Cardiac-derived CTRP9 mediates the protection of empagliflozin against diabetes-induced male subfertility in mice.

IF 6.7 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Clinical science Pub Date : 2024-11-06 DOI:10.1042/CS20241477
Yang Mu, Ling-Bo Luo, Rong Huang, Zhuo-Yu Shen, Dan Huang, Shu-Hong Zhao, Jing Yang, Zhen-Guo Ma
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Abstract

Previous studies have shown beneficial effects of empagliflozin (Empa), a selective inhibitor of the sodium-glucose cotransporter 2 (SGLT2), on diabetes and cardiovascular outcomes in patients with diabetes. However, whether Empa could ameliorate diabetes mellitus (DM)-induced male spermatogenesis dysfunction remains unclear. Our study aimed to investigate the effect of Empa in the development of DM-induced male spermatogenesis dysfunction and to reveal the molecular mechanisms. DM mice were orally treated with Empa to investigate the effects of Empa on DM-induced male mice spermatogenesis dysfunction. We employed a cardiac-specific C1q/tumor necrosis factor-related protein 9 (CTRP9)-deficient mouse model and a cardiac-specific CTRP9 overexpression mouse model to investigate its role in the protection of Empa against diabetes-induced male subfertility. We found that Empa treatment could improve DM-induced male mice subfertility. Interestingly, we discovered that cardiac-derived CTRP9 was decreased in DM mice and this decrease was prevented by Empa treatment. A CTRP9 blocking antibody or cardiac-specific depletion of CTRP9 abolished the protection of Empa on DM-induced male subfertility. Cardiac-specific CTRP9 overexpression ameliorated DM-induced male subfertility. Mechanistically, we identified that cardiac-derived CTRP9 increased steroidogenesis in mice with diabetes in a PKA-dependent manner. We also provided direct evidence that activation of AMP activated protein kinase α (AMPKα)/nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signalling pathway by CTRP9 was responsible for the attenuation of ferroptosis in Leydig cells. In conclusions, we supposed that Empa was a potential therapeutic agent against DM-induced male mice spermatogenesis dysfunction.

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心源性 CTRP9 在保护小鼠免受糖尿病诱导的雄性不育症影响方面起着介导作用。
先前的研究表明,作为钠-葡萄糖共转运体2(SGLT2)的选择性抑制剂,empagliflozin(Empa)对糖尿病患者的糖尿病和心血管预后有好处。然而,Empa能否改善糖尿病(DM)引起的男性生精功能障碍仍不清楚。我们的研究旨在探讨Empa对DM诱导的男性生精功能障碍的影响,并揭示其分子机制。为了研究Empa对DM诱导的雄性小鼠生精功能障碍的影响,我们给DM小鼠口服Empa。我们采用心脏特异性C1q/肿瘤坏死因子相关蛋白9(CTRP9)缺失小鼠模型和心脏特异性CTRP9过表达小鼠模型,研究Empa在保护糖尿病诱导的雄性不育症中的作用。我们发现,Empa治疗可改善DM诱导的雄性小鼠不育症。有趣的是,我们发现DM小鼠的心源性CTRP9减少,而Empa治疗可防止这种减少。CTRP9阻断抗体或心脏特异性CTRP9耗竭可消除Empa对DM诱导的雄性不育症的保护作用。心脏特异性CTRP9过表达可改善DM诱导的男性不育症。从机理上讲,我们发现心源性CTRP9以PKA依赖的方式增加了糖尿病小鼠的类固醇生成。我们还提供了直接证据,证明CTRP9激活了AMP激活蛋白激酶α(AMPKα)/核因子(红细胞衍生2)-类2(Nrf2)信号通路,是削弱犁地细胞中铁细胞凋亡的原因。总之,我们认为Empa是治疗DM诱导的雄性小鼠精子发生功能障碍的潜在药物。
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来源期刊
Clinical science
Clinical science 医学-医学:研究与实验
CiteScore
11.40
自引率
0.00%
发文量
189
审稿时长
4-8 weeks
期刊介绍: Translating molecular bioscience and experimental research into medical insights, Clinical Science offers multi-disciplinary coverage and clinical perspectives to advance human health. Its international Editorial Board is charged with selecting peer-reviewed original papers of the highest scientific merit covering the broad spectrum of biomedical specialities including, although not exclusively: Cardiovascular system Cerebrovascular system Gastrointestinal tract and liver Genomic medicine Infection and immunity Inflammation Oncology Metabolism Endocrinology and nutrition Nephrology Circulation Respiratory system Vascular biology Molecular pathology.
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