Lecture 14: Clocks and Metabolism II Flashcards
Why have such a robust food entrainment system?
food essential to survival.
As such we have many ways of measuring food so it is a robust system.
Food may appear at variable times relative to other environmental cues (light)
Feeding (or conversely fasting) elicits many parallel and mutually reinforcing physiological signals
(thus multiple internal entraining factors which can act on multiple/interacting FEOs)
Bmal1 KO mice?
still show entrainment/FAA
mice v rats
mice cant be fasted for 3 days.
so hard to get long term responses and show it’s a clock, not just a metabolic cycle.
Bmal1 and Per1/2 KO mice?
dont show limits of entrainment, can show 18hr FAA.
does this show it’s not a clock? or limits are huge? ??
PER2 mutant mice?
Challet, 2010 Genes, Brain and Behavior 9(5):467-477
still make PER2 but can’t interact with the clock.
don’t show FAA in LD.
show some FAA in DD, but diminished.
suggests PER2 important for sensing energy status.
Rev-erb a KO mice with RFS
no FAA in KO.
wt. limit energy expendature as hypocalorific diet.
KO mice don’t show this.
wt. decrease body temp to conserve energy.
KO don’t show this.
wt. also show anticipation in body temp, increases before food.
KO don’t show this.
rev-erb a important for timing and energy sensing.
signals that may be involved in the entrainment of clocks?
nutrients (sterols, lipids, and/or carbohydrates),
humoral signals (insulin, glucocorticoid, leptin)
vagal efferents that travel from autonomic centers to the liver.
Feeding induced temperature cycles
In cultured cell assays, many of these stimuli can induce or reset circadian clocks through regulation of clock gene expression
ClockΔ19 mice?
clock protein doesn’t work properly??
obese.
not arrythmic but have diminished rhythms?
clock function and metabolic homeostasis?
Clock function exerts a profound impact on metabolic homeostasis.
most clock KO/mutants are obese, Per2bmrd1 is lean.
obesity in humans
Diurnal rhythms in metabolic function are dampened in metabolic syndrome (obesity).
Clock gene polymorphisms have been associated with obesity in humans
(CLOCK, REVERB).
‘Disruption’ of our circadian rhythms impact metabolic health:
Chronic shift work PAPERS
social jet lag
forced desynchrony -
Forced desyncrony?
Leptin
Glucose/insulin
Effect on orexigenic drive
behavioural 28hr, clock 24hr so they desync.
can test metabolic parameters when in or out of phase with SCN.
Looked at leptin levels -
comparing aligned to misaligned day.
Misaligned reduced circulating leptin.
Glucose/insulin post meal - on misaligned day sensitivity to insulin decreased.
Forced desynchrony leads to altered orexigenic drive, exaggerated post-prandial glucose/insulin response, and hypertension
Leptin
white adipose tissue, suppresses food intake.
Links between circadian disruption and metabolic disease?
Response to changes in metabolic status can be very different at different times of day.
Mice: profound insulin-induced hypoglycemia is observed at night, but not in the day (same animals, same insulin dose)
Inject insulin and look at glucose response in the blood.
same animals, same dose, night dose more sensitive (when would be eating).
clock effects on rate limiting metabolic regulators?
Many rate-limiting metabolic regulators are directly regulated by clock gene transcriptional control.
Reverbα
nuclear hormone receptor.
repressor, regulates/interacts with numerous metabolic regulators (e.g. PPARs, GR, HDAC3).
recruits HDAC3/NcoR1 to promotor sites.
