High-fat diet induces an ovulatory defect associated with dysregulated endothelin-2 in mice.

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.