Restricted Feeding Resets the Peripheral Clocks of the Digestive System

Abstract

All organisms maintain an internal clock that matches the Earth’s rotation over a period of 24 h, known as the circadian rhythm. Previously, we established Period1 luciferase (Per1::luc) transgenic (Tg) mice in order to monitor the expression rhythms of the Per1 clock gene in each tissue in real time using a bioluminescent reporter. The Per1 gene is a known key molecular regulator of the mammalian clock system in the autonomous central clock in the suprachiasmatic nucleus (SCN), and the peripheral tissues. Per1::luc Tg mice were used as a biosensing system of circadian rhythms. They were maintained by being fed ad lib (FF) and subsequently subjected to 4 hour (4 h) restricted feeding (RF) during the rest period under light conditions in order to examine whether the peripheral clocks of different parts in the digestive tract could be entrained. The peak points of the bioluminescent rhythms in the Per1::luc Tg mouse tissue samples were analyzed via cosine fitting. The bioluminescent rhythms of the cultured peripheral tissues of the esophagus and the jejunum exhibited phase shift from 5 to 11 h during RF, whereas those of the SCN tissue remained unchanged for 7 days during RF. We examined whether RF for 4 h during the rest period in light conditions could reset the activity rhythms, the central clock in the SCN, and the peripheral clock in the different points in the gastrointestinal tract. The fasting signals during RF did not entrain the SCN, but they did entrain each peripheral clock of the digestive system, the esophagus, and the jejunum. During RF for 7 days, the peak time of the esophagus tended to return to that of the FF control, unlike that of the jejunum; hence, the esophagus was regulated more strongly under the control of the cultured SCN compared to the jejunum. Thus, the peripheral clocks of the digestive system can entrain their molecular clock rhythms via RF-induced fasting signals in each degree, independently from the SCN.