Peripheral circadian oscillators: time and food.

The suprachiasmatic nucleus (SCN) provides timing to the brain and to the whole organism. Its rhythmic signal to mainly hypothalamic structures results in a synchronized hormonal and autonomic output to the body that coordinates behavior and physiology. As a result of this, the expression of clock genes in all organs has a rhythm that is dictated by the SCN. Together with these clock genes, a number of cellular processes follow a similar rhythm, whereby it has been proposed that these events are driven at least, in part, by clock genes. Together, this forms a multiple oscillating system that interacts and under normal conditions is synchronized by the SCN. The autonomic and hormonal outputs from the SCN are examples of messages that are clearly targeted; the behaviors driven by the SCN are examples of messages that may have more diffuse targets. For example, food intake and locomotor activity, which are normally driven by the SCN, have the capacity to drive the rhythm of clock genes in cells of the liver. The influence of food has been shown by offering food outside the normal activity-food intake period. If such a condition persists, desynchronization follows between centrally and peripherally dictated rhythms because the SCN keeps transmitting temporal signals according to the day-night cycle. These circumstances promote pathologies such as the metabolic syndrome, which is characterized by the progressive onset of hypertension, insulin resistance, and diabetes. As clock genes are proposed to drive the rhythms of metabolic genes, it is very attractive to give the clock genes a central place in this desynchronization and pathology picture. Therefore, in this chapter, we pay special attention to the question of how the SCN is able to transmit its message to the cells of the body and focus on the liver, because of its essential role in metabolism. Here, we review recent evidence that shows how desynchronization may lead to the uncoupling of cellular processes within the liver cells. The basis for this cellular dissociation, we argue, is the fact that the network of brain-body interaction is desynchronized, leading also to an uncoupling of normally coupled systems within the cell.