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

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.