Biology Reference
In-Depth Information
deletion of Bmal1 (Bmal1
-/-
) display complete loss of
locomotor rhythms with poor body weight but increased
adiposity, arthropathy (diseased joints) and myopathy
(weak muscles) at an early age
[191,234
nuclear hormone receptors (NR) are one such class of
molecular integrators. NRs such as REV
ERB
a
provide
robustness to the central clock
[244]
and REV
e
-/-
mice exhibit shorter period in wheel running activity
[162]
.
REV
ERB
a
e
237]
. A study by
McDearmon et al.
[235]
suggests that Bmal1 expression in
the brain is necessary for rhythmic activity and its
expression in the skeletal muscle is required for maintain-
ing body weight. Whereas Per2
-/-
mice gain more weight on
a high-fat diet than controls
[238]
, mice deficient in the
circadian deadenylase nocturin remain lean and resistant to
weight gain compared to control mice
[239]
. Clock
D
19
mutant mice are obese and hyperphagic
[240]
. Further
investigation revealed that clocks in enterocytes (cells
lining the small-intestinal wall) schedule absorption of
triglycerides for night-time
[241]
. These rhythms are lost in
the enterocytes of Clock
D
19
-mutant mice, leading to
hypertriglyceridemia (a causal factor for obesity) in these
mice
[242]
. Next, in a restricted feeding paradigm (food
made available only for 4 hours), Npas2
-/-
mice lost weight
even though the total amount of food consumed was
comparable to that of control mice
[243]
. This suggests
a potential role of Npas2 in synchronizing feeding behavior
with food availability. However, results from the global
knockout mice in the aforementioned studies need to be
interpreted with caution. As discussed earlier, core clock
genes such as Bmal1, Clock and Npas2 are known to have
pleiotropic functions, and their roles in energy and
metabolism are only beginning to be addressed using
tissue-specific knockouts. The gravity of these concerns is
highlighted by two recent studies involving tissue-specific
ablation of Bmal1 in the liver and pancreas. While deletion
of Bmal1 in liver causes hypoglycemia (restricted to the
fasting phase i.e., during the day in nocturnal mice kept
under LD cycle)
[191]
, deletion in the pancreas causes
hyperglycemia and hypoinsulinemia
[192]
, indicating
antagonistic functions of Bmal1 in the liver and pancreas.
Maintaining steady-state serum levels of glucose is critical
as it acts as a fuel source for the brain, and these studies
clearly indicate the importance of peripheral clocks in
glucose homeostasis. Further investigation revealed that
mice with liver-specific knockout of Bmal1 had constitu-
tively low levels of the glucose exporter GLUT2 that led to
the hypoglycemia phenotype. The clock in the pancreas
regulates insulin secretion. In contrast to liver, the absence
of Bmal1 expression in the pancreas led to hyperglycemia
as the normal glucose-stimulated insulin (GIS) secretion
response of the pancreas was lost
[210]
.
e
ERB
a
binds to RORE elements and achieves tran-
scriptional repression by recruiting nuclear receptor co-
repressor 1 (NCoR1) and histone deacetylase 3 (HDAC3)
to its target genes, such as Bmal1
[162,245]
). Inhibiting the
complex of REV
e
ERB
a
and NCoR1-HDAC3 leads to
circadian and metabolic deficits
[246]
. It is interesting to
note that REV
e
ERB
a
was originally identified as a regu-
lator of lipid metabolism and adipogenesis
[247]
. More
recently, the discovery of heme as REV
e
ERB's ligand
e
[248]
has cast REV
ERB as a major nodal point for the
integration of the clock and metabolism
[249]
. Heme is
a cofactor for enzymes such as catalases, peroxidases and
cytochrome p450 enzymes, playing a role in oxygen and
drug metabolism
[250,251]
. Heme is now also known to
improve thermal
e
ERB and hence
enhances its interaction with co-repressor complex
NCoR1-HDAC3
[248]
. Furthermore, the rate-limiting
enzyme in heme biosynthesis, aminolevulinate synthase 1
(ALAS1), is regulated by NPAS2 and expressed in
a circadian manner
[250]
. Heme in turn binds to NPAS2
and inhibits its transactivation activity
[252]
. Thus heme
and heme-binding proteins are beginning to be appreciated
as integrators of the transcriptional feedback loop of the
circadian system and enzymatic reactions in metabolism.
Other nuclear hormone receptors, such as estrogen-related
receptor-
a
(ERR
a
;
[253]
), the family of peroxisome pro-
liferator-activated receptors
stability of REV
e
256]
), and
glucocorticoid receptors
[257]
are being recognized as
integrators and are being incorporated in wire diagrams
depicting the metabolic clock. In fact, an exhaustive
circadian profiling identified the rhythmic expression of 25
of 49 NR in various peripheral tissues
[258]
, indicative of
many more prospective NR integrators of clocks with
metabolism.
In addition to NR, recent studies indicate that nutrient
sensors for energy (AMP/ATP ratio) and redox state
(NAD
þ
/NADH ratio) can also function as couplers of the
circadian and metabolic systems
[259]
.NAD
þ
functions as
a coenzyme for oxidoreductases that connect the glycol-
ysis/citric-acid cycles to mitochondrial oxidative phos-
phorylation leading to ATP production, the energy
currency in cells
[260]
. Additionally, NAD
þ
also functions
as coenzyme for SIRT1, a mammalian ortholog of the
yeast sirtuin family
[261]
. SIRT1 is a nutrient sensor that is
stimulated under conditions such as fasting or calorie
restriction, and restores energy homeostasis by deacety-
lating key proteins in carbohydrate and lipid catabolism,
such as PPAR
g
-coactivator-
a
(PGC1
a
;
[262
(PPAR;
[254
e
Molecular Integrators of Clock
and Metabolism
At the molecular level we can envision proteins with
overlapping functions in circadian and metabolic pathways
that help integrate the two systems. Studies indicate that
265]
)and
liver X receptor (LXR;
[266]
). Recently SIRT1 was iden-
tified to rhythmically bind with CLOCK and counteract
e
