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The biological nuclear clock consists of a positive arm in which BMAL1 and CLOCK heterodimer induces expression of the negative arm, consisting of PER and CRY, which then provide feedback on the inhibition of BMAL1/CLOCK. In addition, BMAL1/CLOCK activates Rev-Erb-alpha/beta and ROR-alpha/gamma, which have opposing roles in the regulation of BMAL1, with Rev-Erb-alpha/beta inhibiting the expression of BMAL1 and ROR-alpha/gamma stimulating expression. Furthermore, the PER and CRY degradation rate, mediated by CK1-delta/epsilon and FBXL3, creates the circadian 24-hour period. Finally, the transcriptional regulation of clock-controlled genes (CCGs) by the nuclear clock establishes a circadian rhythm in various cell functions
Host Immunity is an energetically intense process that requires the coordination of multiple immune cell types to perceive, communicate, and respond to a wide variety of microorganisms. Interestingly, the circadian clock controls the development, function, and transport of immune cells, leading to a variation in the host's susceptibility to microbial pathogens over the day-night cycle. The circadian clock is a network of transcription factors that controls the rhythm of gene expression over a 24-hour cycle
Suprachiasmatic nucleus (SCN) neurons project their axons onto multiple regions of the brain to orchestrate circadian physiology and behavior, including locomotive activity, food intake, hormone secretion, host immunity
The circadian rhythm characterizing multiple biological processes in living organisms is a cycle occurring with a periodicity of ~24 h.
In all cells, a circadian clock (a highly ordered and regulated network of genes and proteins) is influenced by extrinsic factors, including light, temperature, and diet
The suprachiasmatic nucleus (SCN) of the hypothalamus acts as the main pacemaker under the influence of light, synchronizing the peripheral clocks in almost all organs, including the intestine, liver, and white adipose tissue (WAT). The consumption of food is also dependent on it. This, in turn, affects the peripheral clocks and the frequency and function of the gut microbiota. The microbiota plays the role of a modulator for the peripheral clocks with only subtle effects per se. This interaction influences the host's daily transcriptome.
Several other loops controlling BMAL1-Clock / Basic helix-loop-helix ARNT-like protein 1 expression have been described, and therefore cells maintain cyclic gene expression in response to environmental stimuli through modulation of activators and repressors
Some of these tissue clocks have key functions in the circadian regulation of metabolism, ranging from glucose homeostasis to lipid metabolism
These activities are regulated by intrinsic clocks in the liver , heart , kidneys , skeletal muscles , and pancreas , among other things
For over 40 years, it has been known that the suprachiasmatic nucleus (SCN) in the mammalian hypothalamus contains the central circadian clock. This clock regulates a variety of cellular, physiological, and behavioral 24-hour rhythms. Remarkably, most, if not all, cells in the body possess the molecular machinery necessary to generate circadian rhythms .
The genes and proteins that constitute the central molecular clock play a crucial role in regulating the timing of expression for approximately 10% of all transcripts produced in a given tissue or organ.
Recently, research has shown that a variety of human diseases, particularly those associated with chronic inflammation (e.g., obesity , inflammatory bowel disease (IBD) , cancer, and neurological disorders), are linked to disruptions in normal microbiota communities or circadian organization.
A 12-week disruption of the circadian rhythm has been found to promote intestinal hyperpermeability . This effect is further exacerbated when mice are fed a high-fat, high-sugar diet for 10 weeks. The underlying mechanism appears to involve the tight junction protein occludin . Additionally, repeated phase shifts in the light-dark cycle disrupt intestinal barrier function .
In summary, the suprachiasmatic nucleus (SCN) regulation of circadian rhythms is vital for maintaining various physiological processes. Disruptions in these rhythms can lead to significant health issues, particularly those involving chronic inflammation and intestinal barrier function.
References:
. doi: 10.1371/journal.pone.0097500
Dysbiosis and circadian rhythm disruption are associated with similar diseases, including Adiposity / Obesity, metabolic syndrome, and inflammatory bowel disease. Despite this overlap, the potential relationship between circadian disorganization and dysbiosis remains unknown.
. doi: 10.1371/journal.pone.0097500
The synchronization by the master clock includes hormonal signals and neurotransmitters, although the molecular mechanisms are still somewhat unclear
In mammals, there is a master regulator located in the suprachiasmatic nucleus (SCN) of the hypothalamus. It is composed of thousands of neurons, each with an intrinsic clock oscillating in harmony with each other. The SCN responds to signals transmitted from photosensitive receptors in the retina and other stimuli from other brain regions. Moreover, the SCN neurons project their axons to multiple regions of the brain to orchestrate circadian physiology and behavior, including locomotor activity, feeding, and hormone secretion. The SCN also projects to the paraventricular nucleus, which has been demonstrated to have a role in the corticotropin-releasing hormone–adrenocorticotropic hormone axis and ultimately secretion of corticosterone by the adrenal glands
This master clock takes circadian clocks that are found in practically all tissues of the body and thus ensures that all peripheral tissue including those of the immune system, epithelial cells clocks work in coordination with the 24-hour, day-night cycle. The circadian clock coordinates the sleep/wake cycle, body temperature, hormone release, and feeding/fasting patterns
In addition, local circadian clocks regulate tissue-specific gene expression programs
All forms of life on earth, from microscopic to more complex organisms, have adapted to the light and dark cycles in 24-hour periods. They have developed circadian rhythms - a coordinated and entrainable mechanism that orchestrates sleep-wake cycles, feeding patterns, hormone secretions, metabolic homeostasis and body temperature
In mammals, there is one main regulator that is found in the suprachiasmatic nucleus (SCN) of the hypothalamus. It is made up of thousands of neurons, each of which has an intrinsic clock that vibrates in harmony with one another. The SCN responds to signals transmitted by light-sensitive receptors in the retina and to other stimuli from other brain regions
Undoubtedly, the SCN is critical to coordinating multiple functions throughout the body; however, most cells also contain endogenous clocks that can exhibit autonomous oscillations even in the absence of SCN-synchronizing activity. For example, in studies in which liver tissue was explanted from mice, the circadian expression of a group of genes can be maintained without input from the SCN
The circadian clock has a hierarchical organization. The central clock, made up of around 20,000 neurons, is located in a brain region known as the suprachiasmatic nucleus (SCN). The central clock (master clock) is carried away by light signals recorded and transmitted by photoreceptors in the retina. The master clock, the suprachiasmatic nucleus (SCN) located in the mammalian central nervous system (CNS), aligns and controls the self-sustained and independent peripheral clocks in all cells
Complex multicellular organisms have a clock made up of feedback loop mechanisms ensuring the synchronization of energetically complex processes to the time of day when an organism is most active. The main actors in the mammalian clock are transcription factors: brain and muscle ARNT-like 1 (BMAL1) and circadian locomotor output cycles kaput (CLOCK) form heterodimers, translocate into the cell nucleus, and drive the expression of several clock-controlled genes, including their own repressors period and cryptochromes
The SCN also projects onto the paraventricular nucleus, which has been shown to play a role in the corticotropin-releasing hormone-adrenocorticotropic hormone axis and ultimately in the secretion of corticosterone by the adrenal glands
see also:
Circadian Clock / Circadian rhythm & Gut microbiota
Dysbiosis & Intestinal Hyperpermeability
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