Melatonin is a fascinating molecule that has captured the imagination of many scientists since its discovery in 1958. In recent times, the focus has changed from investigating its natural role as a ...transducer of biological time for physiological systems to hypothesized roles in virtually all clinical conditions. This goes along with the appearance of extensive literature claiming the (generally) positive benefits of high doses of melatonin in animal models and various clinical situations that would not be receptor-mediated. Based on the assumption that melatonin is safe, high doses have been administered to patients, including the elderly and children, in clinical trials. In this review, we critically review the corresponding literature, including the hypotheses that melatonin acts as a scavenger molecule, in particular in mitochondria, by trying not only to contextualize these interests but also by attempting to separate the wheat from the chaff (or the wishful thinking from the facts). We conclude that most claims remain hypotheses and that the experimental evidence used to promote them is limited and sometimes flawed. Our review will hopefully encourage clinical researchers to reflect on what melatonin can and cannot do and help move the field forward on a solid basis.
Aim
The aim of this study was to investigate the effects of 4 consecutive simulated night shifts on glucose homeostasis, mitochondrial function and central and peripheral rhythmicities compared with ...a simulated day shift schedule.
Methods
Seventeen healthy adults (8M:9F) matched for sleep, physical activity and dietary/fat intake participated in this study (night shift work n = 9; day shift work n = 8). Glucose tolerance and insulin sensitivity before and after 4 nights of shift work were measured by an intravenous glucose tolerance test and a hyperinsulinaemic euglycaemic clamp respectively. Muscles biopsies were obtained to determine insulin signalling and mitochondrial function. Central and peripheral rhythmicities were assessed by measuring salivary melatonin and expression of circadian genes from hair samples respectively.
Results
Fasting plasma glucose increased (4.4 ± 0.1 vs. 4.6 ± 0.1 mmol L−1; P = .001) and insulin sensitivity decreased (25 ± 7%, P < .05) following the night shift, with no changes following the day shift. Night shift work had no effect on skeletal muscle protein expression (PGC1α, UCP3, TFAM and mitochondria Complex II‐V) or insulin‐stimulated pAkt Ser473, pTBC1D4Ser318 and pTBC1D4Thr642. Importantly, the metabolic changes after simulated night shifts occurred despite no changes in the timing of melatonin rhythmicity or hair follicle cell clock gene expression across the wake period (Per3, Per1, Nr1d1 and Nr1d2).
Conclusion
Only 4 days of simulated night shift work in healthy adults is sufficient to reduce insulin sensitivity which would be expected to increase the risk of T2D.
: Shorter wavelength light has been shown to be more effective than longer wavelengths in suppressing nocturnal melatonin and phase delaying the melatonin rhythm. In the present study, different ...wavelengths of light were evaluated for their capacity to phase advance the saliva melatonin rhythm. Two long wavelengths, 595 nm (amber) and 660 nm (red) and three shorter wavelengths, 470 nm (blue), 497 nm (blue/green), and 525 nm (green) were compared with a no‐light control condition. Light was administered via a portable light source comprising two light‐emitting diodes per eye, with the irradiance of each diode set at 65 μW/cm2. Forty‐two volunteers participated in up to six conditions resulting in 15 per condition. For the active light conditions, a 2‐hr light pulse was administered from 06:00 hr on two consecutive mornings. Half‐hourly saliva samples were collected on the evening prior to the first light pulse and the evening following the second light pulse. The time of melatonin onset was calculated for each night and the difference was calculated as a measure of phase advance. The shorter wavelengths of 470, 495 and 525 nm showed the greatest melatonin onset advances ranging from approximately 40–65 min while the longer wavelengths produced no significant phase advance. These results strengthen earlier findings that the human circadian system is more sensitive to the short wavelengths of light than the longer wavelengths.
There are many situations in which it would be useful to know the phase state of the biological clock. It is recognized that measurement of melatonin levels can provide this information, but ...traditionally blood has been used for the analysis, and there are many problems in extending the measurements into the home or field situations. The aim of this study was to develop and validate a salivary melatonin radioimmunoassay and to compare results obtained against a plasma assay for determining the onset of melatonin secretion. The assay developed was sensitive (4.3 pM) and required only 200 microliters of sample. A rhythm in melatonin was detected in saliva, peaking at approximately 120 pM or 30% of the plasma levels. Using an objective criterion for determining the onset of secretion (mean +/- 2 standard deviations of three daytime samples), the time of onset was shown to exhibit low intraindividual variability (coefficient of variation = 1.5%-4.3%). The time of onset determined using saliva was significantly correlated with the plasma onset (r = .70, p < .05). The onsets determined were 22:30 h +/- 22 min for the saliva and 21:50 h +/- 16 min for plasma for 17 subjects. Similarly, the acrophases of the saliva and plasma melatonin rhythms were significantly correlated. Neither posture alone nor changes in posture affected the calculation of the onset of melatonin secretion using the saliva approach. Very high saliva flow rates induced by citric acid resulted in lower melatonin concentrations compared to the gentle chewing on parafin film. These results firmly establish the use of salivary melatonin measurements for phase typing of the melatonin rhythm in humans.
The suprachiasmatic nucleus (SCN) is the site of the generation and entrainment of circadian rhythms. Similar to other structures, it develops throughout gestation but is still immature for some time ...after. This suggests that the SCN could be vulnerable to maternal influences, such as poor nutrition, stress and drugs, all of which can affect neuronal development. Evidence is accumulating that suggests that this is the case, with body size at birth influencing melatonin production in adult humans and maternal malnutrition, and stress affecting sleep in rodents. Interestingly, the maternal environment affects the phase of rhythms and the response of the circadian timing system to light pulses. The nature of these changes in adult rhythmicity is similar to those commonly associated with depression in humans. Thus, abnormal fetal programming might predispose adults to depressive illness.
There is growing evidence that the maternal environment can affect the developing circadian timing system, resulting in disordered rhythmicity in adults and predisposition to depressive illness.
Maternal nutrient restriction during critical windows of fetal development alters postnatal growth, often in a sexually dimorphic manner. Intrauterine growth restriction is frequently characterized ...by accelerated growth and increased adiposity in later life. Thyroid hormones are implicated as part of the mechanism involved in this scenario via their actions within the hypothalamic–pituitary–thyroid axis. We fed high (H = 240%) and low (L = 70%) levels of recommended daily crude protein intake during the first and second trimesters of gestation to beef heifers to investigate effects to their progeny's plasma concentrations of free and total triiodothyronine (FT3 and TT3) and thyroxine (FT4 and TT4) from birth until weaning at 191 days of age (n = 68). The study design was a two-by-two factorial. For male progeny, exposure to maternal diets low in protein during the first trimester of gestation resulted in greater FT4 at birth (P < 0.05) which was subsequent to lower concentrations of leptin in maternal plasma at 271 days of gestation compared with their high-protein–exposed counterparts. These same animals went on to have greater milk intake during the latter half of the lactation period (P < 0.05) and exhibited faster rates of average daily gain (ADG) relative to birth weight during this time (P < 0.05). For all progeny, independent of sex, exposure to low-protein maternal diets during the second trimester of gestation resulted in greater FT3 relative to TT3 at birth. Because FT3 at birth and 29 days was positively associated with ADG (P < 0.05) and ADG relative to birth weight (P < 0.05), it is proposed that FT3 plays an integral role in catch-up growth in the bovine as per other species. Protein intake during the first and second trimesters of gestation has a sexually dimorphic effect on progeny plasma thyroid hormone concentrations, and these changes are associated with altered milk intake and postnatal growth pathway.
Department of Obstetrics and Gynaecology, Adelaide
University, Medical School, Adelaide, South Australia 5005
There has been
relatively little research conducted on pineal melatonin production in
...laboratory mice, in part, due to the lack of appropriate assays. We
studied the pineal and plasma rhythm, response to light, adrenergic
stimulation, and metabolism of melatonin in CBA mice. With the use of a
sensitive and specific melatonin RIA, melatonin was detected in the
pineal glands at all times of the day >21 fmol/gland in CBA mice but
not in C57Bl mice. Both plasma and pineal melatonin levels peaked
2 h before dawn in a 12:12-h light-dark photoperiod (162 ± 31 pM and 1,804 ± 514 fmol/gland, respectively). A brief light
pulse (200 lx/15 min), 2 h before lights on, suppressed both
plasma and pineal melatonin to near basal levels within 30 min.
Exposure to light pulses 4 h after lights off or 2 h before
lights on resulted in delays and advances, respectively, in the early
morning decline of plasma and pineal melatonin on the next cycle.
Administration of the -adrenergic agonist isoproterenol (20 mg/kg) 2 and 4 h after lights on in the morning resulted in a fivefold
increase in plasma and pineal melatonin 2.5 to 3 h after the first
injection. In the mouse, unlike the rat, melatonin was shown to be
metabolized almost exclusively to 6-glucuronylmelatonin rather than
6-sulphatoxymelatonin. These studies have shown that the appropriate
methodological tools are now available for studying melatonin rhythms
in mice.
pineal gland; circadian rhythm; phase shift; 6-glucuronylmelatonin; 6-sulphatoxymelatonin
Circadian rhythms are generated through a transcription-translation feedback loop involving clock genes and the casein kinases CSNK1D and CSNK1E. In this study, we investigated the effects of the ...casein kinase inhibitor PF-670462 (50 mg/kg) on rhythmic expression of clock genes in the liver, pancreas and suprachiasmatic nucleus (SCN) as well as plasma corticosterone, melatonin and running behaviour in rats and compared them to the responses to a 4 h extension of the light phase. PF-670462 acutely phase delayed the rhythmic transcription of
Bmal1
,
Per1
,
Per2
and
Nr1d1
in both liver and pancreas by 4.5 ± 1.3 and 4.5 ± 1.2 h, respectively, 1 day after administration. In the SCN, the rhythm of
Nr1d1
and
Dbp
mRNA expression was delayed by 4.2 and 4 h, respectively. Despite these changes, the time of peak plasma melatonin secretion was not delayed, although the plasma corticosterone rhythm and onset of wheel-running activity were delayed by 2.1 and 1.1 h, respectively. These changes are in contrast to the effects of the 4 h light extension, which resulted in delays in peak expression of the clock genes of less than 1 h and no change in the melatonin or corticosterone rhythms. The ability of the casein kinase inhibitor to bring about large phase shifts in the rhythms of major metabolic target tissues may lead to new drugs being developed to rapidly phase adjust circadian rhythms to alleviate the metabolic impact of shift work.
Circadian rhythmicity is evident in a wide range of physiological systems including the reproductive axis. The recent discoveries of rhythmic clock gene expression in peripheral tissues, including ...reproductive tissue, suggests that they may play an important role in optimizing fertility. The evidence for rhythmic control of reproduction from studies in laboratory animals is reviewed and where possible this includes evidence from human studies. Clock genes are highly conserved across species including humans and there is no reason to suggest that they are functionless in humans. The challenge issued here is for researchers to probe their function and the consequences of their disruption in both animal and human reproduction.
The appearance of melatonin in saliva in concentrations up to 70% lower than those in blood has led to the suggestion that melatonin is bound to plasma protein and that saliva levels reflect the ...circulating free hormone. To test this directly, melatonin was measured in human plasma from 10 subjects after ultrafiltration through Centrifree micropartition tubes and compared to saliva melatonin levels in samples collected simultaneously. Melatonin was detected in the protein-free fraction and increased throughout the night in parallel with the saliva melatonin level. Peak concentrations ranged from 45-200 pmol/L (mean +/- SEM, 106 +/- 17 pmol/L) and averaged 23% of the total melatonin level. Across all samples, the correlation between the saliva levels and the free hormone levels was significant (r = 0.84; P < 0.05). These results provide the first direct evidence that endogenous melatonin is bound to plasma proteins and that saliva melatonin generally reflects the levels of this binding.
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