Dietary ω3-and ω6-Polyunsaturated fatty acids reconstitute fertility of Juvenile and adult Fads2-Deficient mice
Dietary ω3-and ω6-Polyunsaturated fatty acids reconstitute fertility of Juvenile and adult Fads2-Deficient mice
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DOI：
10.1016/j.molmet.2020.100974
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发表时间：
2020-06-01
影响因子：
8.1
通讯作者：
Wegner, Ina
中科院分区：
文献类型：
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作者：
Stoffel, Wilhelm;Schmidt-Soltau, Inga;Wegner, Ina
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极长链ω 3-和ω 6-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，在人类进化过程中在脑发育、脂质和能量代谢以及女性和男性生育力中起关键作用。许多营养研究表明，PUFA代谢失衡是几种人类生活方式疾病发病机制的关键因素：血脂异常，肥胖，心血管和神经退行性疾病，以及不孕症。缺乏公正的动物模型，阻碍了分子解释的作用，合成和饮食供应的PUFA在这些条件下。在这项研究中，我们使用了Delta 6脂肪酸去饱和酶（FADS 2）缺陷型小鼠突变体，该突变体缺乏从FA生物合成omega 3-和omega 6-PUFA的关键酶活性，以解决PUFA在女性和男性生育力中的分子作用。不育是多效性但营养缺陷型fads 2-/-表型的标志，因此有助于对个体PUFA作用的严格饮食研究。将雌性和性别匹配的不育fads 2-/-小鼠维持在规定的饮食，含有必需脂肪酸的正常饮食，并补充ω 6-花生四烯酸、ω 3-二十二碳六烯酸和花生四烯酸/二十二碳六烯酸，在4月龄雌性和雄性fads 2-/-小鼠中开始（a）断奶后和（B）。卵巢和睾丸膜脂质双层的磷酸化和鞘脂体在每个队列中建立和膜标志物蛋白，膜形态，生殖细胞发育，和女性和男性的生育能力在各自的cohols.Results的表达和拓扑结构的影响：PUFA合成缺陷引起卵泡发育，卵母细胞闭锁，和不育的fads 2-/-雌性小鼠停止。PUFA缺乏的膜脂双层核心结构导致卵泡颗粒细胞的差距连接网络解体。在fads 2-/-睾丸中，血-睾丸屏障被破坏，精子发生受阻，导致不育。AA和DHA的持续供应重塑了PUFA缺陷的卵巢和睾丸膜脂质体，促进了正常卵巢周期的功能性间隙连接网络的重新组装和支持细胞中血-睾丸屏障的重建，不仅在发育中的新生儿中重建了生育能力，而且令人惊讶地在成年不育fads 2-/-小鼠中也重建了生育能力。这些研究结果表明，营养素omega 3-和omega 6-PUFA，性腺膜结构与女性和男性生育力之间存在以前未被认识到的基于膜结构的分子联系，并可能促进对饮食PUFA在人类生育力中的关键作用的研究。(C)2020作者（S）由爱思唯尔有限公司出版。这是一个在CC BY许可证下的开放获取文章（http：//creativecommons.org/licenses/by/4.0/）。
Objective: Polyunsaturated fatty acids (PUFAs), including essential fatty acids linoleic and a-linolenic acid and derived long chain and very long chain omega 3- and omega 6-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 Delta 6 fatty acid desaturase (FADS2) deficient mouse mutant lacking key enzyme activity in the biosynthesis of omega 3- and omega 6-PUFAs from FAs 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 omega 6-arachidonic acid, omega 3-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 PUFAdeficient 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 omega 3-and omega 6-PUFAs, gonadal membrane structures, and female and male fertility and might foster studies of the pivotal role of dietary PUFAs in human fertility. (C) 2020 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).