Peripheral Circadian Oscillators: Time and Food - Progress in Molecular Biology and Translational Science - page 95

the heme oxygenase; this enzyme catalyzes the conversion of heme into bil-
iverdin, iron, and carbon monoxide. Upon exposure to carbon monoxide,
inactive BMAL1 homodimers are formed at the expense of NPAS2-
BMAL1 heterodimers, indicating that the heterodimerization of NPAS2
is regulated by CO through the heme-based sensor of its PAS domains. 86
Finally, heme is considered a link between metabolism and the clock
because its production and destiny can be influenced by the following fac-
tors. First, it is known that the activity of ALAS1 enzyme is inversely reg-
ulated by glucose. 87 Second, insulin blunts hepatocyte ALAS1 induction, by
disrupting the interaction of FOXO1 (forkhead box O1) and PGC-1 a .
All this together suggests a relevant role of the energy state or the redox
potential as an important signal associated with the fasting/feeding cycle
driving not only cellular oscillations but also the rhythm in clock gene
expression. However, as we see in Section 9 , in spite of this wealth of data
illustrating the influence of the feeding pattern on clock gene expression
especially in the liver, and the evidence for this link by in vitro studies, in
conditions where an animal is living under desynchronized conditions,
the suggested connection between clock genes and metabolic genes is lost.
9. THE LINK BETWEEN CLOCK GENES AND METABOLIC
GENES
Circadian disruption induced by night and shift work leads in the long
term to overweight, increased abdominal fat deposition and development of
indicators of metabolic syndrome. 88,89 This and the observation that the
clock gene expression can be driven by food 4 have motivated many scientists
to search for the relationship between clock genes and metabolic processes
within the cell. Using a rat model of shift work, we have examined to what
extent food intake during the sleep phase could be a factor contributing to
the symptoms of the metabolic syndrome that is associated with shift work. 90
Using a model of forced activity in slowly rotating drums during the rest
phase, we demonstrated that this induces a circadian misalignment based
on a spontaneous temporal shift of food intake, metabolic parameters, and
a loss in blood glucose rhythm, while hormonal rhythms, predominantly
dependent on the SCN, remained unchanged. 60 This could be concluded
as shift-working animals that only had food access in their active phase
did not develop this circadian misalignment. 59 In contrast, rats exposed to
forced activity during the active phase do not show signs of circadian disrup-
tion. These observations suggested that the activity during the rest phase and