Peripheral Circadian Oscillators: Time and Food - Progress in Molecular Biology and Translational Science - page 92

7. ENERGY OSCILLATION IN THE CELL
7.1. The NAD/SIRT1 clock gene link
Several molecules have been shown to be involved in the possible reciprocal
relationship between clock genes and metabolic genes, and metabolic pro-
cesses within the cell. Serious attention has been paid to the redox potential,
which is directly linked to the energy state of the cells. Energy metabolism
and consequently glucose modify cellular redox levels which are, for exam-
ple, influenced by the NAD þ to NADH ratio. 71 It is suggested that molec-
ular oscillators in the liver and other peripheral organs may be directly
influenced through elements of the redox potential; in vitro , the DNA bind-
ing of the CLOCK-BMAL1 or NPAS2-BMAL1 heterodimers is highly
sensitive to the proportion of NAD þ cofactors. 72 NAD þ is a classic coen-
zyme that, in mammals, is produced by the conversion of nicotinamide and
5 0 -phosphoribosylpyrophosphate to nicotinamide mononucleotide (NMN)
by the rate-limiting enzyme nicotinamide phosphoribosyltransferase
(NAMPT). 73 Hereby the NAMPT-mediated NAD þ biosynthesis is
suggested to play a critical role in a number of biological processes through
the NAD þ -dependent deacetylase of SIRT1. 30 These associations of one of
the most important cycles involved in the redox potential with the clock
genes 24,74,75 are now widely seen as the logical connection between the
interaction of the rhythms induced by the SCN and the rhythms induced
by food ( Fig. 4.1 ). This agrees with the observation that liver cytoplasm
and mitochondria exhibit a reduced redox which is immediately reverted
to an oxidized state after feeding. 76
7.2. Metabolism, AMPK, and clock genes
Adenosine triphosphate (ATP) is considered as the energy currency of the
cells; the hydrolysis of it to ADP (adenosine diphosphate) and/or AMP
(adenosine monophosphate) can be coupled to transport across membranes,
synthesis reactions, and other processes that require energy. Thus, the ratio
between AMP and ATP is one of the most reliable indicators of the ener-
getic state of the cell. In eukaryotes, the AMP-activated protein kinase
(AMPK) is a conserved enzyme which exquisitely senses small variations
in these molecules and, in turn, phosphorylates a broad range of downstream
targets resulting in the overall effect of increasing ATP-producing pathways
while decreasing ATP-consuming ones. 77-79 The system which senses the