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

摘要 内部生物钟系统的破坏降低了人类和动物的繁殖成功率 模型例如，轮班工作者月经周期中断和子宫内膜异位症的发生率更高， 降低生育能力，并增加早产、低出生体重和流产的风险。的 造成这一公共卫生问题的机制尚不清楚。我们关注的是 食物被消耗，因为昼夜节律紊乱通常会导致正常饮食期间的异常食物消耗。 禁食阶段。在一个临床前模型中，我们发现，不定时的进餐会通过一种新的途径降低小鼠的生育能力。 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， 排卵前促黄体生成激素（LH）激增通常发生在熄灯时，而不是可以发生在任何时候 一整天它从光暗周期和进食周期中被去除。的定时 LH峰由一群kisspeptin神经元控制，这些神经元接受来自 昼夜节律钟和敏感的雌二醇和代谢线索。我们在此应用程序中的目标是 确定食物引起的中枢生物钟中断导致受损的特定机制 繁殖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 将评估生殖功能对不适时食物的影响。第二，我们将确定节奏的光和 前腹侧的kisspeptin神经元是整合食物线索的重要排卵控制系统 室周核最后，我们将讨论与我们的观察相反的匡威，即不匹配 光暗周期和生物钟之间的差异会损害生殖。也就是说，可以适当的食物时间 防止昼夜节律紊乱和挽救生殖能力？此外，我们还将从数量上 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， 环境因素和下丘脑生物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.