Peripheral Circadian Oscillators: Time and Food - Progress in Molecular Biology and Translational Science - page 96

especially the resulting inverted feeding patterns causes a loss of synchrony
between the SCN and the liver which is, as we have seen, importantly driven
by metabolic signals. Therefore, we investigated metabolic parameters, clock
gene expression rhythms, and metabolic gene expression rhythms in this
shift-work rat model. Also as we have seen above, NAMPT plays a critical
role in a number of biological processes through the NAD þ -dependent
deacetylase SIRT1. 73,91 Therefore, we focused in our shift-work model on
the relationship between clock gene expression and the NAMPT-NAD-
SIRT1 cascade, including the changes in Ppar a ,Ppar g , and Pgc1 a .We
hypothesized that an altered activity pattern combined with a shifted feeding
pattern would lead to the loss of synchrony between clock genes and
metabolic genes in the liver and especially affect this cascade.
Circadian misalignment was induced by placing rats in a slow-rotating
wheel for 8 h during their rest phase; this was compared with rats placed
in a slow-rotating wheel during their active phase and with undisturbed
controls. 92 Another set of rats was exclusively exposed to restricted food
intake in the rest period or in the active period. In agreement with our
expectation, we observed that clock genes reversed their rhythm and
became synchronized by food. Surprisingly, in spite of the data suggesting
the direct production of NAMPT via CLOCK/BMAL1, 30,74 we observed
in animals that work and eat during the inactive period that NAD þ and
Nampt did not follow the inversion of the rhythm in the core clock genes:
they lost their rhythm together with the metabolic genes Pgc - 1a , Ppara , and
Pparg

. Similarly, animals that only eat during the rest phase also lost their
rhythm in NAD þ and Nampt , but Pgc - 1a

( Fig. 4.2 ) did
not lose their rhythm but had a flattened rhythm following the food
( Fig. 4.2 ) . Such changes in animals eating and/or working during their
active phase indicate that the change in food intake is the main stimulus that
induced a desynchronization within the liver. In addition, the expression of
Nampt in the liver in animals eating in their sleep phase is decreased, which
agrees with the decrease of Nampt seen in Clock mutant mice 30 and might
consequently also be related to the disturbed food intake of these Clock
mutants. This study also showed that inhibition of Nampt is also associated
with a decrease in Per2 levels possibly via SIRT1 ( Fig. 4.1 ). As Per2 binds to
and affects the activity of many nuclear receptors such as PPAR a , this may
also explain why there is a chance in the rhythm in the PPARs. The coen-
zyme NAD þ together with its rate-limiting biosynthetic enzyme NAMPT
stimulates the production of SIRT1 which is a protein that coordinates met-
abolic programs like gluconeogenesis, glycolysis, and lipid metabolism 29 and

, Ppara , and Pparg