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BBS2051 Case 2 Circadian disturbance
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BBS2051 Case 2 Circadian disturbance
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Case 2 Circadian disturbanceLearning goals:
How does jet lag influence the internal clock?
o delayed phase, advanced phase -> difference traveling to east or west
o symptoms
Travelers fatigue is caused by an cramped environment with little option for exercise,
restricted food choice, dehydration due to dry air and cabin hypoxia which increases fatigue.
The symptoms of jet lag do not disappear after a good night of sleep and take a number of
days.
Jet lag is due to the effects in the new time zone of an unadjusted body clock. The absence of
rapid adjustment leads to loss of sleep at night and all daily circadian rhythms are
inappropriately phased.
Flights to the east are associated with more jet lags than flights west
Eastward flights: phase advance
- Tired during the day
- Early tired, wake up earlier
- Takes about 2/3 of the time zones crossed
If you cross 6 time zones, it will take 4 days to recover.
Westward flights: phase delay
- Tired later
- Takes about 1/2 of the time zones crossed
If you cross 6 time zones, it will take 3 days to recover.
The cyclic processes and behaviour gets disrupted by shifts of the external light/dark cycle. It
alters clock-gene expression in people.
Zeitgebers can produce a phase advance, phase delay or no phase shift. This relation
between the time of presentation of the zeitgeber and the phase shift produced is called a
phase-response curve. The resistance to phase shifting is the cause of jet lag.
The circadian rhythms with a larger exogenous component (food intake, physical
activity) will adjust more rapidly than those with a larger endogenous component
(sleep, mood, mental performance)
How can we restore circadian misalignment?
o sleeping medicine, exercise, etc.
The most effective way to re-set the clock is with the help of the photic entrainment. A light
stimulus causes CREB-regulated transcription factor 1 (=CRTC1) to activate the transcription
factor CREB-protein, which in turn sets the clock gene expression.
To stabilize the adjusted clock rhythm, there is a negative feedback mechanism controlled by
salt inducible kinase 1 (=SIK1).
Drugs to promote alertness, including modafinil, dextroamphetamine sulphate and caffeine
have been investigated. Of these drugs, only caffeine can be considered for more general
use. Moreover many reviews and reports have confirmed the effectiveness of melatonin
ingestion, generally 3-5 mg being taken 2-3 h before bedtime. it has be showed that the
melatonin improved sleep (when assessed in the morning) and decreased daytime sleepiness
and fatigue (when assessed in the evening). Whether the success of melatonin is because it
, acts as a natural hypnotic (soporific) or promotes adjustment of the body clock via the phase
response curve that exists for melatonin is unknown.
The phase response curve to light is well established and light exposure and avoidance in the
new time zone are regarded as an effective way to adjust the body clock. After flights to the
west, the time when light should be avoided tend to be during the night. This consonance
between the requirement of light avoidance based on the phase response curve and the
natural light-dark cycle is one reason why jet lag after flights to the west is generally felt to
be less pronounced.
There is no information about how exercise alone affects jet lag, and very little about food
intake. However one study showed positive results in soldiers who has used the Argonne diet
(alternate days of fasting and feeding on a protein rich breakfast and carbohydrate rich
evening meal for 4 days before a trans meridian flight.) effects of jet lag were reduced
slightly but, there were methodological weaknesses in the investigation.
Melatonin levels will be earlier if you exercise before 7 pm. Melatonin levels will be later if
you exercise after 7 pm. Light exercise helps to maintain alertness during the day.
After a long flight you are probably a little dehydrated, that’s why moderate to light
exercise is better than heavy workouts. Also exercising outdoors is better, because of
the influence of light and temperature on climate adjustment
Which other factors can lead to circadian misalignment?
o late eating, artificial light, etc.
Nonphotic factors
Exercise: Advances and delays phases
Learning goals:
What is the connection between the circadian clocks and metabolism?
o molecular pathway -> liver, pancreas (insulin resistance…)
Direct evidence for metabolic input into the core clock includes the finding that the orphan
nuclear hormone receptor (NHR) reverse-erb alpha (REV-ERBα) (a repressor) and the
opposing retinoic acid orphan receptors (RORα and β) (activators) constitute a short
feedback loop controlling Bmal1 transcription. Peroxisome proliferator–activated receptor a
(PPARα) and the coactivator peroxisome proliferators–activated receptor gamma
coactivator 1-α (PGC1α) also modulate Bmal1 transcription through this feedback loop,
indicating that REV-ERBα is a nodal point for metabolic input into the clock. NHR profiling has
revealed rhythmic clustering of these factors in metabolic tissues across the day/night cycle,
suggesting extensive coupling between circadian and nuclear receptor signalling network.
!!
Activation of PPARα promotes uptake, utilization, and catabolism of fatty acids by
upregulation of genes involved in fatty acid transport, fatty acid binding and activation, and
peroxisomal and mitochondrial fatty acid β-oxidation.
PGC1α is a co-activator of ROR and thus a co-stimulator of BMAL1. It is also important in
mitochondrial biogenesis regulation. PPARα is important in hepatic lipid metabolism. It is a
clock controlled gene that controls BMAL1.
- Increased when fasting, exercising or when cold
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