Peripheral Circadian Oscillators: Time and Food - Progress in Molecular Biology and Translational Science - page 87

demonstrated for the PPARs, like Ppar g , Ppar a , Ppar b , Pgc- a , and silent
mating-type information regulator homolog1 (Sirt1), which is a member
of the Sirtuin family. Decreased expression of both Sirt1 and Ppar g is asso-
ciated with development of the metabolic syndrome. 27-29 Likewise, changes
in the metabolic condition, especially the redox state and energy availability,
influence the expression of Bmal1 and Per2, resulting in a strong interaction
between metabolic and circadian regulation in hepatocytes. 1,30 However, all
this evidence has emerged only from in vitro studies, which may give a lim-
ited picture of what is really going on in the organ in vivo .
Circadian rhythms governing organ functions may be produced by other
cycling processes than endogenous clock genes expression. This has been
observed in specific liver Bmal1 knockout animals, where due to the absence
of this clock gene many liver genes loose their rhythm, but the glucose
rhythm in the circulation remains, indicating a rhythmic liver output. 31
A similar type of observation was made by Cailotto et al.

32,33

who demon-
strated that, after sympathetic denervation, the liver lost its rhythmic glyco-
gen storage and enzymatic expression, but that in spite of this, the clock
genes did not lose their rhythmicity. These observations indicate that, when
observed in vivo , the suggested link between clock genes and metabolic
genes or metabolism is not as firm as suggested and that when the organ
is embedded in the system of the whole body, there might be several alter-
native ways to drive the rhythmic physiology of the organ.
Many events, metabolic, endocrine, and homeostatic (e.g., temperature,
corticosterone), may drive the rhythmic expression of the organs. For exam-
ple, in an elegant parabiosis experiment between SCN lesioned and intact
mice, Guo et al.

34

demonstrated that behavioral or blood-borne signals
are sufficient to maintain circadian rhythms of clock gene expression in liver
and kidney, but not in heart, spleen, or skeletal muscle. Therefore, in this
chapter, we use the term peripheral oscillator to refer to rhythmic functions
or processes within organs or tissues.

4. THE SCN AS THE DRIVING FORCE BEHIND
THE OSCILLATORS

Many tissues show a different sensitivity or different output depending
on the time the organ was removed. For example, Ungar and Halberg dem-
onstrated already in 1962 that the adrenal, when removed from the rat in the
evening, was more sensitive to ACTH than when it was removed in
the morning. 35 Later, similar observations were reported on the liver and