Xing-Hui Li1, Hai-Ping Wang1, Jing Tan1, Yan-di Wu1, Ming Yang1, Cheng-Zhou Mao2, Sai-Fei Gao2, Hui Li2, Hui Chen3, Wei-Bin Cai4. 1. Guangdong Engineering & Technology Research Center for Disease-Model Animals, Program in Cardiovascular Disease and Metabolism, the Fifth Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China; Department of Biochemistry, Zhongshan Medical School, Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China; Laboratary Animal Center, Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China. 2. Guangdong Engineering & Technology Research Center for Disease-Model Animals, Program in Cardiovascular Disease and Metabolism, the Fifth Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China; Laboratary Animal Center, Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China. 3. Department of Obstetrics and Gynecology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong Province, China. Electronic address: chenhui9@mail.sysu.edu.cn. 4. Guangdong Engineering & Technology Research Center for Disease-Model Animals, Program in Cardiovascular Disease and Metabolism, the Fifth Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China; Department of Biochemistry, Zhongshan Medical School, Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China; Laboratary Animal Center, Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China; The Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou 510080, Guangdong Province, China. Electronic address: caiwb@mail.sysu.edu.cn.
Abstract
AIMS: This study aims to investigate the pathophysiological role and mechanism of pigment epithelium-derived factor (PEDF) deletion in ovarian damage. METHODS: Female PEDF-knockout mice and their wild-type littermates were used in this study. Relevant tests were performed at 8-10 weeks or 32 weeks of age. KEY FINDINGS: Compared to the wild-type mice, the PEDF-knockout mice showed diminished ovarian reserve (DOR), worse ovum quality after injection to induce controlled ovarian stimulation, increased serum follicle stimulating hormone (FSH) level and an follicle stimulating hormone/luteinizing hormone (FSH/LH) ratio. Moreover, severe ovarian oxidative damage was found in ovaries of PEDF-knockout mice that mainly manifested as an accumulation of reactive oxygen species (ROS), NF‑E2-related factor 2 (Nrf2) pathway activation, significantly upregulated expression of ROS-generating genes. Correspondingly, the PEDF-knockout mice exhibited lipid metabolism disorder and insulin resistance, which mainly manifested as obesity, abdominal fat accumulation, adipocyte enlargement, severe ectopic fat deposition, dyslipidemia, changes in adipokine levels, hyperglycemia, hyperinsulinemia, impaired glucose tolerance, impaired insulin tolerance and significantly declined protein kinase B (Akt) phosphorylation levels. SIGNIFICANCE: Loss of PEDF leads to ovarian oxidative damage accompanied by DOR in mice, this is related to PEDF deficiency induced severe insulin resistance and lipid metabolism disorder. Therefore, PEDF may be a potential target for the treatment of diseases related to ovarian oxidative damage.
AIMS: This study aims to investigate the pathophysiological role and mechanism of pigment epithelium-derived factor (PEDF) deletion in ovarian damage. METHODS: Female PEDF-knockout mice and their wild-type littermates were used in this study. Relevant tests were performed at 8-10 weeks or 32 weeks of age. KEY FINDINGS: Compared to the wild-type mice, the PEDF-knockout mice showed diminished ovarian reserve (DOR), worse ovum quality after injection to induce controlled ovarian stimulation, increased serum follicle stimulating hormone (FSH) level and an follicle stimulating hormone/luteinizing hormone (FSH/LH) ratio. Moreover, severe ovarian oxidative damage was found in ovaries of PEDF-knockout mice that mainly manifested as an accumulation of reactive oxygen species (ROS), NF‑E2-related factor 2 (Nrf2) pathway activation, significantly upregulated expression of ROS-generating genes. Correspondingly, the PEDF-knockout mice exhibited lipid metabolism disorder and insulin resistance, which mainly manifested as obesity, abdominal fat accumulation, adipocyte enlargement, severe ectopic fat deposition, dyslipidemia, changes in adipokine levels, hyperglycemia, hyperinsulinemia, impaired glucose tolerance, impaired insulin tolerance and significantly declined protein kinase B (Akt) phosphorylation levels. SIGNIFICANCE: Loss of PEDF leads to ovarian oxidative damage accompanied by DOR in mice, this is related to PEDF deficiency induced severe insulin resistance and lipid metabolism disorder. Therefore, PEDF may be a potential target for the treatment of diseases related to ovarian oxidative damage.