Metabolic synchronization of the liver circadian clock

Abstract

The daily rotation of the earth around its axis determines the day length of 24 hours and the periodic change from day to night. Organisms evolved endogenous clocks to anticipate the light/dark alteration and associated occurrences. Every day this clock is usually reset anew to keep the exact 24 h periodicity. Responsible for the resetting, called entrainment, are so called Zeitgeber, which is a German word for time-giver. The circadian clock is based on a transcriptional/translational feedback loop (TTL) of so called clock genes which are characterized by their own rhythmic expression and their ability to drive rhythmic expression of other genes, called clock controlled genes. Light is seen as the predominant Zeitgeber, because it resets the master pacemaker of the circadian system, situated in the suprachiasmatic nucleus (SCN) in the hypothalamus. In addition, food is an important Zeitgeber for peripheral clocks. If food is only available at certain times of the day, peripheral clocks phase uncouple from the SCN and shift towards the food time. In this project we targeted to identify factors which are responsible for the food entrainment of the liver. We identified the peptide hormone oxyntomodulin (OXM), which is postprandially released in intestinal L-cells, as a potent factor to reset the liver clock. We could show that OXM induces the expression of period genes (Pers), which are a core part of the TTL. This, in turn, leads to phase shifts of the liver clock in vivo and in vitro. The in vitro experiments, done with cultured organotypic liver slices, confirm the direct effect of OXM on the liver clock. In agreement with the decoupling from the master pacemaker, the SCN was not influenced by OXM administration. We found that the action of OXM in the liver is dependent on a receptor, related to the GLP-1 receptors known from other organs. Blocking this receptor diminishes the actions of OXM in the liver and also the clock gene reaction on food in the liver in vivo. These findings are an important step in under standing the mechanisms of internal desynchronization which occurs for example in shift workers.