Circadian Clocks, Food Intake, and Metabolism - Progress in Molecular Biology and Translational Science - page 107

and skin, express circadian oscillations of the molecular actors of the clock-
work, called clock genes. 4,5 The mammalian clock machinery generates
autoregulatory transcriptional loops, leading to rhythmic expression of clock
genes and clock-controlled genes (i.e., downstream targets of the clockwork).
In the core of these oscillatory mechanisms are transcription factors, BMAL1
(Brain and Muscle Aryl hydrocarbon receptor nuclear translocator-Like pro-
tein1) andCLOCK(CircadianLocomotorOutputCyclesKaput), or its analog
NPAS2 (Neuronal PAS domain protein 2), that dimerize together to activate
the transcription of other clock genes, including three Period ( Per1 - 3 )andtwo
Cryptochrome ( Cry1 - 2 ) genes viaE-box sequences in their promoter, thus defin-
ing a main positive loop. 4,6 The PER and CRY proteins then form complexes
that are translocated in the nucleus where they inhibit their own CLOCK
(NPAS2)/BMAL1-induced transactivation, defining a main negative loop.
There are also reinforcing loops comprising other transcription factors,
REV-ERB ( Reverse Viral Erythroblastosis oncogene products ) ab , and ROR
( Retinoic acid - related Orphan Receptors ) abg that modulate the transcription
of Bmal1 , Npas2 ,and Clock via retinoic acid-related orphan receptor response
elements. Furthermore, PER/CRY repressor complexes are inactivated via
ubiquitination and proteasome degradation by F-box proteins 3 and 21 for
the CRYs, 7,8 and b -transducin repeat containing proteins 1 and 2 for the
PERs. 9 Besides its role as a transcriptional activator, CLOCK is also a histone
acetyltransferase that drives the cyclic acetylation of various targets, including
BMAL1. 10 The internal coordination of circadian rhythmicity is structured
as a multistep network, in which the master suprachiasmatic clock is a conduc-
tor that provides temporal signals to the secondary clocks/oscillators in the brain
and peripheral organs via nervous and endocrine messages. 3,11,12 Light per-
ceived by the retina, that contains its own clock, is widely recognized as the
most potent synchronizer of the master clock. Nevertheless, several cues asso-
ciated with feeding (and fasting) also impact circadian functioning at different
steps of the circadian system.
The first purpose of this chapter is to provide an overview of the complex
physiological interactions between feeding-fasting cycles and the various
clocks/oscillators, including feedback effects of nutritional cues on the cir-
cadian clocks that control feeding rhythmicity ( Fig. 5.1 ) . Another issue that
will be covered is the reciprocal disturbances between circadian rhythmicity
and metabolic pathologies of energy metabolism. Finally, emerging
chronotherapeutic approaches in the field of dieting and prevention of met-
abolic risks will be briefly introduced.