Biology Reference
In-Depth Information
(NPY/AgRP) or suppress appetite (anorexigenic) namely
pro-opiomelanocortin/cocaine and amphetamine-regulated
transcript (POMC/CART;
[203]
). Ex vivo monitoring of 27
brain regions from transgenic rats expressing a luciferase
reporter expressed under the control of the Per1 promoter
(Per1:LUC) demonstrated that about half of them are
rhythmic in the explant culture
[204]
. From this study it
was not surprising to discover an ARC clock, given that the
ARC reciprocally innervates the SCN and regulates two
robust circadian events, namely appetite and feeding. Also,
orexin/hypocretin-producing neurons in the LHA are
known to be important in long-term weight homeostasis
[205]
. Connecting via relay centers such as the PVN, the
SCN can communicate with the nucleus of the solitary tract
(NTS), a satiety center in the brainstem and dorsally placed
pituitary gland, the basecamp of all major regulatory
hormones (see
Figure 21.1
;
[205,206]
). However, the
mechanistic relevance of the ARC clock, or SCN innerva-
tions into the LHA, for appetite and feeding remains to be
fully characterized. The extensive breadth of the SCN's
innervation is beyond the scope of this discussion, but the
basic message here is that SCN carries the advantage of
prime real estate: it resides in the premier homeostatic
neighborhood in the brain, the hypothalamus, allowing
association with clocks that also happen to be major
homeostatic regulators of energy and metabolism in
peripheral organs
[207
Furthermore, genome-wide association studies have
suggested a connection between clock-gene poly-
morphisms and obesity and diabetic disorders
[221,222]
.
Concurrently, narcoleptic patients who display extreme
daytime sleepiness due to loss of hypocretin-producing
neurons are associated with an increased incidence of
obesity
[223
225]
. Similarly, patients with night-time
eating syndrome (NES) show disrupted patterns of sleep
and metabolic rhythms
[226]
, consume significantly more
food at night, and are prone to obesity with a high risk for
diabetes (although their total food-intake is similar to that
of control subjects;
[227]
). Similar results have been
obtained from animal studies. Scheduling an isocaloric
high-fat diet
[228]
or even a normal diet
[229]
to the wrong
time of day in rodents leads to increased weight gain. Thus
the interplay of lighting and feeding schedules is probably
required to maintain the homeostatic control of body
weight
[230,231]
. Interestingly, when genetically obese
strains of mice that exhibit disrupted diurnal feeding
rhythms were fed exclusively at night (active phase), they
displayed an amelioration in their metabolic and obesity
status
[232]
. Thus a reciprocal relationship between clock
disruption and metabolic pathologies seems to create
a reinforcing loop leading to rapid progression of the
metabolic disease.
In summary, our discussion suggests that we need
peripheral clocks to provide time stamps for the various
organs involved in food processing and metabolism for
maximal efficiency. Also, within any given peripheral
organ, clocks compartmentalize biochemically incompat-
ible reactions to different times of the day, a functionality
conserved throughout evolution (see above). For example,
metabolic enzymes involved in glycogenolysis (energy
producing) and glycogenesis (energy storage) need to be
synthesized in temporally restricted timeframes corre-
sponding with food absorption and nutrient metabolism.
Finally, liver enzymes such as cytochrome P450 mono-
oxidase detoxify xenobiotics at the cost of producing
harmful reactive oxygen species, a worthwhile endeavor
only after consumption of food. It therefore makes sense to
schedule such reactions to times when they are needed. So,
taken together, we need peripheral clocks for three main
functions: circadian alignment of different organ systems,
compartmentalization of incompatible reactions, and
restricted expression of reactions with adverse side effects
to time-points when they are needed (see
Figure 21.3
;
reviewed in
[233]
).
e
209]
.
To recap, we have clocks in peripheral organs that are
entrained by various environmental cues but eventually
are reset by the master oscillator in the SCN. This brings
us to the most pertinent question of this discussion: Why
do we need so many clocks? One of the first things we do
after waking up is break our fast, i.e., breakfast. While
eating our gut motility increases, nutrition from food is
absorbed, metabolized in the liver, and the energy
generated is stored as fat or used by muscles for activity.
As our energy needs are met, the CNS registers satiety to
inhibit the feeding drive. Just as we show behavioral
rhythms in sleep/activity, many aspects of our metabolism
also show circadian variation, such as serum levels of
insulin
e
[210
e
212]
,
glucagon
[213]
,
adiponectin
[192,214]
, corticosterone
[215
217]
, leptin and ghrelin
[218,219]
. The circadian alignment of our behavioral and
metabolic rhythms is critical for maintaining homeostasis.
Using the forced desynchrony protocol, Scheer et al.
recently investigated the impact of a misalignment
between metabolic rhythms and the central clock in
human subjects
[220]
. Participants in this study slept 12
hours out of phase from their habitual times and were
found to have decreased leptin (predictive of increased
appetite), increased blood glucose levels despite increased
insulin (also termed insulin resistance), inverted cortisol
rhythm, and increased blood pressure, and some were
symptomatic of a pre-diabetic state.
e
Understanding Energy Homeostasis
with Animal Models of the Clock
Genetic animal models with global and tissue-specific
clock deficiencies have indicated a major role for clocks in
lipid and carbohydrate metabolism. Mice with a global
