Circadian Clocks, Food Intake, and Metabolism - Progress in Molecular Biology and Translational Science - page 112

lengthens the circadian period of SCN PER2:LUC rhythms. 44 At a molec-
ular level, heme was first shown to bind to NPAS2, thereby modulating
DNA binding of NPAS2/BMAL1 in response to the presence of carbon
monoxide. 45 Further work involved PER2 in heme effects on the molecular
clock, but this is still a subject of debate. 46,47 Heme can also serve as a phys-
iological ligand for REV-ERB a and REV-ERB b to modulate their tran-
scriptional efficiency. 48,49 REV-ERBs are also responsive to carbon
monoxide and nitric oxide. 50,51 Other examples of intracellular interactions
between the metabolic and circadian systems will be mentioned below.

2.3. Cross talk between molecular clocks and intracellular
metabolic pathways
Peroxiredoxins are ubiquitous antioxidant enzymes that detoxify reactive
oxygen species, such as hydrogen peroxide. Reduction-oxidation (redox)
cycles of peroxiredoxins define 24-h metabolic cycles that can work in
the absence of the transcriptional/translational circadian clockwork, for
instance in red blood cells. 52 A comparative analysis reveals that these
24-h redox cycles are conserved in all living organisms studied so far, includ-
ing bacteria. 53 In mammalian nucleated cells, peroxiredoxin oscillations are
influenced by the transcriptional/translational circadian clockwork, as
shown by altered phase relationships from Cry1 in fibroblasts / ;

mice. 52
Redox reactions are involved in multiple biological processes, including
the molecular clockwork itself. For instance, the DNA-binding activity of
CLOCK/BMAL1 and NPAS2/BMAL1 heterodimers in silico is enhanced
by the reduced form (NDAH, from NAD þ ) of nicotinamide adenine dinu-
cleotide (NAD). 54 Intracellular levels of NAD þ show circadian oscillations in
fibroblasts fromwild-type mice, but they are arrhythmic in fibroblasts sampled
from Clock mutant or Cry1

Cry2 /

mice. 55 Synthesis of NAD þ is
largely controlled by the enzyme nicotinamide phosphoribosyltransferase
(NAMPT) whose circadian expression is regulated by CLOCK/BMAL1
heterodimers. In turn, NAMPT modulates the molecular clockwork of
peripheral clocks (fibroblasts, hepatocytes), thus defining a new feedback
loop. 55,56 Another example of interactions between clock mechanisms and
redox reactions is given by the fact that transcription repression mediated
by heme-bound REV-ERBs is sensitive to redox states. 50
5 0 -Adenosine monophosphate-activated protein kinase (AMPK) is an
enzyme that plays a key role in the cellular regulation of fatty acid and

/ ; Cry2 /