背景:代谢综合征是全球范围内严重的公共卫生问题。然而,与代谢综合征相关的生育力下降的典型代谢产物和机制仍然难以捉摸.
目的:本研究的目的是探索与代谢综合征相关的生育力下降的典型代谢产物和机制。
方法:利用代谢组学,对高、低繁殖性能母猪各组织的脂肪酸组成进行了比较分析。此外,研究了高脂饮食(HFD)诱导的代谢综合征模型(肥胖小鼠)中的血清脂肪酸组成,以阐明与代谢综合征相关的脂质代谢产物.此外,使用啮齿动物动物模型(大鼠和小鼠)检查了神经酸(NA)对卵巢功能的影响。通过生物技术,如转录组学,CUT&Tag,以及翻译后蛋白质修饰的分析,基于利用猪卵巢颗粒细胞的模型,进一步阐明了NA介导的卵巢炎症的分子机制,人类,和老鼠。最后,对诊断为多囊卵巢综合征的患者的卵巢进行了验证.
结果:体外,靶向血清脂质组学分析显示,胚胎存活率低的母猪表现出异常的脂质代谢,其特征是肝脏中NA的异常积累,子房,和脂肪组织。此外,升高的NA水平会引发卵巢炎症,从而导致母猪和大鼠的卵巢功能障碍。机械上,NA通过抑制呼吸链蛋白CYTB和NDFUB8激活NLRP3炎性体诱导线粒体氧化应激,它触发procaspase-1转化为活性caspase-1,并将细胞因子前体pro-IL-1β转化为卵巢颗粒细胞中具有生物活性的IL-1β。值得注意的是,我们证明NA通过增加IL-1β启动子区的H3K9ac修饰水平和调节转录因子AP-1的表达来促进IL-1β的活性。最后,我们发现CerS2在卵巢中的表达减少和趋化因子CXCL14的水平增加可能是NA异常积累的原因。令人惊讶的是,多囊卵巢综合征患者,肥胖,非酒精性脂肪肝或妊娠期糖尿病表现出高水平的血清NA。
结论:总的来说,我们目前的研究表明NA是代谢综合征的典型代谢产物,这强烈影响卵巢功能和胚胎存活,并且还提供了干扰线粒体ROS产生是解决异常NA积累的潜在强大策略。
BACKGROUND: Metabolic syndrome is a serious public health concern across the globe. However, the typical metabolites and mechanisms underlying the decreased fertility related to metabolic syndrome is still elusive.
OBJECTIVE: The aim of the present study was to explore the typical metabolites and mechanisms underlying the decreased fertility related with metabolic syndrome.
METHODS: Utilizing metabolomics, a comparative analysis was conducted on fatty acid compositions in various tissues of sows with high and low reproductive performance. Additionally, serum fatty acid compositions in a metabolic syndrome model (obese mice) induced by a high-fat diet (HFD) were investigated to elucidate the lipid metabolites associated with metabolic syndrome. Furthermore, the impact of nervonic acid (NA) on ovarian function was examined using rodent animal models (rats and mice). Through biological techniques such as transcriptomics, CUT&Tag, and analysis of post-translational protein modifications, the molecular mechanisms underlying NA mediated ovarian inflammation were further elucidated based on models utilizing ovarian granulosa cells from pigs, humans, and mice. Finally, validation was performed on ovaries from patients diagnosed with polycystic ovary syndrome.
RESULTS: In vitro, targeted serum lipidomic analysis revealed that sows with low embryo survival rates exhibited abnormal lipid metabolism characterized by abnormal accumulation of NA in the liver, ovary, and adipose tissue. Additionally, elevated NA levels trigger ovarian inflammation to cause ovarian dysfunction in both sows and rats. Mechanistically, NA induce mitochondrial oxidative stress through inhibiting respiratory chain proteins CYTB and NDFUB8 to activate NLRP3 inflammasome, which triggers procaspase-1 into active caspase-1, and convert the cytokine precursors pro-IL-1β into biologically active IL-1β in ovarian granulosa cells. Notably, we evidenced that NA promotes IL-1β activities by increasing H3K9ac modification level of IL-1β promoter regions and regulating the expression of the transcription factor AP-1. Finally, we found that the decreased expression of CerS2 in ovaries and the increased level of chemokine CXCL14 may be the cause of abnormal NA accumulation. Surprisingly, individuals with polycystic ovary syndrome, obesity, non-alcoholic fatty liver or gestational diabetes mellitus exhibit a high level of serum NA.
CONCLUSIONS: Collectively, our current study suggests that NA is a typical metabolite of metabolic syndrome, which strongly influences the ovarian function and embryo survival and also provides that interfering with mitochondrial ROS production is a potential strong strategy for target solving abnormal NA accumulation.