10 Questions
What happens when traveling eastwards, and how does it affect jet lag symptoms?
When traveling eastwards, one has to advance the clock, which can cause resistance to phase shifting jet lag symptoms.
How does melatonin normally act on MT1 receptors, and what is the consequence of decreased melatonin?
Normally, melatonin acts on MT1 receptors by inhibiting cAMP signaling and linoleic acid uptake, preventing growth pathway. Decreased melatonin leads to increased growth pathway, increasing the risk of cancer.
What is the connection between clock genes and metabolic pathways in relation to circadian rhythm and metabolic health?
Clock genes, such as ROR and REV-ERB, regulate metabolic pathways, including mitochondrial biogenesis, thermogenesis, and gluconeogenesis, through their effects on PGC1α and PPAR.
What is the role of PPAR in regulating metabolic pathways, and how is it expressed?
PPAR activates BMAL1 and REV-ERB, regulating metabolic pathways, and is expressed in high fat tissues.
How do energy sensors SIRT1 and AMPK regulate metabolic pathways, and what are the conditions that activate them?
SIRT1 is activated by high NAD+ ratio, deacetylating histones and silencing gene expression of Per2, while AMPK is activated by high AMP ratio, phosphorylating Cry and CKIe, and degrading Per2.
What is the role of the pancreatic clock in regulating insulin secretion, and how does melatonin affect it?
The pancreatic clock controls insulin secretion, and melatonin binds to MT1/2, inhibiting cAMP and decreasing insulin release.
How do PER1 and PER2 genes regulate circadian rhythms, and what are the consequences of their deregulation?
PER1 and PER2 genes regulate circadian rhythms by controlling the expression of clock-controlled genes, and their deregulation can lead to circadian rhythm disorders and metabolic syndrome.
What is the role of ROR and REV-ERB in regulating circadian rhythms, and how do they interact with BMAL1?
ROR regulates the activation of BMAL1, while REV-ERB inhibits BMAL1 transcription, and together they regulate circadian rhythms.
How does light-induced phase shifting affect circadian rhythms, and what are the consequences of its disruption?
Light-induced phase shifting can reset the circadian clock, and its disruption can lead to circadian rhythm disorders, such as jet lag and shift work disorder.
What is the role of melatonin in regulating metabolic processes, and how does it relate to the risk of metabolic syndrome?
Melatonin regulates metabolic processes, including glucose and lipid metabolism, and its dysregulation can contribute to the risk of metabolic syndrome.
Study Notes
Biological Clock
- The biological clock, also known as the circadian rhythm, is a circa 24-hour cycle that adapts to environmental changes to maximize energy expenditure.
Suprachiasmatic Nucleus (SCN)
- The SCN, located in the anterior hypothalamus, is the main circadian rhythm regulator.
- It consists of 20,000 neurons divided into core and shell regions, with the core region expressing VIP and GRP, and the shell region expressing AVP.
- The SCN causes circadian effects in the body through the neural firing rate, with gap junctions between core and shell regions allowing for coherent rhythm within and between neuron populations.
- The SCN outputs mainly to the pineal gland and hypothalamus.
Molecular Mechanism of Circadian Rhythm
- The circadian rhythm is regulated by a transcription-translation feedback loop (TTFL) involving clock genes, transcriptional activators, and repressors.
- The primary loop involves the dimerization of BMAL1/2 with Clock, transcription of Per1/2/3 and Cry1/2, formation of Per/Cry complexes, and negative feedback loop on BMAL1/Clock.
- The secondary loop involves the dimerization of BMAL1/2 with Clock, transcription of REV-ERB and RORα, and the regulation of BMAL1 by REV-ERB and RORα.
Light Entrainment
- Light is the most important zeitgeber, resetting the clock daily.
- The retinohypothalamic tract (RHT) transmits light information from the retina to the SCN, releasing glutamate and PACAP, which activate cAMP, PKA, and CreB, binding to CRE for Per1&2 transcription.
- Light exposure during early nights causes a permanent phase delay, while exposure during late nights causes a permanent phase advance.
Sleep and Melatonin
- The paraventricular nucleus (PVN) activates the sympathetic nervous system, causing the pineal gland to release melatonin.
- SCN activity inhibits PVN during the day, preventing melatonin release, while inhibition of SCN during the night allows melatonin release.
- Melatonin acts on MT1&2 receptors and regulates metabolic processes.
Processes Regulated by Circadian Rhythm
- Body temperature: low during night, high during the day
- Melatonin: decreased SCN activity increases melatonin
- Cortisol: SCN controls cortisol via PVN, peaking in the morning
Circadian Misalignment
- Jet lag is caused by traveling across 3+ time zones, requiring the body to adjust to a new rhythm.
- Symptoms include sleepiness, concentration problems, and gastrointestinal issues.
- Eastward travel is harder to adjust to due to the need to advance the clock.
Shift Working
- Shift working can lead to cardiovascular diseases, insomnia, and decreased melatonin, increasing the risk of cancer and metabolic syndrome.
Circadian Rhythm and Metabolic Health
- Clock genes regulate metabolic pathways via ROR, REV-ERB, and PGC1α.
- Energy sensors SIRT1 and AMPK regulate energy metabolism, with SIRT1 activating PGC1α and AMPK phosphorylating Cry and CKIe.
Tissue Clocks (Peripheral Clocks)
- Pancreatic clock: controls insulin secretion, with melatonin inhibiting insulin release.
- Other peripheral clocks include liver, muscle, and adipose tissue clocks.
Understand the biological clock, its 24-hour cycle, and how it adapts to environmental changes. Learn about the role of the supra chiasmatic nucleus (SCN) as the main regulator of circadian rhythm.
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