Melatonin and the pathologies of weakened or dysregulated circadian oscillators

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 MT 2 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-offunction mutants of the MT 2 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. K E Y W O R D Saging, cancer, circadian, melatonin, sirtuin 1, type 2 diabetes

The case for too little melatonin signalling in increased diabetes risk

“…Our data suggested that decreased melatonin signalling through deleterious MT2 receptor activity increases type 2 diabetes risk. These conclusions were in line with various studies done in rodents, beta cells and human cohorts, which showed that high melatonin levels, or the administration of melatonin or of melatonergic agonists, lead to decreased (and not augmented) risk of diabetes [9,13,14]. Indeed, for instance, a 12 year prospective study including 370 women who developed type 2 diabetes and 370 matched control participants showed that decreased levels of melatonin secretion during the night is independently associated with a higher risk of developing type 2 diabetes [13].…”

The Underrated Circadian System and Its Contribution to Neurodegeneration in Mood Disorders

“…Additionally, the anti-inflammatory properties of the accessory oscillator component SIRT1 and the circadian regulator molecule melatonin have to be taken into account 28,29 . Notably, melatonin has been repeatedly shown to upregulate SIRT1 expression, when acting in the context of inflammation, especially neuroinflammation, and of aging, in contrast to its downregulation in cancer cells, as summarized elsewhere 28,29,45 .…”

“…These may be longer or shorter than in the general population, an observation that is by no means contradictory, but rather reflects the difficulties of the organism to be fully synchronized with the 24 h environment under either of these conditions, as soon as the so-called range of entrainment is exceeded. As the circadian system is not only based on a single master clock, but is composed of numerous central and peripheral oscillators, this can also lead to difficulties of internal synchrony between rhythms that depend to a variable degree on the hypothalamic master clock, the suprachiasmatic nucleus (SCN) and may be semi-autonomous or, in the extreme, more or less autonomous with regard to the SCN 45,46 . Misalignment of rhythms both in relation to external time cues and internally within the body may contribute to physiological problems, which, in the end, may turn into difficulties of sleep and mood disorders.…”

“…Collectively, these data strongly support a contribution of deviations in the circadian system to the etiologies of mood disorders. Notably, various of these oscillator genes, in particular, Per1, Per2, Bmal1, Clock, Npas2 and Sirt1, have been found to be modulated by melatonin 45,46,49,50 . Insofar, it is not surprising that polymorphisms of genes involved in melatonin synthesis and signaling were also reported to be associated with depressive disorders 46,51 .…”

Interactions of Melatonin and MicroRNAs

“…In melatonin research, this is an emerging field [1][2][3]. Among the multiple epigenetic changes, the contribution of microRNAs (miRNAs) as regulators of countless functions is of particular interest [4][5][6][7][8][9].…”