improved the...
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BMC
2024-11-01
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| Series: | Cell Communication and Signaling |
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| Online Access: | https://doi.org/10.1186/s12964-024-01939-6 |
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| author | Bining Zhao Haowen Wu Qiyang Yao Wenpei Bai Jihong Kang |
| author_facet | Bining Zhao Haowen Wu Qiyang Yao Wenpei Bai Jihong Kang |
| author_sort | Bining Zhao |
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| description | Abstract Background Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility. The ketogenic diet (KD), a diet high in fat and low in carbohydrates, has been applied clinically for the treatment of obese women with PCOS. We have previously demonstrated that KD improved the reproductive phenotype in an androgen-induced PCOS mouse model, yet the underlying molecular mechanisms remain largely unclear. The aim of the present study was to investigate the effect of KD on the reproductive phenotype of a letrozole-induced PCOS mouse model. Methods Female C57BL/6N mice were divided into three groups, designated control, letrozole, and letrozole + KD groups. Mice of control and letrozole groups were fed the control diet, whereas letrozole + KD mice were fed a KD with 89.9% (kcal) fat for 3 weeks after the PCOS mouse model was generated. β-hydroxybutyrate (BHB), the most abundant ketone body in the body, was used to treat KGN cells with testosterone (T) to simulate the KD effect on PCOS mouse ovaries in vitro. Results Our data showed that KD treatment significantly increased blood ketone levels and reduced body weight. Ovarian functions were improved in some letrozole + KD mice. Results from in vitro experiments indicated mitochondrial damage owing to high T levels, which resulted in the leakage of cytochrome C and mitochondrial DNA into the cytosol and thus induced the activation of the intracellular caspase cascade and the cGAS-STING-NF-κB pathway, leading to granulosa cell inflammation and apoptosis. BHB exhibited certain protective effects on mitochondria of T-treated KGN cells via inhibiting the cGAS-STING pathway. Moreover, the cGAS-STING pathway was activated in ovaries of letrozole mice and was down-regulated in letrozole + KD mice. Conclusion These findings, for the first time, revealed that hyperandrogenism induced ovarian dysfunction possibly through activation of the cGAS-STING pathway, which could be partially inhibited by ketone bodies produced from KD administration. |
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| institution | Kabale University |
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| language | English |
| publishDate | 2024-11-01 |
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| series | Cell Communication and Signaling |
| spelling | doaj-art-dbbbedcbd5594e7990d4fcfedc3a62c52024-12-01T12:37:15ZengBMCCell Communication and Signaling1478-811X2024-11-0122111810.1186/s12964-024-01939-6A ketogenic diet alleviates the apoptosis of granulosa cells by inhibiting the activation of cGAS-STING signaling pathway in PCOS miceBining Zhao0Haowen Wu1Qiyang Yao2Wenpei Bai3Jihong Kang4Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking UniversityDepartment of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking UniversityDepartment of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking UniversityDepartment of Obstetrics and Gynecology, Beijing Shijitan Hospital Affiliated to Capital Medical UniversityDepartment of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking UniversityAbstract Background Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility. The ketogenic diet (KD), a diet high in fat and low in carbohydrates, has been applied clinically for the treatment of obese women with PCOS. We have previously demonstrated that KD improved the reproductive phenotype in an androgen-induced PCOS mouse model, yet the underlying molecular mechanisms remain largely unclear. The aim of the present study was to investigate the effect of KD on the reproductive phenotype of a letrozole-induced PCOS mouse model. Methods Female C57BL/6N mice were divided into three groups, designated control, letrozole, and letrozole + KD groups. Mice of control and letrozole groups were fed the control diet, whereas letrozole + KD mice were fed a KD with 89.9% (kcal) fat for 3 weeks after the PCOS mouse model was generated. β-hydroxybutyrate (BHB), the most abundant ketone body in the body, was used to treat KGN cells with testosterone (T) to simulate the KD effect on PCOS mouse ovaries in vitro. Results Our data showed that KD treatment significantly increased blood ketone levels and reduced body weight. Ovarian functions were improved in some letrozole + KD mice. Results from in vitro experiments indicated mitochondrial damage owing to high T levels, which resulted in the leakage of cytochrome C and mitochondrial DNA into the cytosol and thus induced the activation of the intracellular caspase cascade and the cGAS-STING-NF-κB pathway, leading to granulosa cell inflammation and apoptosis. BHB exhibited certain protective effects on mitochondria of T-treated KGN cells via inhibiting the cGAS-STING pathway. Moreover, the cGAS-STING pathway was activated in ovaries of letrozole mice and was down-regulated in letrozole + KD mice. Conclusion These findings, for the first time, revealed that hyperandrogenism induced ovarian dysfunction possibly through activation of the cGAS-STING pathway, which could be partially inhibited by ketone bodies produced from KD administration.https://doi.org/10.1186/s12964-024-01939-6Polycystic ovary syndromeKetogenic dietHyperandrogenemiaMitochondrial dysfunctioncGAS-STING pathwayInflammation |
| spellingShingle | Bining Zhao Haowen Wu Qiyang Yao Wenpei Bai Jihong Kang A ketogenic diet alleviates the apoptosis of granulosa cells by inhibiting the activation of cGAS-STING signaling pathway in PCOS mice Cell Communication and Signaling Polycystic ovary syndrome Ketogenic diet Hyperandrogenemia Mitochondrial dysfunction cGAS-STING pathway Inflammation |
| title | A ketogenic diet alleviates the apoptosis of granulosa cells by inhibiting the activation of cGAS-STING signaling pathway in PCOS mice |
| title_full | A ketogenic diet alleviates the apoptosis of granulosa cells by inhibiting the activation of cGAS-STING signaling pathway in PCOS mice |
| title_fullStr | A ketogenic diet alleviates the apoptosis of granulosa cells by inhibiting the activation of cGAS-STING signaling pathway in PCOS mice |
| title_full_unstemmed | A ketogenic diet alleviates the apoptosis of granulosa cells by inhibiting the activation of cGAS-STING signaling pathway in PCOS mice |
| title_short | A ketogenic diet alleviates the apoptosis of granulosa cells by inhibiting the activation of cGAS-STING signaling pathway in PCOS mice |
| title_sort | ketogenic diet alleviates the apoptosis of granulosa cells by inhibiting the activation of cgas sting signaling pathway in pcos mice |
| topic | Polycystic ovary syndrome Ketogenic diet Hyperandrogenemia Mitochondrial dysfunction cGAS-STING pathway Inflammation |
| url | https://doi.org/10.1186/s12964-024-01939-6 |
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