UC San Diego

Time-restricted feeding (TRF) is a dietary intervention that limits food intake within 8-10 hours of the active phase. For mice, it has been shown to protect from metabolic disease, as well as reduce damage and inflammation in the context of chronic illnesses. The alignment of feeding with underlying circadian rhythms optimizes the time for when tissues are metabolically active versus undergoing repair and maintenance. Using sequencing and mass spectrometry, we have curated a unique timeseries dataset of male and female mice fed a Western high-fat diet undergoing TRF. Physiologically, male and female mice responded similarly to TRF by reducing hepatic lipid storage and improve glucose tolerance, however females were not protected from gaining fat mass. Improvements to motor coordination was only observed in male mice as well. Moreover, organizing a multi- tissue and multi- omics response to TRF has highlighted that males respond more than females to temporal restrictions in feeding but the curious effect of increasing rhythmicity is observed in both sexes. Furthermore, the question of hormonal differences in females due to the estrous cycle presents another avenue to be explored, as estrogen has been implicated in protections from metabolic diseases as well. To do so, we examined differences in female transcriptome across the peak (proestrus) and trough (metestrus) of the estrous cycle. Not surprisingly, reproductive tissues such as the uterus respond more greatly than metabolic tissues like the liver to different stages of the hormonal profiles. However, the liver does seem to prioritize certain metabolic states according to the stage of the estrous cycle. Utilizing high-fat diet as a challenge, we observe that diet induces transcriptomic differences at specific stages of the estrous cycle, resulting in chronic disruption of estrous- regulated processes and eventual disruption of the reproductive cycle. In applying TRF, females on high- fat diet were observed to reduce the amount of time spent in low- estrogen states and complete more cycles in a fixed period compared to their ad lib counterparts. Overall, our results suggest that TRF is beneficial life-style intervention for both sexes and estrous cycle consideration depends on experimental design.