Light phase feeding and estradiol reverse ovariectomy-induced alterations in metabolism and liver clock gene expression in rat.

Abstract

During aging, the decline in ovarian hormone levels in women is associated with increased weight gain, fat accumulation, and alterations in the circadian timing system. Aligning eating with the activity phase improves metabolic outcomes. In contrast, misalignment entrains the circadian clock in peripheral organs and raises spontaneous locomotor activity (SLA) before mealtime. Given that ovarian estradiol (E2) modulates both metabolism and circadian function, this study aimed to investigate the role of ovariectomy (OVX) on the time-restricted (TR) feeding effects on metabolism. Two-month-old female rats underwent OVX and were fed with TR during either the light or dark phases. TR-DARK feeding did not reverse the weight and fat gain observed in OVX rats under ad libitum (AD) feeding, likely because it did not change the food intake pattern in OVX rats. Conversely, TR-LIGHT reversed the OVX-induced metabolic effects. Next, we test if OVX affects food-entrainment of circadian clocks. TR-LIGHT, regardless of OVX, abolished the peak Per1, Bmal1, Cry2, and Reverb-ɑ expression in the liver. It also increased SLA at food onset independently of OVX. In contrast, OVX elevated liver expression of Per1, Bmal1, and Cry2 at baseline (zeitgeber time, ZT1), and of Reverb-ɑ at peak (ZT6 and ZT13) compared to SHAM-AD rats. To assess the role of E2, OVX rats received a daily injection of E2 at ZT1 for 3 days, and the expression of clock genes was evaluated on the fourth day. In a different group of E2-treated OVX rats, the daily rhythm of SLA was also monitored. E2 treatment reversed the OVX-induced increase in both weight and fat gain, as well as in Per1, Bmal1, and Cry2. However, it did not affect the Reverb-α. E2 promotes an increase in SLA at ZT1 and ZT2. In conclusion, TR-DARK neither alleviates the lack of ovarian hormones in OVX-induced metabolic changes, nor do ovarian hormones participate in food-entrainment of circadian clocks. However, E2 seems to modulate clock gene expression in the liver.