Peripheral Circadian Oscillators: Time and Food - Progress in Molecular Biology and Translational Science - page 91

food is scheduled to the day. 56-58 However, one note of caution: all these
data are collected in animals by which the food is restricted to 2-4 h/day.
When food is restricted to the whole inactive period, several parameters,
for example, corticosterone, glucose, temperature, and activity, either show
phase small changes or do not show a rhythm. 59,60
The above-mentioned parabiosis experiments 34 illustrated that under such
conditions, indeed, liver and kidney clock genes may follow the circulating
signals, but that these are not sufficient to synchronize clock genes in other
tissues. Because the heart, spleen, and kidney were not entrained in this para-
biosis model, it is also clear that the resetting of these tissues might require
different combinations of signaling cues including neuronal signals from the
SCN. This observation also suggests that circadian clocks in peripheral tissues
require different combinations of temporal signals. Hereby one also should
consider the role of glucocorticoids and maybe also melatonin. 61-63 Hereby
it is still questionable whether their entraining effect is reached by their influ-
ence on Per1 (clock gene) expression or via other mechanisms. 64
However, in spite of all the evidence for some role of circulating hor-
mones, the circulating metabolite that evidently can be modified by food
intake is glucose. Glucose is the main metabolite, providing energy to the
cell; it exhibits a daily rhythm driven by the SCN 65 and may as such provide
a time signal to the cells. Indeed, the oscillation of clock gene expression in
cultured rat fibroblasts is induced or reset when these cells are exposed to a
glucose bolus. 66 In the same study, it was shown that glucose as well as fruc-
tose, mannose, and lactose triggered robust circadian expression of Per2,
Dbp, and Bmal1 that lasted for at least three cycles, while proteins did
not. Moreover, in experimental animals, food intake after fasting was shown
to immediately shift clock genes in the liver and not in the lung. 67 All these
studies indicate that the liver is capable of responding immediately and with a
wide range of oscillatory genes to food especially when animals have been
fasting. 68 Still, it is also known that food is not the only driving force, as liver
oscillatory genes maintain their rhythm under fasting conditions. 69,70 Con-
sequently, a picture emerges in which food has the capacity to change espe-
cially clock gene expression in the liver, while on the other hand, food is not
essential for sustaining rhythms of these genes. The rhythm imposed by the
SCN (without the food intake) is sufficient to drive the rhythms of clock
genes even though a robust rhythm is only observed when both SCN
and food give the signal. 69 Up till now the precise cellular mechanisms that
are responsible for the oscillations in both clock genes and metabolic genes
are still not clear.