Circadian Clocks, Food Intake, and Metabolism - Progress in Molecular Biology and Translational Science - page 111

highlighted by larger and lower RQ values during night and day, respec-
tively. Thus, lack of REV-ERB a causes not only an increased utilization
of fatty acids during both resting (daytime) and acute fasting but also an
enhanced nocturnal glucose utilization (used for de novo lipogenesis from
dietary carbohydrates), as well as diet-induced obesity. Thus, these findings
indicate that REV-ERB a is crucial for the daily variations of fuel utiliza-
tion. 29 Notwithstanding, the molecular mechanisms underlying this tempo-
ral partitioning of fuel utilization remain to be further elucidated.
Glucose, the main source of energy for cells, comes from the liver or
from dietary carbohydrate via the intestine and circulates easily in the blood-
stream. In most tissues, cellular uptake of glucose via facilitated diffusion is
controlled by insulin, except for the liver and the brain. Another major fuel
source is fat. As hydrophobic molecules, lipids cannot circulate readily in the
aqueous blood. As a matter of fact, lipids are transported as particles associ-
ating them with hydrophilic molecules, called apolipoproteins. The expres-
sion of apolipoproteins is activated and repressed by the circadian factors
ROR a and REV-ERB b , respectively. 37-39 The lipid particles in the plasma
include chylomicrons, very low-density lipoproteins (VLDL), low-density
lipoproteins, and high-density lipoproteins.
Lipoprotein lipase (LPL) is an enzyme that catalyses the hydrolysis of the
triacylglycerols in chylomicrons and VLDL, releasing nonesterified fatty
acids and facilitating their cellular uptake. 40

Lpl is strongly expressed in tis-
sues that store lipids (i.e., white adipose tissue) or use them as fuel (i.e., mus-
cles and brown fat). Of note, LPL activity displays marked daily variations
according to organs, but with opposite timing depending on their role:
LPL activity in epididymal fat of nocturnal rats is highest at night for lipo-
genesis, while it rises progressively from morning to early night in skeletal
muscle for fat oxidation. 41 LPL expression and activity are modulated by
a number of factors, such as PPARs, insulin, glucose, and fatty acids. 42
Furthermore, CLOCK alone or together with BMAL1 can also transactivate
Lpl expression. 29,40
Heme, being notably an iron-containing compound embedded to the
hemoglobin, is a crucial component of the intermediary metabolism. More-
over, circadian rhythmicity can be modulated by heme bioavailability, illus-
trating a systemic link between metabolic and circadian pathways.
A decrease in heme biosynthesis shortens the circadian period of in vivo body
temperature rhythm. 43 Also, heme and inhibitors of heme oxygenase dose-
dependently dampen circadian oscillations rhythms of SCN explants from
PER2:LUC mice, while pharmacological

inhibition of heme synthesis