Hohos Natalie M, Elliott Emily M, Giornazi Asma, Silva Elena, Rice John D, Skaznik-Wikiel Malgorzata E
Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora, Colorado, USA.
Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora, Colorado, USA.
Reproduction. 2021 Mar;161(3):307-317. doi: 10.1530/REP-20-0290.
High-fat diet (HFD) consumption in female rodents causes impaired estrous cyclicity, fewer pups per litter, and dysregulation of key ovulatory genes suggesting that HFD-induced subfertility may be due to ovulatory dysfunction. To test this hypothesis female mice were fed chow or HFD for 10 weeks at which point ovulation and ovarian gene expression of endothelin-2 (Edn2), a gene critical for ovulation, were assessed. After 10 weeks of HFD, both mice that remained lean and those that became obese had fewer ovulated oocytes than chow controls (P = 0.041, P = 0.0030, respectively). In chow controls, Edn2 was expressed as expected with basal levels during diestrus and proestrus, increased 11.6-fold during estrus, and decreased to basal levels during metestrus. In HFD mice, Edn2 was dysregulated across the entire estrous cycle as were other Edn2 system components (endothelin converting enzyme 1 (Ece-1), and the endothelin receptors (Ednra, Ednrb)). Interestingly, we found dysregulation of key ovarian steroidogenic genes after HFD. We also found that estradiol treatment in prepubertal mice increased Edn2 expression in the ovary (P = 0.030), suggesting that impaired steroidogenesis may be involved in the HFD-induced dysregulation of ovarian Edn2. In conclusion, HFD leads to ovulatory dysfunction regardless of the development of obesity, which appears to be mediated through dysregulation of ovarian Edn2 expression.
雌性啮齿动物食用高脂饮食（HFD）会导致发情周期紊乱、每窝幼崽数量减少以及关键排卵基因失调，这表明HFD诱导的生育力下降可能是由于排卵功能障碍所致。为了验证这一假设，将雌性小鼠喂食普通饲料或HFD 10周，然后评估排卵情况以及对排卵至关重要的基因内皮素-2（Edn2）的卵巢基因表达。喂食HFD 10周后，体重保持 lean 的小鼠和肥胖小鼠排出的卵母细胞均比喂食普通饲料的对照组少（分别为P = 0.041，P = 0.0030）。在喂食普通饲料的对照组中，Edn2的表达符合预期，在间情期和发情前期处于基础水平，在发情期增加11.6倍，在动情后期降至基础水平。在HFD小鼠中，Edn2在整个发情周期均失调，其他Edn2系统成分（内皮素转换酶1（Ece-1）和内皮素受体（Ednra、Ednrb））也是如此。有趣的是，我们发现HFD后关键的卵巢类固醇生成基因失调。我们还发现，对青春期前小鼠进行雌二醇处理可增加卵巢中Edn2的表达（P = 0.030），这表明类固醇生成受损可能参与了HFD诱导的卵巢Edn2失调。总之，无论肥胖是否发展，HFD都会导致排卵功能障碍，这似乎是通过卵巢Edn2表达失调介导的。
