Diet-induced obesity impairs spermatogenesis: the critical role of NLRP3 in Sertoli cells.
Diet-induced obesity impairs spermatogenesis: the critical role of NLRP3 in Sertoli cells.
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饮食诱导的肥胖损害精子发生：NLRP3在支持细胞中的关键作用。
DOI：
10.1186/s41232-022-00203-z
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发表时间：
2022-08-02
影响因子：
8.1
通讯作者：
中科院分区：
文献类型：
--
作者：
越来越多的证据表明支持细胞（SC）功能障碍在肥胖引起的精子发生障碍中发挥着关键作用。具有pyrin结构域3的核苷酸结合寡聚化结构域样受体（NLRP3）在SC中表达，但NLRP3在肥胖引起的男性不育的病理过程中的作用仍不清楚。 NLRP3 缺陷小鼠被喂食高脂肪饮食 24 周，以建立与肥胖相关的精子发生障碍。在另一组实验中，将含有 microRNA (miR)-451 抑制剂的慢病毒载体注射到 AMP 激活蛋白激酶 α (AMPKα) 缺陷的小鼠生精小管中。人类睾丸样本是通过睾丸穿刺从患有梗阻性无精症的男性身上获得的，其样本表现出组织学上正常的精子发生。用棕榈酸 (PA) 处理分离的人类 SC，以模拟体外肥胖模型。在肥胖啮齿动物的睾丸中观察到 NLRP3 表达增加。 NLRP3 在 PA 处理的人类 SC 中也上调。 NLRP3 缺乏减轻了肥胖相关的男性不育症。 SC 衍生的 NLRP3 促进白介素 1β (IL-1β) 分泌，损害睾酮合成和精子性能，并增加基质金属蛋白酶 8 (MMP-8) 表达，通过激活核因子 kappa B (NF-κB) 降解 Occludin。肥胖引起的 miR-451 增加、AMPKα 表达减少以及 NADPH 氧化酶活性依次增加是 NLRP3 激活的原因。抑制 miR-451 可预防与肥胖相关的男性不育症，而这些保护作用会因小鼠中 AMPKα 缺陷而被消除。 NLRP3 促进肥胖相关的精子发生障碍。 miR-451 表达增加、AMPKα 通路受损以及随后的 ROS 产生是 NLRP3 激活的原因。我们的研究为肥胖相关男性不育症的潜在机制提供了新的见解。在线版本包含可在 10.1186/s41232-022-00203-z 获取的补充材料。
Accumulating evidence indicates a key role of Sertoli cell (SC) malfunction in spermatogenesis impairment induced by obesity. Nucleotide-binding oligomerization domain-like receptor with a pyrin domain 3 (NLRP3) is expressed in SCs, but the role of NLRP3 in the pathological process of obesity-induced male infertility remains unclear. NLRP3-deficient mice were fed a high-fat diet for 24 weeks to establish obesity-related spermatogenesis impairment. In another set of experiments, a lentiviral vector containing a microRNA (miR)-451 inhibitor was injected into AMP-activated protein kinase α (AMPKα)-deficient mouse seminiferous tubules. Human testis samples were obtained by testicular puncture from men with obstructive azoospermia whose samples exhibited histologically normal spermatogenesis. Isolated human SCs were treated with palmitic acid (PA) to mimic obesity model in vitro. Increased NLRP3 expression was observed in the testes of obese rodents. NLRP3 was also upregulated in PA-treated human SCs. NLRP3 deficiency attenuated obesity-related male infertility. SC-derived NLRP3 promoted interleukin-1β (IL-1β) secretion to impair testosterone synthesis and sperm performance and increased matrix metalloproteinase-8 (MMP-8) expression to degrade occludin via activation of nuclear factor-kappa B (NF-κB). Increased miR-451 caused by obesity, decreased AMPKα expression and sequentially increased NADPH oxidase activity were responsible for the activation of NLRP3. miR-451 inhibition protected against obesity-related male infertility, and these protective effects were abolished by AMPKα deficiency in mice. NLRP3 promoted obesity-related spermatogenesis impairment. Increased miR-451 expression, impaired AMPKα pathway and the subsequent ROS production were responsible for NLRP3 activation. Our study provides new insight into the mechanisms underlying obesity-associated male infertility. The online version contains supplementary material available at 10.1186/s41232-022-00203-z.
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影响因子：
4.6
作者：
Hayrabedyan S;Todorova K;Jabeen A;Metodieva G;Toshkov S;Metodiev MV;Mincheff M;Fernández N
通讯作者：
Fernández N
影响因子：
6.7
作者：
Hammoud A;Carrell DT;Meikle AW;Xin Y;Hunt SC;Adams TD;Gibson M
通讯作者：
Gibson M
DOI：
10.1124/jpet.115.226936
发表时间：
2015-12-01
影响因子：
3.5
作者：
Minutoli, Letteria;Antonuccio, Pietro;Altavilla, Domenica
通讯作者：
Altavilla, Domenica
影响因子：
2.8
作者：
Deng, Shou-Long;Wang, Zhi-Peng;Liu, Yi-Xun
通讯作者：
Liu, Yi-Xun
影响因子：
4.4
作者：
Lech, Maciej;Avila-Ferrufino, Alejandro;Anders, Hans-Joachim
通讯作者：
Anders, Hans-Joachim