Peripheral Circadian Oscillators: Time and Food - Progress in Molecular Biology and Translational Science - page 88

the heart. 36,37 These changing responses can be induced by the SCN by
altering the sensitivity of the organs to circulating hormones 14 ; in particular,
the circadian sensitivity of the adrenal to ACTH is induced by the auto-
nomic nervous system 38 by means of a polysynaptic pathway originating
in the SCN. 39,40 A similar role for the SCN was further illustrated by
Cailotto et al. who showed that light affected the expression of the liver met-
abolic enzymes GLUT2 and glucokinase time dependently (at ZT14 but not
at ZT20 for GLUT2 and the reverse for glucokinase) in intact but not in
denervated animals, demonstrating that the SCN via the autonomic nervous
system may change directly the production of liver enzymes. 41 Conse-
quently, temporal changes in liver metabolic enzymes are directly induced
by SCN-mediated autonomic input. The same study revealed that light
could only modify Per1 and Per2 expression at ZT14 and not at ZT20,
while, for example, PEPCK was changed at both time points, indicating that
light may induce changes in metabolic enzymes via other cellular mecha-
nisms that are also influenced by the autonomic input to the liver. Also
in support for autonomic influence of the clock gene expression in the liver
are the experiments of Terazano 42 who demonstrated that electrical stimu-
lation of the sympathetic output to the liver induces a phase shift of clock
gene expression.
The SCN can also induce and control the rhythmicity of peripheral
oscillators via humoral or metabolic signals. Corticosterone and melatonin,
both driven by the SCN, have been proposed as important humoral signals
for transmitting daily rhythms to the body. 43 In addition, the SCN, by deter-
mining the sleep/activity cycle, can drive feeding rhythms and metabolic
rhythms that can serve as additional internal entraining signals.
The discovery of clock genes has been an enormous help to evaluate the
possibilities of the SCN to influence the activity of peripheral tissues by
means of metabolic signaling and hormones. At first, it was shown that fibro-
blasts can be induced to show a cyclic expression of clock genes by a serum
shock, implying a metabolic stimulus. 44 Then, in view of the important role
of glucocorticoids to transmit the daily signal of the SCN to the tissues of the
body, their role in synchronizing peripheral clock genes was demon-
strated. 43 Finally, temperature, another variable strongly under the influence
of the SCN, is also able to sustain, however, not to induce de novo , clock
gene expression. 45 Studies on isolated fibroblast suggest that temperature
may also affect clock gene expression via cold-inducible mRNA. 46 All this
evidence indicates that, under physiological conditions, the SCN may
use multiple strategies

to drive rhythmicity in peripheral oscillators.