Objective

Polyunsaturated fatty acids (PUFAs), including essential fatty acids linoleic and α-linolenic acid and derived long chain and very long chain ω3-and ω6-polyunsaturated fatty acids, are vital structures in mammalian membrane systems and signaling molecules, pivotal in brain development, lipid, and energy metabolism and in female and male fertility during human evolution. Numerous nutritional studies suggest imbalance of PUFA metabolism as a critical factor in the pathogenesis of several human lifestyle diseases: dyslipoproteinemia, obesity, cardiovascular and neurodegenerative diseases, and infertility. The lack of unbiased animal models impedes molecular interpretation of the role of synthesized and dietary supplied PUFAs in these conditions. In this study, we used a Δ6 fatty acid desaturase (FADS2) deficient mouse mutant lacking key enzyme activity in the biosynthesis of ω3-and ω6-PUFAs from EFAs to address the molecular role of PUFAs in female and male fertility. Infertility is a hallmark of the pleiotropic but auxotrophic fads2−/− phenotype and is therefore helpful for stringent dietary studies on the role of individual PUFAs.

Methods

Feeding regimens: Age- and gender-matched infertile fads2−/− mice were maintained on defined diets, normal diet containing essential fatty acids, and supplemented with ω6-arachidonic acid, ω3-docosahexaenoic acid, and arachidonic/docosahexaenoic acid, starting (a) after weaning and (b) initiated in 4-month-old female and male fads2−/− mice. Phospho- and sphingolipidomes of ovarian and testicular membrane lipid bilayers in each cohort were established and the impact on the expression and topology of membrane marker proteins, membrane morphology, germ cell development, and female and male fertility in the respective cohorts was elaborated.

Results

PUFA synthesis deficiency caused a halt to folliculogenesis, atresia of oocytes, and infertility of fads2−/− female mice. A PUFA-deficient membrane lipid bilayer core structure led to the disassembly of the gap junction network of the follicular granulosa cells. In fads2−/− testis, the blood-testis barrier was disrupted and spermatogenesis arrested, leading to infertility. Sustained supply of combined AA and DHA remodeled the PUFA-deficient ovarian and testicular membrane lipidomes, facilitating the reassembly of the functional gap junction network for regular ovarian cycles and the reconstitution of the blood-testis barrier in Sertoli cells, reconstituting fertility not only in developing newborns, but surprisingly also in adult infertile fads2−/− mice.

Conclusions

These findings demonstrate the previously unrecognized membrane structure-based molecular link between nutrient ω3-and ω6-PUFAs, gonadal membrane structures, and female and male fertility and might foster studies of the pivotal role of dietary PUFAs in human fertility.

中文翻译：

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饮食中的ω3-和ω6-多不饱和脂肪酸可重构幼年和成年Fads2缺乏小鼠的生育能力。

目的

多不饱和脂肪酸（PUFA），包括必需脂肪酸亚油酸和α-亚麻酸，以及衍生的长链和超长链ω3和ω6多不饱和脂肪酸，是哺乳动物膜系统和信号分子中的重要结构，对大脑发育至关重要，脂质，能量代谢以及人类进化过程中的男女生殖能力。许多营养研究表明，PUFA代谢失衡是几种人类生活方式疾病的发病机理中的关键因素：脂蛋白血症，肥胖症，心血管和神经退行性疾病以及不育。缺乏无偏见的动物模型阻碍了在这些条件下分子对合成和饮食供应的PUFA的作用的解释。在这个研究中，我们在由EFAs合成ω3-和ω6-PUFAs中使用了缺少关键酶活性的Δ6脂肪酸去饱和酶（FADS2）缺陷型小鼠突变体，以研究PUFAs在雌性和雄性育性中的分子作用。不育是多效但营养缺陷的标志fads2 -/-表型，因此有助于严格的饮食研究中各个PUFA的作用。

方法

喂养方式：按年龄，性别匹配的不育fads2 //-小鼠维持规定饮食，含必需脂肪酸的正常饮食，并补充ω6-花生四烯酸，ω3-二十二碳六烯酸和花生四烯酸/二十二碳六烯酸，开始（a ）断奶后（b）在4个月大的雌性和雄性fads2 -/-小鼠中启动。建立了每个队列中的卵巢和睾丸膜脂质双层的磷酸脂和鞘脂脂组，并阐述了对各个队列中膜标志物蛋白的表达和拓扑，膜形态，生殖细胞发育以及雌性和雄性育性的影响。

结果

PUFA合成缺乏导致卵泡生成停止，卵母细胞闭锁和fads2 -/-雌性小鼠的不育。PUFA缺乏的膜脂质双层核心结构导致卵泡颗粒细胞的间隙连接网络的拆卸。在fads2 -/-睾丸中，血液-睾丸屏障被破坏，精子发生停止，导致不孕。持续供应AA和DHA可以重塑PUFA缺陷型卵巢和睾丸膜脂质体，从而促进功能性间隙连接网络的重组，促进规则的卵巢循环，并重建Sertoli细胞的血液-睾丸屏障，不仅在发育中重建生育能力新生儿，但令人惊讶的是，也在成年不育fads2 -/-小鼠中。

结论

这些发现证明了营养素ω3-和ω6-PUFA，性腺的膜结构以及雌性和雄性生育力之间以前无法识别的基于膜结构的分子联系，并可能促进对饮食PUFAs在人类生育力中的关键作用的研究。