The circadian time of food intake and its effect on reproductive health

摘要 体内生物钟系统的破坏降低了人类和动物的生殖成功率 模特们。例如，轮班工人月经周期紊乱和子宫内膜异位症的发生率更高， 降低生育率，增加早产、低出生体重和流产的风险。这个 造成这一公共卫生问题的机制尚不清楚。我们一直专注于以下方面的变化 食物之所以被消耗，是因为在正常情况下，昼夜节律的扰乱往往会导致食物的异常消耗 禁食阶段。在一个临床前模型中，我们发现不当的膳食通过一种 交配行为和排卵节律的分离。特别是，在休息阶段进食的小鼠中， 通常在关灯时出现的排卵前促黄体生成素(LH)高峰可能在任何时候发生 一整天。它与明暗周期和取食周期都不同步。这次会议的时间安排 黄体生成素激增是由一群Kispeptin神经元控制的，这些神经元接受来自 生物钟和对雌二醇和代谢信号敏感的生物钟。我们在此应用程序中的目标是 确定食物引起的中枢昼夜节律紊乱导致受损的具体机制 繁衍成功。这将通过三个目标来实现。第一，男性和女性的相对敏感性 将评估对不合时宜的食物的生殖功能。第二，我们将确定有节奏的光和 食物线索被一个重要的排卵控制系统整合在一起--前腹侧的Kispeptin神经元 脑室周围核。最后，我们将解决与我们的观察结果直接相反的问题，即不匹配 在明暗周期和生物钟之间会损害生殖。也就是说，能不能适时进食 防止昼夜节律紊乱，挽救生殖能力？此外，我们将在数量上 评估生物钟在Kispeptin神经元功能中的作用。这些研究的结果将说明 环境线索和下丘脑时钟在控制生育方面相互作用。

Abstract Disruptions of the internal circadian clock system reduce reproductive success in both humans and animal models. For example, shift workers have greater rates of menstrual cycle disruption and endometriosis, reduced fertility, and have an increased risk for pre-term birth, low birth weight, and miscarriage. The mechanisms that contribute to this public health problem are unknown. We have focused on changes in when food is consumed, because circadian disruption often leads to abnormal food consumption during normal fasting phases. In a preclinical model, we have found that mis-timed meals reduce fertility in mice via an uncoupling of mating behavior and ovulation rhythms. In particular, in mice that eat during their rest phase, the pre-ovulatory luteinizing hormone (LH) surge that normally occurs at lights-off instead can occur at any time throughout the day. It is desynchronized from both the light-dark cycle and the feeding cycle. The timing of the LH surge is controlled proximately by a population of kisspeptin neurons that receive direct input from the circadian clock and that are sensitive to estradiol and metabolic cues. Our goals in this application are to identify specific mechanisms by which food-induced disruptions of central circadian clocks lead to impaired reproductive success. This will be accomplished in three aims. First, the relative sensitivity of male and female reproductive function to mis-timed food will be assessed. Second, we will determine how rhythmic light and food cues are integrated by an important ovulatory control system—kisspeptin neurons in the anteroventral periventricular nucleus. Finally, we will address the direct converse of our observation that a mismatch between the light-dark cycle and the circadian clock impairs reproduction. Namely, can appropriate food timing protect against circadian disruption and rescue reproductive competence? In addition, we will quantitatively assess the role of circadian clocks in kisspeptin neuronal function. The results of these studies will show how environmental cues and hypothalamic clocks interact in the control of fertility.