Peripheral Circadian Oscillators: Time and Food - Progress in Molecular Biology and Translational Science - page 84

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.
1. INTRODUCTION
In mammals, the circadian system is coordinated by the sup-
rachiasmatic nucleus (SCN). The SCN is synchronized to daily light-dark
cycles by direct photic inputs received from the retina through the ret-
inohypothalamic tract. The endogenous timekeeping mechanism in SCN
cells is modeled as a network of interlocked transcription-translation feed-
back loops that oscillate with a 24-h periodicity. In this mammalian clock
machinery, the transcription factors CLOCK and BMAL1 heterodimerize
to drive the transcription of genes containing E-box enhancer elements,
and among these are the Period (Per) and Cryptochrome (Cry) genes.
PER and CRY proteins, in turn, multimerize and inhibit the action of
CLOCK-BMAL1, resulting in a rhythmic oscillation of its own transcrip-
tion and of many downstream targets. 1,2
This molecular circadian machinery is present not only in the SCN but
also in peripheral organs. While in the SCN this clock machinery can pro-
duce self-sustained oscillations for indefinite cycles, in peripheral organs
when tested in vitro , in general, the evidence points to a progressive loss
of rhythm in the absence of the SCN. 3
Many behavioral and physiological aspects, that is, feeding/fasting, rest/
activity, neuroendocrine secretion, and autonomic control, are used by the
SCN to induce circadian expression of clock genes in peripheral organs;