Peripheral Circadian Oscillators: Time and Food - Progress in Molecular Biology and Translational Science - page 86

is essential to sustain the SCN rhythm. On this basis, we propose that similar
network connections are also important in the functioning of the whole cir-
cadian system, that is, the SCN needs signals back from the body and the
brain in order to function optimally.
Without a doubt, the rhythmic message of the SCN to mainly hypotha-
lamic structures drives hormonal and autonomic output in a 24-h pattern,
resulting in a rhythm in behavior that is synchronized with, for example,
the adequate hormone or glucose levels together with adequate temperature
and cardiovascular parameters to ensure an optimal physiology. 12-14 In addi-
tion, these rhythmic patterns are not fixed but are highly adaptive and take
into account the homeostatic situation of the animal. For example, the
response of corticosterone to psychological stress is the highest during the
beginning of the sleep period, 14-16 while the corticosterone response to
hypoglycemia is the highest in the beginning of the active period. 17 Such
interactions lead to a rhythmic organization of body functions, which is
dependent on the integrity of the SCN and its output pathways.
3. THE PERIPHERAL OSCILLATORS AND THEIR
RELATIONSHIP WITH CLOCK GENES
The phase of the rhythmic expression of clock genes in the periphery
is opposite or phase delayed to the rhythm of the same clock genes expressed
in the SCN. 15,16 In spite of their demonstration in all mammalian tissues,
already more than 10 years ago, the link between the rhythmic clock gene
expression to functional rhythms in these tissues is still weak. Evidence that
supports the relevance of peripheral clock genes in physiology is provided in
studies that show the involvement of clock genes in cell division
processes, 18,19 cardiovascular function, 20,21 and adrenal function. 22 Possible
connections of clock genes with metabolic processes have been explored
especially in the liver, one of the most active organs of the body associated
with metabolism. For example, peroxisome proliferator-activated receptor
a (PPAR a ), involved in lipid and lipoprotein metabolism, binds directly to
the Bmal1 promoter, 23 indicating a possible mechanism via which metab-
olism may influence clock mechanisms in the periphery. Especially in the
liver, clock genes interact with metabolic genes and regulate their transcrip-
tion, endowing cells with rhythmic molecular mechanisms that allow
adapting to the daily cycles in metabolic demand. 6,24-26 In particular, genes
that regulate gluconeogenesis and fatty acid oxidation are suggested to
interact with clock genes for their rhythmic expression. This has been