5/17/2023 0 Comments Around the clockThese two fields are intimately linked, as various studies have shown that metabolism is extensively regulated by the molecular Acknowledgments Simultaneously, our understanding of how metabolism is a guiding force for immune function also continues to grow. The ever-increasing evidence of circadian rhythmicity in the immune system suggests that time-of-day and clock status are central to immunity. There is now rapid and complementary growth occurring in the fields of circadian biology and immunometabolism. In fibroblasts, rhythmic post-translational modification of DRP1 (a Concluding Remarks Collectively, these processes are known as mitochondrial dynamics, have profound effects on cell metabolism 102., 103., and display circadian rhythmicity, as reviewed in (Figure 6). Mitochondria can have a fused or fragmented morphology, the former leading to a higher mitochondrial metabolic output. The mammalian target of rapamycin (mTOR) complexes Mitochondrial Dynamics, Metabolism, and Circadian RhythmsĪ key feature of mitochondria is their ability to alter their morphology or size depending on the needs of a cell. This means that amino acid levels can fluctuate through alterations in amino acid synthesis pathways (nonessential amino acids) or through alterations in amino acid uptake receptors (essential amino acids). While some amino acids (nonessential) can be synthesised through metabolic pathways, others (essential) are required from external sources. As described above, DCs require the induction of a ‘futile’ loop of lipid synthesis to respond to pathogens Amino Acid Metabolism in ImmunityĬells require an adequate supply of amino acids for routine protein synthesis and cell growth. In a mouse model of sepsis, inhibition of FAS with C75 provided protection by reducing NLR family pyrin domain containing 3 ( Nlrp3) expression and bioactive IL-1β. The enzyme FAS plays a key role in synthesising palmitate (Figure 4). Fatty acid and cholesterol synthesis are major pathways in lipid metabolism. Lipid metabolism is critical for an efficient inflammatory response. Glucose is the major energy source for macrophages and DCs and, depending on their activation state, these cells alter glucose metabolism Lipid Metabolism in Immunity Pathogen recognition receptors (PRRs) on these cells recognise pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) and mobilise the innate immune response to remove them. Macrophages and DCs are important components of the innate immune system, which can eliminate pathogens and resolve cellular and tissue damage. Clock Δ19/Δ19, Bmal1 −/−, Cry1 −/−/ Cry2 −/−, and Rev-erbα −/− transgenic Glucose Metabolism in Innate Immunity Similarly, whole-body circadian glucose tolerance has been demonstrated in humans and mice 31., 43., 44. Whole-body glucose tolerance was observed to be higher in rats during their active phase, lower during resting phase, and completely abrogated with SCN lesioning, demonstrating circadian control. Glucose metabolism was one of the first key metabolic pathways discovered that is under the control of the clock 42., 43. Circadian misalignment in humans lowers glucose Circadian Glucose Metabolism Numerous studies have reported increased risk of breast cancer and metabolic conditions such as heart disease and diabetes with shift-workers 25., 26., 27. This leads to disruption of peripheral clocks with respect to the master SCN clock (Figure 3). With night-time shift work, behaviours such as activity and eating occur during the ‘biological night’ and sleep must then occur in the ‘biological day’, when the SCN is receiving light inputs. Light is sensed by melanopsin-expressing retinal Circadian Disruption, Metabolism, and Human Health Entraining stimuli are known as zeitgebers, the German word for time-giver, the most dominant of which are light and food. Perhaps the most important factor in maintaining healthy The Inner Workings of the Molecular ClockĬircadian rhythms possess three core properties: (i) an endogenous nature, whereby rhythms will continue to oscillate independent of external cues (ii) potential for entrainment by external stimuli and (iii) temperature compensation, whereby rhythms are kept relatively constant within a physiological temperature range. Molecular clocks regulate the timing of cellular activities depending on environmental cues such as light and food, creating temporal harmony between tissues and the external environment. Thus, most organisms have evolved molecular clocks (see Glossary) to match their physiology with the solar cycle. Life on Earth has evolved in a 24-h cyclic environment due to Earth’s daily rotation about its axis and its position relative to the sun. Section snippets Biological Processes Controlled by the Molecular Clock
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