Circadian Clocks, Food Intake, and Metabolism - Progress in Molecular Biology and Translational Science - page 113

glucose metabolism aiming at keeping energy homeostasis via phosphoryla-
tion of a number of metabolic enzymes. AMPK is viewed as a cellular sensor
of energy status because, beside AMP, it is also activated by many physio-
logical stimuli, such as stress, food deprivation, acute exercise, or hormones
(e.g., leptin). Some of AMPK targets are clock components. CRY1 is
phosphorylated and destabilized by AMPK. 57 When phosphorylated by
AMPK, casein kinase I e degrades the clock protein PER2, thereby impacting
circadian oscillating. Fibroblasts treated with metformin, an activator of
AMPK, display a shortened circadian period. Furthermore, in vivo injections
of metformin produce phase advances of clock gene oscillations in peripheral
tissues. 58
The NAD þ -dependent SIRT1 (Sirtuin 1) histone deacetylase is a redox
sensor that has been involved in a multitude of processes related to cellular
metabolism, stress, and senescence. 59 In particular, SIRT1 modulates the
activity of the metabolic transcription factor PGC-1 a (peroxisome
proliferator-activated receptor (i.e., PPAR g ) coactivator 1 a ), 60,61 also iden-
tified as a modifier of the transcription of clock genes, such as Bmal1 and
Rev - erba , in part via coactivation of RORs. 62 Moreover, SIRT1 binds cir-
cadianly to CLOCK/BMAL1 heterodimers, thus adding another functional
link between cellular energy state and the molecular clockwork. 63,64
Strikingly, nuclear receptors recognized as circadian factors, that is, REV-
ERBs and RORs, have also been reported having regulatory roles in meta-
bolic function. A pioneer work discovered that REV-ERB a promotes and
ROR a inhibits in vitro adipocyte differentiation. 65,66 BMAL1, whose tran-
scription is regulated by both REV-ERbs and RORs, was also considered
to play a prominent role in adipogenesis. 67 More recently, PER2 has been
shown to promote adipogenesis via PPAR g (see below). 35 Apointthat
remains to be clarified is whether the effects reported above result from abnor-
mal metabolic function due to noncircadian roles of these circadian factors, or
from altered circadian control of metabolic pathways. Furthermore, it is note-
worthy that metabolic factors activated by fatty acids, such as PPAR, are tightly
linked bidirectionally to the molecular clockwork. Actually, Rev - erba expres-
sion in the adipocytes and hepatocytes is induced respectively by PPAR g and
PPAR a . 65,68 In addition, PPAR a in the liver activates the transcription of
Bmal1 ,whiledailyexpressionof Ppara involves BMAL1. 69 Although not
exhaustive, this brief overview of multiple and interconnected regulatory
loops highlights the now established functional and molecular cross talk
between the circadian and metabolic systems ( Fig. 5.1 ) .