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Circadian Entrainment of Drosophila Melanogaster
Published on: June 3, 2020
Melatonin and the pathologies of weakened or dysregulated circadian oscillators
1Johann Friedrich Blumenbach Institute of Zoology and Anthropology, University of Göttingen, Göttingen, Germany.
Abstract:
Dynamic aspects of melatonin's actions merit increasing future attention. This concerns particularly entirely different effects in senescent, weakened oscillators and in dysregulated oscillators of cancer cells that may be epigenetically blocked. This is especially obvious in the case of sirtuin 1, which is upregulated by melatonin in aged tissues, but strongly downregulated in several cancer cells. These findings are not at all controversial, but are explained on the basis of divergent changes in weakened and dysregulated oscillators. Similar findings can be expected to occur in other accessory oscillator components that are modulated by melatonin, among them several transcription factors and metabolic sensors. Another cause of opposite effects concerns differences between nocturnally active laboratory rodents and the diurnally active human. This should be more thoroughly considered in the field of metabolic syndrome and related pathologies, especially with regard to type 2 diabetes and other aspects of insulin resistance. Melatonin was reported to impair glucose tolerance in humans, especially in carriers of the risk allele of the MT2 receptor gene, MTNR1B, that contains the SNP rs10830963. These findings contrast with numerous reports on improvements of glucose tolerance in preclinical studies. However, the relationship between melatonin and insulin may be more complex, as indicated by loss-of-function mutants of the MT2 receptor that are also prodiabetic, by the age-dependent time course of risk allele overexpression, by progressive reduction in circadian amplitudes and melatonin secretion, which are aggravated in diabetes. By supporting high-amplitude rhythms, melatonin may be beneficial in preventing or delaying diabetes.
Insights
Melatonin has complex effects, acting differently in aging cells versus cancer cells. In humans, melatonin may worsen glucose tolerance, particularly in those with a specific MTNR1B gene variant, contrasting with animal studies.
Area of Science:
- Chronobiology
- Endocrinology
- Cancer Biology
- Metabolic Syndrome Research
Background:
- Melatonin's diverse roles extend beyond sleep regulation, influencing cellular processes and metabolic health.
- Opposing effects of melatonin observed in different physiological states (e.g., aging vs. cancer) and species (rodents vs. humans) necessitate further investigation.
- The MTNR1B gene, specifically the rs10830963 SNP, is linked to human glucose metabolism and melatonin's effects.
Purpose of the Study:
- To explore the dynamic and context-dependent actions of melatonin.
- To reconcile conflicting findings regarding melatonin's impact on glucose tolerance in humans versus preclinical models.
- To elucidate the role of melatonin in aging, cancer, and metabolic syndrome, particularly type 2 diabetes.
Main Methods:
- Review and synthesis of existing literature on melatonin's effects in various cellular contexts and species.
- Analysis of gene expression patterns, including sirtuin 1, in aged and cancerous cells.
- Examination of human genetic data (MTNR1B SNP rs10830963) and its association with glucose tolerance.
Main Results:
- Melatonin upregulates sirtuin 1 in aged tissues but downregulates it in cancer cells, reflecting divergent oscillator dynamics.
- Human studies indicate melatonin can impair glucose tolerance, especially in individuals with the MTNR1B risk allele, contrasting with preclinical data.
- Melatonin's relationship with insulin resistance is complex, influenced by MT2 receptor function, genetic variations, and circadian rhythm amplitude.
Conclusions:
- Melatonin's effects are highly context-dependent, varying with cellular health, species, and genetic background.
- The contrasting effects in humans and rodents highlight the importance of species-specific considerations in melatonin research.
- Maintaining high-amplitude circadian rhythms, potentially supported by melatonin, may offer benefits in preventing or delaying type 2 diabetes.
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