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

摘要 内部生物钟系统的破坏会降低人类和动物的繁殖成功率 模型。例如，轮班工人的月经周期中断和子宫内膜异位症的发生率更高， 生育能力下降，早产、低出生体重和流产的风险增加。的 导致这一公共卫生问题的机制尚不清楚。我们关注的是何时的变化 食物被消耗，因为昼夜节律紊乱通常会导致正常期间的异常食物消耗 禁食阶段。在临床前模型中，我们发现不合时宜的进餐会通过以下方式降低小鼠的生育能力： 交配行为和排卵节律脱钩。特别是，在休息阶段进食的小鼠中， 排卵前黄体生成素 (LH) 激增通常发生在熄灯时，但也可能随时发生 全天。它与明暗周期和进食周期都不同步。的时间安排 LH 激增主要由一群 Kisspeptin 神经元控制，这些神经元接收来自 LH 的直接输入。 生物钟，对雌二醇和代谢信号敏感。我们在此应用程序中的目标是 确定食物引起的中央生物钟破坏导致受损的具体机制 繁殖成功。这将通过三个目标来实现。一、男女相对敏感度 将评估不合时宜的食物的生殖功能。其次，我们将确定节奏光和 食物信号由重要的排卵控制系统——前腹侧的 Kisspeptin 神经元整合 室周核。最后，我们将讨论与我们观察到的不匹配的直接相反的问题 明暗周期和生物钟之间的相互作用会损害繁殖。即可以适当的进食时间 防止昼夜节律紊乱并挽救生殖能力？此外，我们还将定量地 评估生物钟在 Kisspeptin 神经元功能中的作用。这些研究的结果将表明如何 环境因素和下丘脑时钟在生育力的控制中相互作用。

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.