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CLOCK's intrinsic acetyltransferase activity for target
proteins like BMAL1 [267,268] . Taken together, SIRT1 is
aNAD þ dependent nutrient sensor, and the rhythmic
binding of CLOCK-SIRT1 potentially leads to a counter-
balancing interplay of acetylation/deacetylation of target
genes. Subsequent studies have identified that NAMPT
(nicotinamide and 5 0 -phosphoribosy1 1-pyrophosphatase),
a rate-limiting enzyme in the NAD þ biosynthesis pathway,
is regulated by the SIRT1-CLOCK-BMAL complex
driving rhythms in NAMPT expression [269,270] .Thusin
addition to the transcriptional and translational feedback
loops, an enzymatic feedback loop involving clock and
NAD þ -dependent sensors such as SIRT1 is emerging as
molecular integrator of the clock and metabolic systems.
Another integrator identified recently is an enzyme, AMP-
activated protein kinase (AMPK), which is activated by
high AMP/ATP ratio (indicative again of a low energy
state; [271] ). AMPK levels were found to be rhythmic in
mouse liver, hypothalamus and isolated fibroblasts; once
activated, AMPK can relieve the negative feedback arm of
the core clock by destabilizing Per2 and Cry1 proteins
[272,273] . Interestingly, AMPK is also known to regulate
NAD þ levels [259,274] , and AMPK -/- mice lose rhythms
in Nampt expression and core-body temperature [275] .
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CONCLUSION
In conclusion, if homeostasis is the seesaw act of keeping
physiology and behavior constant, then the circadian clock
is its counterweight, helping to offset predictable daily
changes to this balance imposed by the environment. What
might have started billions of years ago as a way to keep
chemically incompatible reactions separated in time, has
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increasingly complex physiology and behavior of multi-
cellular and multiorgan organisms. Of a litany of examples,
we have focused on three: sleep, other cognitive processes,
and metabolism. Sleep, the most obvious of these exam-
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clock, and a sleep homeostat, which measures how much
we have against how much we need. Circadian clock-
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little sleep or wake up at the wrong time, and performance
suffers. The converse is also true: a litany of CNS diseases
from Alzheimer's to schizophrenia to depression are all
comorbid with sleep and clock disorders. These links
continue to metabolism, where sleep disruption can cause
metabolic problems, and metabolic perturbations can affect
sleep and the clock. For homeostasis, timing may not be the
only thing, but it is indispensable.
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