ArticlePDF AvailableLiterature Review

Abstract

Melatonin is an old and ubiquitous molecule in nature showing multiple mechanisms of action and functions in practically every living organism. In mammals, pineal melatonin function as a hormone and a chronobiotic, playing a major role in the regulation of the circadian temporal internal order. The anti-obesogen and the weight-reducing effects of melatonin depend on several mechanisms and actions. Experimental evidence demonstrates that melatonin is necessary for the proper synthesis, secretion and action of insulin. Melatonin acts by regulating GLUT4 expression and/or triggering, via its G-protein-coupled membrane receptors, the phosphorylation of the insulin receptor and its intracellular substrates mobilizing the insulin-signaling pathway. Melatonin is a powerful chronobiotic being responsible, in part, by the daily distribution of metabolic processes so that the activity/feeding phase of the day is associated to high insulin sensitivity and the rest/fasting is synchronized to the insulin resistant metabolic phase of the day. Furthermore, melatonin is responsible for the establishment of an adequate energy balance mainly by regulating energy flow to and from the stores and directly regulating the energy expenditure through the activation of brown adipose tissue and participating in the browning process of white adipose tissue. The reduction in melatonin production, as during aging, shift-work or illuminated environments during the night, induces insulin resistance, glucose intolerance, sleep disturbance and metabolic circadian disorganization characterizing a state of chronodisruption leading to obesity. The available evidence supports the suggestion that melatonin replacement therapy might contribute to restore a more healthy state of the organism.This article is protected by copyright. All rights reserved.
REVIEW ARTICLE
Melatonin, energy metabolism, and obesity: a review
Abstract: Melatonin is an old and ubiquitous molecule in nature showing
multiple mechanisms of action and functions in practically every living
organism. In mammals, pineal melatonin functions as a hormone and a
chronobiotic, playing a major role in the regulation of the circadian temporal
internal order. The anti-obesogen and the weight-reducing effects of melatonin
depend on several mechanisms and actions. Experimental evidence
demonstrates that melatonin is necessary for the proper synthesis, secretion,
and action of insulin. Melatonin acts by regulating GLUT4 expression and/or
triggering, via its G-protein-coupled membrane receptors, the phosphorylation
of the insulin receptor and its intracellular substrates mobilizing the insulin-
signaling pathway. Melatonin is a powerful chronobiotic being responsible, in
part, by the daily distribution of metabolic processes so that the activity/
feeding phase of the day is associated with high insulin sensitivity, and the
rest/fasting is synchronized to the insulin-resistant metabolic phase of the day.
Furthermore, melatonin is responsible for the establishment of an adequate
energy balance mainly by regulating energy flow to and from the stores and
directly regulating the energy expenditure through the activation of brown
adipose tissue and participating in the browning process of white adipose
tissue. The reduction in melatonin production, as during aging, shift-work or
illuminated environments during the night, induces insulin resistance, glucose
intolerance, sleep disturbance, and metabolic circadian disorganization
characterizing a state of chronodisruption leading to obesity. The available
evidence supports the suggestion that melatonin replacement therapy might
contribute to restore a more healthy state of the organism.
J. Cipolla-Neto
1
, F. G. Amaral
1
,
S. C. Afeche
2
, D. X. Tan
2
and
R. J. Reiter
3
1
Department of Physiology and Biophysics,
Institute of Biomedical Sciences, University of
S~
ao Paulo, S~
ao Paulo, Brazil;
2
Laboratory of
Pharmacology, Institute Butantan, S~
ao Paulo,
Brazil;
3
Department of Cellular and Structural
Biology, UT Health Science Center, San
Antonio, TX, USA
Key words: circadian rhythm, energy
metabolism, insulin, melatonin, obesity, review
Address reprint requests to J. Cipolla-Neto,
Department of Physiology and Biophysics,
Institute of Biomedical Sciences, University of
S~
ao Paulo, Av. Lineu Prestes, 1524, Bldg 1,
05508000 S~
ao Paulo, SP, Brazil.
E-mail: cipolla@icb.usp.br
Received March 15, 2014;
Accepted March 17, 2014.
Introduction
Melatonin (N-acetyl-5-methoxytryptamine or, according to
IUPAC, N-[2-(5-methoxy-1H-indol-3-yl) ethyl] acetamide)
is an ancient molecule ubiquitously present in nature
including both plant and animals [15]. It is well known
that in mammals, melatonin is synthesized in several cells,
tissues, and organs mainly for local utilization (autocrine
and paracrine actions) and that circulating melatonin is lar-
gely provided by the pineal gland where it is produced and
directly released to the blood and cerebrospinal fluid [69].
While pineal melatonin has all the characteristics of a
hormone, it also has features, which distinguish it from
classical hormones. It is centrally produced in an endo-
crine gland, circulates in a free and albumin-linked form
[1012], and can act through specific G-protein-coupled
membrane receptors (MT1 or MTRN1a, MT2 or
MTRN1b and MT3) [13, 14] as well as on putative nuclear
RZR/ROR retinoid receptors [1517]. Melatonin’s mem-
brane receptor-mediated mechanisms of action and its
physiological effects via those receptors have been defined
[1820]. Conversely, its mechanisms of action at the
nuclear level are less well defined [21, 22]. Melatonin’s
direct free radical scavenging actions account for its recep-
tor-independent effects [2325].
Pineal melatonin production is under control of the
paraventricular nucleus of the hypothalamus, which pro-
ject, eventually, to the intermediolateral column of the
upper thoracic segments of the spinal cord where the sym-
pathetic preganglionic neurons are located. The axons of
these neurons exit the cord and pass to the rostral third of
the superior cervical ganglia, which in turn send postgan-
glionic sympathetic projections through the conarii nerves
to the pineal gland [26, 27]. Norepinephrine is released
from these nerve endings where it interacts with b
1
and a
1
postsynaptic adrenoreceptors to trigger several intracellu-
lar transduction mechanisms that activate melatonin
synthesis in the pinealocytes [1].
The activation/deactivation of this complex neural path-
way controlling pineal melatonin synthesis is under the
precise control of the master circadian clock, the suprach-
iasmatic nucleus of the hypothalamus (SCN). Via this
pathway, melatonin production expresses a circadian
rhythm that is tightly synchronized to the light/dark cycle.
The circadian control is such that melatonin production is
always circumscribed to the night, regardless the behav-
ioral distribution of activity and rest of the considered
mammalian species (diurnal, nocturnal, or crepuscular
species), that is, it is considered the chemical expression of
darkness [28]. Moreover, high production is maintained
371
J. Pineal Res. 2014; 56:371–381
Doi:10.1111/jpi.12137
©2014 John Wiley & Sons A/S.
Published by John Wiley & Sons Ltd
Journal of Pineal Research
Molecular, Biological, Physiological and Clinical Aspects of Melatonin
during the dark phase of the light/dark cycle provided
there is no light in the environment, as light during the
night (related to the irradiance, wavelength, and duration)
blocks melatonin production [2933]. These functional
particularities of the mammalian system that control
pineal melatonin production guarantee that the circadian
clock triggers melatonin production daily at night and that
environmental light and the clock determine the duration
of the daily episode of melatonin synthesis [3436]. In this
way, given the adequate ecological and social habitat con-
ditions, the physiological system that controls melatonin
synthesis allows the nocturnal profile of circulating mela-
tonin to vary according to the duration of the daily scoto-
period reflecting therefore the season of the year and
acting as a neuroendocrine mediator of the photoperiod
[27, 37]. Because of this, the circadian melatonin rhythm
drives annual reproductive and metabolic cycles in photo-
period-sensitive mammals [3840]. In part due to the
above chronobiological characteristics of production, mel-
atonin is one of the main mediators used by the central
master clock to time central and peripheral tissues, acting
as an internal synchronizer or ‘internal zeitgeber’ [41].
Moreover, melatonin is able to act on peripheral oscilla-
tors regulating their phase and period, mainly by control-
ling the transcription/translation circadian cycle of the
peripheral clock genes [42, 43]. This functional aspect
makes melatonin one of the most important chronobiotic
[41, 44] that directly participates in the organization of the
circadian temporal coordination of physiological and
behavioral phenomena.
Melatonin and energy metabolism
All physiological and behavioral processes of the body are
organized to balance energy intake, storage, and expendi-
ture. The energy balance guarantees the individual’s sur-
vival, growth and reproduction, and, consequently, species
perpetuation. Through the adequate circadian distribution
and organization of the metabolic processes, most animals
optimize energy balance by concentrating energy harvest-
ing and intake during the active phase of the day and
mobilizing body energy stores during the resting phase in
order to produce the energy necessary to sustain the living
processes. Melatonin is the key mediator molecule for the
integration between the cyclic environment and the circa-
dian distribution of physiological and behavioral processes
and for the optimization of energy balance and body
weight regulation, events that are crucial for a healthy
metabolism [45]. In this scenario, to fully understand the
role played by melatonin in the control of energy metabo-
lism, it is necessary to address the subject from following
the perspectives: i), from the perspective of the classical
endocrinology, examining the role played by melatonin in
the regulation of metabolic processes; ii), from the per-
spective of the chronobiology, considering the role played
by melatonin in the regulation of the circadian internal
temporal order of the physiological processes involved in
energy metabolism; iii), and finally, understanding the role
played by melatonin in the regulation of energy balance
and its final outcome, that is, body weight, as a way to
sum up its regulatory role on energy metabolism.
Melatonin and the regulation of metabolic
processes
The relation between pineal gland, melatonin, and energy
metabolism was initially hinted at in both humans [46]
and rodents [47] many years ago. The very first experi-
ments [4852] demonstrated that infusion of pineal
extracts led to hypoglycemia, increased glucose tolerance,
and hepatic and muscular glycogenesis after glucose load-
ing, while pinealectomy induced a diminished glucose tol-
erance and a reduced hepatic and muscular glycogenesis.
More recently, the metabolic disruption caused by the
absence of melatonin in the pinealectomized animal was
characterized as a diabetogenic syndrome that includes
glucose intolerance and peripheral (hepatic, adipose, and
skeletal muscle) and central (hypothalamus) insulin resis-
tance [5355]. This dramatic pathological picture can be
reverted by melatonin replacement therapy or restricted
feeding [54, 56, 57], but not by physical training [5860].
Moreover, insulin resistance, glucose intolerance, and sev-
eral alterations in other metabolic parameters can be seen
in some physiological or pathophysiological states associ-
ated with reductions in blood melatonin levels, as aging,
diabetes, shift work, and environmental high level of illu-
mination during the night [6168]. It is emphasized that
adequate melatonin replacement therapy alleviates most of
the mentioned metabolic alterations in these situations.
Furthermore, a similar metabolic syndrome is seen in
MT1-knockout animals [69].
The genesis of the pinealectomy-induced insulin resis-
tance and glucose intolerance is related to the cellular con-
sequences of the absence of melatonin, such as a deficiency
in the insulin-signaling pathway and reduction in GLUT4
gene expression and protein content. The insulin-sensitive
tissues (white and brown adipose tissue and skeletal and
cardiac muscles) of the pinealectomized animal exhibit a
greater reduction in GLUT4 mRNA and microsomal and
membrane protein contents that reverts to the level of the
intact animal following adequate melatonin replacement
therapy [53, 56, 7073]. Moreover and emphasizing the
functional synergism between melatonin and insulin, it
was shown that melatonin by itself, acting through MT1
membrane receptors, induces rapid tyrosine phosphoryla-
tion and activation of the tyrosine kinase b-subunit of the
insulin receptor, and mobilizing several intracellular trans-
duction steps of the insulin-signaling pathway (tyrosine
phosphorylation of IRS-1; IRS-1/PI(3)-kinase and IRS-1/
SHP-2 associations; and downstream AKT serine, MAP-
kinase, and STAT3 phosphorylation) [7476].
One of the first direct pieces of evidence of the func-
tional synergism between melatonin and insulin was pub-
lished by Lima and coworkers two decades ago [77]. This
group showed that in vitro incubation of isolated visceral
white adipocytes with melatonin shifted the dose x
response curve for C
14
-2-deoxy-D-glucose uptake stimu-
lated by insulin to the left. This was the first demonstra-
tion that the peripheral function of insulin was potentiated
by the action of melatonin, and, in addition, it was the
first evidence of a direct action of melatonin on adipo-
cytes. This indicated that the adipose tissue is a peripheral
target of melatonin for the regulation of the overall
372
Cipolla-Neto et al.
metabolism. Similarly, Brydon et al. [78] demonstrated
that melatonin activation of MT2 receptors in human
adipocytes modulates glucose uptake by these cells.
In reference to adipose tissue physiology, it was possi-
ble to document the synergistic effect of melatonin on sev-
eral other insulin actions in addition to glucose uptake. In
a series of reports, Alonso-Vale et al. [42, 79, 80] demon-
strated that insulin-induced leptin synthesis and release in
isolated adipocytes is potentiated by the MT1-mediated
melatonin action. This potentiating effect is enhanced by
100% if the in vitro incubation with melatonin mimics its
usual 24-hr cycle; this was achieved by alternating melato-
nin-added medium for 12 hr (in vitro induced night) with
melatonin-free medium for the following 12 hr (in vitro
induced day) for 35 cycles. There are data confirming
that melatonin regulates other aspects of adipocyte
biology that influence energy metabolism, lipidemia, and
body weight, as lipolysis, lipogenesis, adipocyte differen-
tiation, and fatty acids uptake among others [42, 78,
8183].
Another major site of melatonin’s action in reference to
the regulation of energy metabolism is the pancreatic islets
where it influences insulin and glucagon synthesis and
release. MT1- and/or MT2-mediated melatonin action
decreases glucose-stimulated insulin secretion in isolated
rat pancreatic islets and rat insulinoma beta-cells [8490].
The activation of these receptors inhibits glucose- and
forskolin-induced insulin secretion showing that melatonin
acts by inhibiting the adenylate cyclase/cAMP system and
reducing the content of PKA with no alteration in the con-
tent of PKCa-subunit, in parallel to a reduction in cGMP.
In addition, through MT1 activation, melatonin induces
insulin receptor, IRS-1, AKT, ERK1/2, and STAT3 phos-
phorylation, controlling insulin synthesis and release by
islets B cells [76, 9193].
Additionally, this indolamine induces IGF-1 receptor
phosphorylation, which participates in the integrity and
trophism of islet cells [94], [76]. Moreover, it has been
demonstrated, as well, that melatonin stimulated glucagon
synthesis and secretion either in vivo or in a particular glu-
cagon-producing alpha-cell line [95, 96]. Most importantly,
however, is that these actions of melatonin are required to
build the circadian profile of insulin secretion, keeping the
daily peak allocated to the first half of the active phase of
the day and contributing to the synchronization of the
pancreas metabolic rhythms with the circadian rhythm of
activity-feeding/rest-fasting [97].
Finally, considering the physiological and pathophysio-
logical importance of the regulatory action of melatonin
on the pancreatic islet function, it has been suggested,
using genome-wide association studies, that common non-
coding variants in MTNR1B (encoding melatonin receptor
1B, also known as MT2) increase type 2 diabetes risk
[98, 99]. This is a result of a putative inadequate pancre-
atic beta-cell response to the action of melatonin on insu-
lin secretion, resulting in morning hyperglycemia. It
should be noted that insulin is able to regulate pineal mel-
atonin synthesis by potentiating norepinephrine-stimulated
melatonin production at two sensitive time points during
the night, one immediately after lights off and another just
before lights on [100, 101].
As an addition to the importance of melatonin on the
regulatory processes in energy metabolism, it was recently
demonstrated that the intrauterine metabolic program-
ming is modified if there is deficiency of melatonin in the
pregnant mother [102]. The adult offspring of melatonin-
deficient dams show glucose intolerance, insulin resistance,
and a serious impairment in the glucose-induced insulin
secretion by isolated pancreatic islets. These programming
effects disappear with the appropriate schedule of melato-
nin replacement therapy to the mothers during gestation.
Melatonin and the regulation of daily
rhythms in energy metabolism
The mammalian circadian master clock (SCN) times all
peripheral clocks and, consequently, all the physiological
and behavioral processes. This regulatory effect is accom-
plished using direct or indirect neural connections and/or
humoral/hormonal mediators. As mentioned above, mela-
tonin is one of these mediators, being one of the most
important internal synchronizing agents. As a conse-
quence, melatonin is fundamental for the maintenance of
the internal circadian temporal organization, timing many
physiological processes, including energy metabolism and
their synchronization, which is crucial for health mainte-
nance [103, 104].
The energy balance and energy metabolism are under
control of the circadian system and exhibits a clear differ-
ential 24-hr distribution [105108] (Fig. 1). The active/
wakefulness phase of the day is, typically, associated with
energy harvesting and eating that results in energy intake,
utilization, and storage. It is a period associated with high
central and peripheral sensitivity to insulin and high glu-
cose tolerance, elevated insulin secretion, high glucose
uptake by the insulin-sensitive tissues, glycogen synthesis
and glycolysis (hepatic and muscular), blockade of hepatic
gluconeogenesis, and increased adipose tissue lipogenesis
and adiponectin production. By comparison, the rest/sleep
phase of the day is characterized by the usual fasting per-
iod that requires the use of stored energy for the mainte-
nance of cellular processes. This phase of the daily cycle
exhibits insulin resistance, accentuated hepatic gluconeo-
genesis and glycogenolysis, adipose tissue lipolysis, and
leptin secretion.
Several metabolic parameters exhibit a pronounced
diurnal rhythm [109111], including blood glucose and
insulin levels. Although blood insulin and glucose levels
being correlated to the feeding schedule, their diurnal vari-
ation in fasted animals was clearly demonstrated. These
data and free-running experiments point to the possible
role of endogenous factors, in addition to environmental
ones, such as food availability, on the regulation of the
24-hr rhythmic fluctuations of energy metabolism
[112, 113]. There is experimental evidence that melatonin
and the autonomic nervous system output are among the
mediators of the circadian master clock in the regulation
of circadian glucose and insulin blood levels [114, 115].
It is well known that both humans [116120] and rats
[121] exhibit a diurnal fluctuation in response to an oral
and intravenous glucose tolerance test as well as in the
insulin tolerance test. In humans, during the first hours
373
Melatonin, energy metabolism, and obesity
after awaking, the glucose tolerance and insulin sensitivity
were reported as the highest of the day, and both dimin-
ished as the day progresses reaching their nadir at the time
of sleep onset. In rodents, a similar phenomenon is
observed, but as these animals have nocturnal habits, the
pattern of variation in glucose tolerance and insulin sensi-
tivity is in phase opposition in comparison with humans.
There are consistent experimental data showing that the
absence of melatonin cycle in the blood of pinealectomized
animals impairs the temporal organization and circadian
distribution of several metabolic functions associated with
energy metabolism, such as daily insulin secretion [97,
122], glucose tolerance and insulin sensitivity [53, 54], met-
abolic adaptations to activity/feeding and rest/fasting [54,
58, 59, 80, 123], and daily distribution of glycogen synthe-
sis and lipogenesis as opposite to those of glycogenolysis
and lipolysis [123] (Fig. 2). The picture of circadian meta-
bolic chronodisruption [113, 124] in pinealectomized ani-
mals is reversed by the appropriate melatonin replacement
therapy.
Fig. 2. Deficiency in melatonin produc-
tion leads to a state of internal circadian
desynchronization between the circadian
activity-feeding/rest-fasting rhythm and
the metabolic periods of high insulin
sensitivity and insulin resistance.
Fig. 1. Melatonin and the circadian
control of energy metabolism. An adequate
diurnal profile of plasma melatonin is
important for the maintenance of the
circadian synchronization between the
activity-feeding/rest-fasting rhythm and
the necessary metabolic physiological
processes that subsides the proper intake,
storage, and expenditure of energy.
374
Cipolla-Neto et al.
To emphasize this critical role of melatonin, it is docu-
mented that the adult offspring of pinealectomized dams
experience a misalignment of their circadian rhythms of
energy metabolism by misplacing gluconeogenesis predom-
inance to the active/feeding daily phase. Rhythmic melato-
nin replacement therapy to the pregnant mothers
completely eliminates this dyssynchrony [102].
Other hormones that exert powerful influences on cellu-
lar metabolism, for example, glucocorticoids, growth hor-
mone, and catecholamines, also show circadian rhythmic
fluctuations in their secretion and action. One of the puta-
tive roles of melatonin in the circadian organization of the
metabolic processes is to prepare and modify the central
and peripheral metabolic tissues to respond to several of
those hormones [79, 125].
The importance of melatonin in the timing of circadian
metabolic processes was confirmed in an in vitro adipocyte
preparation subjected to 24-hr rhythmic melatonin expo-
sure [42]. In this experimental setup, melatonin was added
to the preparation media in a rhythmic fashion so that the
cells were exposed to alternating periods of 12 hr with
melatonin followed by 12 hr of an absence of melatonin;
this was repeated for four cycles. Under these conditions,
melatonin synchronized the expression of clock genes, par-
ticularly Bmal1, Clock, and Per1. More interesting, how-
ever, was that important metabolic functions of the
adipocytes were synchronized by the rhythmic addition of
melatonin so that during the in vitro induced night (mela-
tonin present for 12 hr) high lipogenesis, incorporation of
glucose into lipids, high fatty acid incorporation, and low
lipolysis were observed. During the in vitro induced sub-
jective day (12 hr of absence of melatonin), the opposite
was observed.
Melatonin and the regulation of energy
balance and obesity
Figure 3 shows the classical energy balance cycle and the
putative points of action of melatonin. A precondition of
life is being able to balance energy intake, storage, and
expenditure, and it is the net result of this balance that
determines the final body weight. When energy intake
exceeds energy expenditure, overweight and obesity are
the consequence. The postulated anti-obesogenic effect of
melatonin is, in part, a result of its regulatory role on the
balance of energy, acting mainly on the regulation of the
energy flux to and from the stores and in energy expendi-
Fig. 3. Melatonin and the regulation of energy balance. Melato-
nin regulates the flow of energy to and from the energy stores
and, in particular, regulates energy expenditure controlling the
size and activity of the brown adipose tissue as well the browning
process of the white adipose tissue.
Fig. 4. Summary of metabolic and chronobiological actions of
melatonin resulting in the regulation of energy metabolism, energy
balance, and ultimately body weight.
Fig. 5. Consequences of the absence or reduction in melatonin
production. The consequences are of two types: those related to
the metabolism leading to insulin resistance, glucose intolerance,
and dyslipidemia; and those related to circadian synchronization
of metabolic processes leading to chronodisruption.
375
Melatonin, energy metabolism, and obesity
ture. Moreover, its association with all the physiological
processes typical of the daily activity-wakefulness/rest-
sleep rhythm may impact body weight.
In spite of the well-defined regulatory action of melatonin
on the seasonal variation in food intake and body weight
[126130], herein we concentrate the discussion on the role
of melatonin on the day-by-day control of body weight.
Unpublished observations from our group show that, in
rats, long-term pinealectomy leads to overweight and that
daily rhythmic melatonin replacement therapy completely
reverses this effect (Castro, C. L., Ferreira, S. G., Scialfa,
J. H., and Cipolla-Neto, J.).
Additionally, however, it was demonstrated that even
with an intact pineal production of melatonin, melatonin
supplementation therapy in young animals reduces long-
term body weight gain (roughly by 25%) and the size of
the visceral fat deposits (by 50%) [131]. These effects were
not dependent on a reduction in food intake. The same
anti-obesity protective effect of melatonin was seen in
experiments of diet-induced obesity [132, 133].
The anti-obesogen and the weight-reducing effects of
melatonin supplementation therapy are clearly seen in
another experimental model as well, that is, the aging ani-
mal. When middle aged (10 months), already fat animals,
monitored to old age (22 months), were supplemented
with melatonin in the drinking water [61, 134137], they
showed a significant reduction in body mass and intra-
abdominal visceral fat. The reduced body weight, already
apparent within 2 wk, persisted throughout the study per-
iod (14 wk) and disappeared with the interruption of mel-
atonin administration. It is important to stress that the
body weight and abdominal visceral fat reductions were
not dependent on either the decreased food intake or on
alteration (compared with the age-matched control group)
of any other hormones that could influence energy metab-
olism, for example, testosterone, total thyroxine (T4), total
triiodothyronine (T3), or insulin-like growth factor I
(IGF-I). The exceptions were nonfasted plasma insulin
and plasma leptin levels, which dropped in melatonin-trea-
ted animals.
This study also demonstrated that, in addition to an
increase in the nocturnal locomotor activity by 19% (see
also, [138]), the treated rats showed an increase in the core
body temperature, indicating a putative rise in energy expen-
diture rather than a reduction in the energy intake. This ele-
vation in core body temperature is consistent with a rise in
the energy expenditure dependent on the trophic and metab-
olism-activating effect of melatonin in the brown adipose tis-
sue (BAT) and in the browning of the white adipose tissue
[139143]. Recently, Tan et al. [131] suggested the potential
involvement of brown adipose tissue as a factor whereby
animals lose weight in response to melatonin administration
(and gain weight when there is a deficiency of melatonin).
BAT has high metabolic activity and is responsible for non-
shivering thermogenesis; as a result, BAT burns large num-
bers of calories for the purpose of heat production, thereby
consuming glucose and fatty acids and limiting fat deposi-
tion [144]. Moreover, BAT seems to be of crucial importance
in the regulation of glycemia, lipidemia, and insulin sensitiv-
ity [145, 146]. As BAT is present in adult humans [147, 148],
the observed effect of melatonin as a weight-reducing agent
in rodents may be applicable to humans as recently sug-
gested [131].
It should be noted that during the aging process, the
insulin-signaling pathway is impaired, which accounts for
the appearance of insulin resistance and glucose intoler-
ance that might be partially responsible for the observed
age-associated weight gain. Related to this, we recently
demonstrated [149] that the rhythmic melatonin supple-
mentation treatment of aged rats provoked a full recovery
of central (hypothalamus) and peripheral (liver, adipose,
and skeletal muscle tissues) insulin signaling well before
any detectable concurrent weight loss. In addition, melato-
nin supplementation of aging rats improves considerably
the metabolic and body weight reduction beneficial effects
of physical training [57].
In summary, it seems that the adequate supplementation
of melatonin lowers body weight and body weight gain as
well as the intra-abdominal visceral fat deposition. This
might be the result of the re-establishment of the circadian
distribution of energy metabolism, the recovery of insulin
signaling, the consequent disappearance of insulin resistance
and glucose intolerance and, most importantly, the accentu-
ation of the energy expenditure over the energy intake,
resulting in weight loss and stabilization of weight gain.
Concluding Remarks
Melatonin is the key mediator molecule in the integration
between the cyclic environment and the circadian distribu-
tion of physiological and behavioral processes necessary
for a healthy metabolism and for the optimization of
energy balance and body weight regulation (Fig. 4). Mela-
tonin acts by potentiating central and peripheral insulin
action either due to regulation of GLUT4 expression or
triggering the insulin-signaling pathway. Thus, it induces,
via its G-protein-coupled membrane receptors, the phos-
phorylation of the insulin receptor and its intracellular
substrates. Melatonin is a powerful chronobiotic influenc-
ing, among others, the circadian distribution of metabolic
processes synchronizing them to the activity-feeding/rest-
fasting cycle. Melatonin is responsible for the establish-
ment of an adequate energy balance mainly by regulating
energy flow to and from the stores and directly regulating
the energy expenditure through the activation of brown
adipose tissue. Additionally, melatonin causes the brown-
ing of the white adipose tissue, thereby aiding in regulating
Fig. 6. The deficiency in melatonin production, as in aging, shift-
work and illuminated environments during the night, induces
insulin resistance, glucose intolerance, sleep disturbance, and met-
abolic circadian disorganization characterizing a state of chrono-
disruption and metabolic disorders that constitute a vicious cycle,
aggravating the health condition and leading to obesity.
376
Cipolla-Neto et al.
body weight. The absence or reduction in melatonin pro-
duction (Fig. 5), as during aging, shift-work or illuminated
environments during the night, induces insulin resistance,
glucose intolerance, sleep disturbance, and metabolic cir-
cadian disorganization characterizing a state of chronodis-
ruption and metabolic diseases that constitute a vicious
cycle (Fig. 6), aggravating overall health and leading to
obesity. The available evidence supports the suggestion
that melatonin replacement therapy, if adequately carried
out (in terms of dose, formulation, and time of the day of
administration), might prevent and/or contribute to the
elimination of the above pathologies and restore a more
healthy state to the organism.
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Melatonin, energy metabolism, and obesity
... Its production is controlled by the light-dark cycle; exposure to light blocks its secretion. There is no storage of melatonin in the body and, therefore, its plasma levels reflect pineal activity 7,8 . The main role of melatonin is to act as an endogenous synchronizer of central and peripheral tissues 7 . ...
... There is no storage of melatonin in the body and, therefore, its plasma levels reflect pineal activity 7,8 . The main role of melatonin is to act as an endogenous synchronizer of central and peripheral tissues 7 . In addition to its fundamental role in promoting sleep, melatonin has antioxidant, oncostatic, anti-apoptotic and immunomodulatory effects 8 . ...
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Objectives: Night-shift work has been associated with several negative effects on worker’s health, possibly due to circadian desynchronization, sleep deprivation and suppression of nocturnal melatonin secretion including exposure to light during the work shift. The objective of this study was to evaluate the impact of fixed night-shift work versus day-shift work on the sleep-wake cycle and on the night and day levels of cortisol and melatonin. Material and Methods: Saliva samples were obtained from 36 individuals, 19 day workers (12 women and 7 men) and 17 night workers (12 women and 5 men) from a university hospital in southern Brazil, with no history of chronic diseases. Demographic and personal information were obtained through a self-administered questionnaire and sleep information by the Munich chronotype questionnaire. Results: Salivary cortisol showed normal circadian rhythm in day- and night-shift workers, but was attenuated in night-shift workers during their working hours and on leave days. Night workers sleep fewer hours at night and have higher negative social jet lag than day workers. Conclusion: Intervals between night shifts can be beneficial for the recovery of the hypothalamic-pituitary-adrenal axis, minimizing the negative effects on workers’ health, in addition to a preventive approach to aspects related to sleep hygiene and healthy life habits.
... In addition, independent of sleep duration, poor sleep quality-a common characteristic of the late chronotype pattern-seems to be associated with excessive weight. 99 Cipolla-Neto et al 100 found that the decrease in melatonin secretion predisposes one to obesity through the dysregulation of energy balance and brown adipose tissue. The melatonin production mechanism is mediated by diurnal and nocturnal light exposure, 101,102 and melatonin secretion usually starts when light diminishes and ends before sunrise. ...
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Context Recent studies show that dietary habits and obesity seem to be influenced by chronotype, which reflects an individual’s preference for the timing of sleeping, eating, and activity in a 24-hour period. Objective This review aimed to analyze the association of chronotype with dietary habits, namely energy and macronutrient intakes, meal timing, and eating patterns, as well as with obesity. Data Sources PubMed/MEDLINE, LILACS, and Google Scholar databases were searched between 2004 and 2020. Study selection was performed by 2 authors independently; disagreements on eligibility of articles were resolved by a third author. After assessment of 12 060 abstracts, 43 studies (21 articles on obesity; 13 on food consumption, meal timing, and eating patterns; and 9 that addressed both obesity and dietary behavior) were included. Data Extraction A standard form was used to extract study design, country, number of participants, method of chronotype determination, and main findings. Data Analysis Approximately 95% of included studies showed an association between eveningness and at least 1 unhealthy eating habit. Morningness was associated with regular consumption of fresh and minimally processed foods. In addition, about 47% of studies showed a higher association between late types and obesity. Conclusion Late types are more likely to present unhealthy eating habits, such as eating late at night, skipping breakfast often, and eating processed/ultraprocessed foods, while early types are more likely to have healthy and protective habits, such as eating early and eating predominantly fresh/minimally processed foods. Intermediate types tend to have a pattern of health and eating more similar to early types than to late types. Late types are also more likely to present higher weight and body mass index than early or intermediate types. Systematic Review Registration PROSPERO registration no. CRD42021256078.
... Typically, melatonin is synthesised from tryptophan (Trp) and regulates circadian and seasonal rhythms [7]. It is also involved in energy and glucose metabolism [8,9] and immune function [10,11], and has multiple extraordinary functions such as antioxidant, antiinflammatory and antitumour activity [12][13][14]. Thus, melatonin is regarded as a cornucopia of the 21st century [14]. ...
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Aims/hypothesis It has been shown that melatonin plays a general beneficial role in type 2 diabetes in rodents but its role in humans is controversial. In the present study, we investigated the association between serum melatonin and type 2 diabetes risk in a southern Chinese population in a case–control study. We also examined the role of gut microbiota in this relationship. Methods Individuals with type 2 diabetes (cases) and healthy individuals (controls) (n=2034) were recruited from a cross-sectional study and were matched for age and sex in a case–control study. The levels of serum melatonin were measured and the association between serum melatonin and type 2 diabetes risk was examined using a multivariable logistic regression model. We further conducted a rigorously matched case–control study (n=120) in which gut microbial 16S rRNA was sequenced and metabolites were profiled using an untargeted LC-MS/MS approach. Results Higher levels of serum melatonin were significantly associated with a lower risk of type 2 diabetes (OR 0.82 [95% CI 0.74, 0.92]) and with lower levels of fasting glucose after adjustment for covariates (β −0.25 [95% CI −0.38, −0.12]). Gut microbiota exhibited alteration in the individuals with type 2 diabetes, in whom lower levels of serum melatonin, lower α- and β-diversity of gut microbiota (p<0.05), greater abundance of Bifidobacterium and lower abundance of Coprococcus (linear discriminant analysis [LDA] >2.0) were found. Seven genera were correlated with melatonin and type 2 diabetes-related traits; among them Bifidobacterium was positively correlated with serum lipopolysaccharide (LPS) and IL-10, whereas Coprococcus was negatively correlated with serum IL-1β, IL-6, IL-10, IL-17, TNF-α and LPS (Benjamini–Hochberg-adjusted p value [false discovery rate (FDR)] <0.05). Moreover, altered metabolites were detected in the participants with type 2 diabetes and there was a significant correlation between tryptophan (Trp) metabolites and the melatonin-correlated genera including Bifidobacterium and Coprococcus (FDR<0.05). Similarly, a significant correlation was found between Trp metabolites and inflammation factors, such as IL-1β, IL-6, IL-10, IL-17, TNF-α and LPS (FDR<0.05). Further, we showed that Trp metabolites may serve as a biomarker to predict type 2 diabetes status (AUC=0.804). Conclusions/interpretation A higher level of serum melatonin was associated with a lower risk of type 2 diabetes. Gut microbiota-mediated melatonin signalling was involved in this association; especially, Bifidobacterium- and Coprococcus-mediated Trp metabolites may be involved in the process. These findings uncover the importance of melatonin and melatonin-related bacteria and metabolites as potential therapeutic targets for type 2 diabetes. Graphical abstract
... Одна из важных функций этого гормона в циркадианной организации метаболических процессов -подготовка центральных и периферических тканей к адекватному ответу на дневной выброс ряда гормонов, например, инсулина и глюкокортикоидов [48]. В частности, если немедленный эффект мелатонина на толерантность к глюкозенегативный, он обусловлен ингибированием аденилатциклазы, уменьшением количества вторичного посредника цАМФ и угнетением секреции инсулина; то отсроченный эффект, проявляющийся после снижения его концентрации в крови -наоборот, направлен на повышение чувствительности тканей к инсулину и рост глюкозотолерантности [49]. Сходным образом мелатонин регулирует синтез и секрецию половых гормонов. ...
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Sleep restriction and sleep disturbances are very common in modern industrialized societies, increasing the risk for the development of chronic sleep deficiency in the long term. Sleep disturbances are known to affect cognitive functions, primarily, working memory - the ability to store, update, and manipulate information over brief intervals for use in complex cognitive problems solving. However, the specific mechanisms underlying the decline in working memory due to disturbed sleep are still unclear. Since insufficient or disturbed sleep affects the physiological and endocrine processes involved in the regulation of carbohydrate metabolism, the authors hypothesize that the effect of sleep disturbances on working memory may be due to changes in glucose metabolism; also the review discusses the mechanisms mediating the effect of sleep disturbances on glucose tolerance and provides data on the dependence of working memory on changes in carbohydrate metabolism.
... MEL also ameliorates the energy charge and may maintain an adequate cellular ATP reserve in the heart tissue (Cimen et al., 2017). Moreover, it contributes to the regulation of metabolism and the energy balance of the organism (Cipolla-Neto et al., 2014). Furthermore, MEL ingestion enhances the aerobic tolerance and improves the physical performance (Beck et al., 2018;Cheikh et al., 2018Cheikh et al., , 2020. ...
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Background: While the promotion of the beneficial effects of melatonin (MEL) ingestion on the modulation of oxidative stress is widespread, less attention is given to the biological influence that it could exert on the results of hematology and clinical chemistry parameters. This study was undertaken to assess the effects of acute MEL ingestion on these parameters during a maximal running exercise. Methods: In double blind randomized design, 12 professional soccer players [age: 17.54 ± 0.78 yrs, body mass: 70.31 ± 3.86 kg, body height: 1.8 ± 0.08 m; maximal aerobic speed (MAS): 16.85 ± 0.63 km/h; mean ± standard deviation], all males, performed a diurnal (17:00 h ± 30 h) running exercise test (RET) at 100% of their MAS following either MEL or placebo ingestion. Blood samples were obtained at rest and following the RET. Results: Compared to placebo, MEL intake decreased post-exercise biomarkers of liver damage (aspartate aminotransferase, p<0.001; alanine aminotransferase, p<0.001; gamma-glutamyltransferase; p<0.05) and improved post-exercise renal function markers (i.e., creatinine, p<0.001). However, lipid profile, glucose, lactate and leukocyte were not affected by MEL ingestion. Regarding the time to exhaustion, no difference was found between MEL (362.46 ± 42.06 s) and PLA (374.54 ± 57.97 s) conditions. Conclusion: The results of this investigation clearly attest that MEL ingestion before a maximal running exercise might protect athletes from liver damage and perturbation in renal function biomarkers. However, this study comprises an acute MEL supplementation and no assessment on chronic effects or circadian rhythm the day before was done.
... Melatonin is the main hormone produced by the pineal gland in vertebrate animals. Among its functions, melatonin synchronizes the circadian rhythm, initiates immune function, prolongs lifespan, and prevents tumor progression and cancer cell growth; it is a strong antioxidant and hydroxyl radical scavenger (Cipolla-Neto et al. 2014;Manchester et al. 2015). However, the research progress on melatonin in plants, especially in fruits and vegetables, has been slow. ...
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Melatonin has attracted widespread attention after its discovery in higher plants. Tomato is a key model economic crop for studying fleshy fruits. Many studies have shown that melatonin plays important role in plant stress resistance, growth, and development. However, the research progress on the role of melatonin and related mechanisms in tomatoes have not been systematically summarized. This paper summarizes the detection methods and anabolism of melatonin in tomatoes, including (1) the role of melatonin in combating abiotic stresses, e.g., drought, heavy metals, pH, temperature, salt, salt and heat, cold and drought, peroxidation hydrogen and carbendazim, etc., (2) the role of melatonin in combating biotic stresses, such as tobacco mosaic virus and foodborne bacillus, and (3) the role of melatonin in tomato growth and development, such as fruit ripening, postharvest shelf life, leaf senescence and root development. In addition, the future research directions of melatonin in tomatoes are explored in combination with the role of melatonin in other plants. This review can provide a theoretical basis for enhancing the scientific understanding of the role of melatonin in tomatoes and the improved breeding of fruit crops.
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Melatonin, a phylogenic conserved molecule, presents in almost all living organisms and it is believed to be originated to protect the unicellular organisms from oxidative products which were emerged from aerobic respiration. Even with the acquisition of a variety of other functions along evolution, the crucial autocrine, paracrine and endocrine actions of melatonin in the regulation of cell biology were well preserved. The molecular mechanisms involved in the cell cycle that determine survival and death need to be tightly regulated. Changes in these mechanisms can trigger pathologies that compromise the entire balance of the body. In this context, melatonin acts on cellular homeostasis by regulating the main molecular mechanisms that sustain life and control death, such as synthesis and degradation of protein, energy supply and pathways which trigger death to remove the defective cell or any microorganism from the tissues. Thus, this review aims to briefly present the action mechanisms of melatonin, in addition to discussing its fundamental role in cellular processes such as synthesis and degradation of protein, mitochondrial function and cell death control.
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Environmental cues synchronize endogenous rhythms of many physiological processes such as hormone synthesis and secretion. Little is known about the diurnal pattern of hormones and gene expression of the Callinectes sapidus molt cycle. We aimed to investigate in the eyestalk and hepatopancreas of premolt and intermolt C. sapidus the following parameters: 1) the diurnal expression of the ecdysteroid receptor CasEcR isoforms, and the molt inhibiting hormone CasMIH; 2) the diurnal hemolymph ecdysteroid and melatonin levels; and 3) melatonin effects on the transcripts of the above-mentioned genes in intermolt C. sapidus. Ecdysteroid levels were higher in the premolt than the intermolt animals at all time points evaluated (ZTs). Premolt crabs displayed a variation of ecdysteroid concentration between time points, with a reduction at ZT17. No difference in the melatonin level was seen in either molt stage or between stages. In the eyestalk of intermolt animals, CasEcR expression oscillated, with a peak at ZT9, and premolt crabs have a reduction at ZT9; CasMIH transcripts did not vary along 24h in either molt stage. Moreover, the evaluated eyestalk genes were more expressed at ZT9 in the intermolt than the premolt crabs. In the hepatopancreas, CasEcR expression showed a peak at ZT9 in premolt crabs. Exogenous melatonin (10−7 mol/animal) reduced the expression of both genes in the eyestalk at ZT17. In the hepatopancreas, melatonin markedly increased the expression of the CasEcR gene at ZT9. Taken altogether, our results are pioneer in demonstrating the daily oscillation of gene expression associated to molt cycle stages, as well as the daily ecdysteroid and melatonin levels and the remarkable influence of melatonin on the molt cycle of C. sapidus.
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Background: Shift work may be associated with insulin resistance. Objective: This study aimed to investigate the potential association between shift work and the homeostatic model assessment of insulin resistance (HOMA-IR) index in professional drivers. Method: A total of four hundred fifty-three professional drivers were invited to participate in the study within a periodic medical examination in the occupational setting. One hundred seventy-seven daytime workers were compared with 175 night shifts and 101 early morning shift drivers. Demographic, occupational, and medical examination including blood pressure, anthropometric data was assessed. Measurement of serum insulin, fasting blood glucose and lipid profile were done for all drivers. Results: Compared with day workers, night shift and early morning shift drivers displayed higher levels of HOMA-IR. Metabolic syndrome was found to be significantly increased in night workers. In linear regression analysis, insulin resistance was correlated with shift work independently of demographic and occupational characteristics. Conclusion: The study revealed that shift work could be a risk factor in developing the risk of metabolic syndrome and insulin resistance. Suggestively, health strategies such as structured lifestyle counseling in occupational health settings are warranted to improve and modify cardiometabolic risk factors.
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Psoriasis is an inflammatory and auto-immune skin-disease characterized by uncontrolled keratinocyte proliferation. Its pathogenesis is not still fully understood; however, an aberrant and excessive inflammatory and immune response can contribute to its progression. Recently, more attention has been given to the anti-inflammatory and immunomodulators effects of melatonin in inflammatory diseases. The aim of this paper was to investigate the effect of melatonin on psoriatic phenotype and also in S. aureus infection-associated psoriasis, with an in vitro model using Skinethic Reconstructed Human Epidermis (RHE). An in vitro model was constructed using the RHE, a three-dimensional-model obtained from human primary-keratinocytes. RHE-cells were exposed to a mix of pro-inflammatory cytokines, to induce a psoriatic phenotype; cells were also infected with S. aureus to aggravate psoriasis disease, and then were treated with melatonin at the concentrations of 1 nM, 10 nM, and 50 nM. Our results demonstrated that melatonin at higher concentrations significantly reduced histological damage, compared to the cytokine and S. aureus groups. Additionally, the treatment with melatonin restored tight-junction expression and reduced pro-inflammatory cytokine levels, such as interleukin-1β and interleukin-12. Our results suggest that melatonin could be considered a promising strategy for psoriasis-like skin inflammation, as well as complications of psoriasis, such as S. aureus infection.
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The pineal gland participates in the internal temporal organization of the vertebrate organism by the rhythmic synthesis of its hormone melatonin. This hormone is considered the darkness hormone because of its unique feature of being synthesized exclusively at night, regardless of the organism activity pattern. The presence and absence of this indolamine help to mark, respectively, dark and light time, i.e., night and day, to the organism. Moreover, the daily duration of the secretory episode of melatonin, synchronized to the duration of the night in the environment, times the several physiological regulatory processes in order to adapt the organism to the annual seasonal environmental variation. The mechanisms of melatonin production are different among the several classes of vertebrates. In fishes, amphibians, some reptiles and birds, the pineal gland is photosensitive, whereas in mammals the photosensitivity is absent. In this case, the light periodical information is conveyed to the gland through a neural pathway that originates in the retina, projects to the hypothalamic suprachiasmatic region, including the suprachiasmatic nuclei (the circadian biological clock in vertebrates) and, then, indirectly to the pineal gland. The signal that stimulates melatonin synthesis during the dark period of the daily light/dark cycle, in mammals, is the neurotransmitter noradrenaline, which is released from the sympathetic terminals of neurons whose cell body are located in the superior cervical ganglia. This transmitter interacts with adrenoreceptors in the pinealocytes membrane, resulting in cAMP and calcium elevation that induces melatonin synthesis. The signaling cascade that involves cAMP triggers and/or increases the arylalkylamine N-acetyltransferase transcription and translation, as well as its activation by phosphorylation and association with 14-3-3 protein. This enzyme converts serotonin into N-acetylserotonin that is then transformed by hydroxyindole-O-methyltransferase into melatonin. These two steps occur only at night. Melatonin, immediately after being synthesized, is released to the systemic circulation and it influences almost every physiological function in the organisms. It regulates the circadian clock, rest-activity and wake-sleep cycles, immunological system, energy metabolism and many other functions. Melatonin also influences the seasonal rhythms through the variation observed in its plasmatic profile duration according to the length of night. Among the seasonal physiological functions modulated by melatonin are reproduction, immune response, and metabolic adaptations and weight. Melatonin is an ancestral molecule as it appears soon in the evolutionary chain and it is ubiquitous in the living organisms. It seems that early in evolution melatonin could have had an anti-oxidative role, protecting the primitive life from the possible oxidation process mainly dependent on light and aerobiosis. This property is still conserved by its intracellular direct interaction with other molecules involved in oxidation. Besides, melatonin has its proper receptors, known as MT1, MT2 and MT3 which are found in the central nervous system and peripheral organs. Thus, melatonin is part of a photo-neuroendocrine temporal system, which adapts the organisms to the external environmental cyclic fluctuations, like day and night and the seasons, regulating most of the physiological regulatory processes, including insulin synthesis and action, playing a putative role in the pathophysiology of diabetes mellitus.
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Historically, the direct release of pineal melatonin into the capillary bed within the gland has been accepted as the primary route of secretion. Herein, we propose that the major route of melatonin delivery to the brain is after its direct release into the cerebrospinal fluid (CSF) of the third ventricle (3V). Melatonin concentrations in the CSF are not only much higher than in the blood, also, there is a rapid nocturnal rise at darkness onset and precipitous decline of melatonin levels at the time of lights on. Because melatonin is a potent free radical scavenger and antioxidant, we surmise that the elevated CSF levels are necessary to combat the massive free radical damage that the brain would normally endure because of its high utilization of oxygen, the parent molecule of many toxic oxygen metabolites, i.e., free radicals. Additionally, the precise rhythm of CSF melatonin provides the master circadian clock, the suprachiasmatic nucleus, with highly accurate chronobiotic information regarding the duration of the dark period. We predict that the discharge of melatonin directly into the 3V is aided by a number of epithalamic structures that have heretofore been overlooked; these include interpinealocyte canaliculi and evaginations of the posterodorsal 3V that directly abut the pineal. Moreover, the presence of tanycytes in the pineal recess and/or a discontinuous ependymal lining in the pineal recess allows melatonin ready access to the CSF. From the ventricles melatonin enters the brain by diffusion and by transport through tanycytes. Melatonin-rich CSF also circulates through the aqueduct and eventually into the subarachnoid space. From the subarachnoid space surrounding the brain, melatonin penetrates into the deepest portions of the neural tissue via the Virchow–Robin perivascular spaces from where it diffuses into the neural parenchyma. Because of the high level of pineal-derived melatonin in the CSF, all portions of the brain are better shielded from oxidative stress resulting from toxic oxygen derivatives.
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The insulin/insulin-like growth factor-1 (IGF-1) signalling pathways are present in most mammalian cells and play important roles in the growth and metabolism of tissues. Most proteins in these pathways have also been identified in the β-cells of the pancreatic islets. Tissue-specific knockout of the insulin receptor (βIRKO) or IGF-1 receptor (βIGFRKO) in pancreatic β-cells leads to altered glucose-sensing and glucose intolerance in adult mice, and βIRKO mice show an age-dependent decrease in islet size and β-cell mass. These data indicate that these receptors are important for differentiated function and are unlikely to play a major role in the early growth and/or development of the pancreatic islets. Conventional insulin receptor substrate-1 (IRS-1) knockouts manifest growth retardation and mild insulin resistance. The IRS-1 knockouts also display islet hyperplasia, defects in insulin secretory responses to multiple stimuli both in vivo and in vitro, reduced islet insulin content and an increased number of autophagic vacuoles in the β-cells. Re-expression of IRS-1 in cultured β-cells is able to partially restore the insulin content indicating that IRS-1 is involved in the regulation of insulin synthesis. Taken together, these data provide evidence that insulin and IGF-1 receptors and IRS-1, and potentially other proteins in the insulin/IGF-1 signalling pathway, contribute to the regulation of islet hormone secretion and synthesis and therefore in the maintenance of glucose homeostasis.
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Pineal melatonin secretion declines with aging, whereas visceral fat, plasma insulin, and plasma leptin tend to increase. We have previously demonstrated that daily melatonin administration at middle age suppressed male rat intraabdominal visceral fat, plasma leptin, and plasma insulin to youthful levels; the current study was designed to begin investigating mechanisms that mediate these responses. Melatonin (0.4 μg/ml) or vehicle was administered in the drinking water of 10-month-old male Sprague Dawley rats (18/treatment) for 12 weeks. Half (9/treatment) were then killed, and the other half were submitted to cross-over treatment for an additional 12 weeks. Twelve weeks of melatonin treatment decreased (P < 0.05) body weight (BW; by 7% relative to controls), relative intraabdominal adiposity (by 16%), plasma leptin (by 33%), and plasma insulin (by 25%) while increasing (P < 0.05) locomotor activity (by 19%), core body temperature (by 0.5 C), and morning plasma corticosterone (by 154%), restoring each of ...
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Although brown adipose tissue in infants and young children is important for regulation of energy expenditure, there has been considerable debate on whether brown adipose tissue normally exists in adult humans and has physiologic relevance in this population. In the last decade, radiologic studies in adults have identified areas of adipose tissue with high 18F-fluorodeoxyglucose (18F-FDG) uptake, putatively identified as brown fat. This radiologic study assessed the presence of physiologically significant brown adipose tissue among 1972 adult patients who had 3640 consecutive 18F-FDG positron-emission tomographic and computed tomographic whole-body scans between 2003 and 2006. Brown adipose tissue was defined as areas of tissue that were more than 4 mm in diameter, had the CT density of adipose tissue, and had maximal standardized uptake values of 18F-FDG of at least 2.0 gm per mL. A sample of 204 date-matched patients without brown adipose tissue served as the control group. Using these criteria, positron-emission tomographic and computed tomographic scans identified brown adipose tissue in 106 of the 1972 patients (5.4%). The most common location for substantial amounts of brown adipose tissue was the region extending from the anterior neck to supraclavicular region. Immunohistochemical staining for uncoupling protein 1 in this region confirmed the identity of immunopositive, multilocular adipocytes as brown adipose tissue. More brown adipose tissue was detected in women (7.5% [76/1013]) than in men (3.1% [30/959]); the female:male ratio was 2.4:1.0 (P 64) (P 64 years) (P for trend = 0.007). These findings show that functional brown adipose tissue is prevalent in adult humans, and significantly more frequently in women. The inverse correlation of body mass index with the amount of brown adipose tissue, especially in older patients, suggests to the investigators a possible role of brown adipose tissue in protecting against obesity.
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Several reports have demonstrated that the pineal hormone, melatonin, plays an important role in body mass regulation in mammals. To date, however, the target tissues and relevant biochemical mechanisms involved remain uncharacterized. As adipose tissue is the principal site of energy storage in the body, we investigated whether melatonin could also act on this tissue. Semiquantitative RT-PCR analysis revealed the expression of MT1 and MT2 melatonin receptor mRNAs in the human brown adipose cell line, PAZ6, as well as in human brown and white adipose tissue. Binding analysis with 2-[¹²⁵I]iodomelatonin (¹²⁵I-Mel) revealed the presence of a single, high affinity binding site in PAZ6 adipocytes with a binding capacity of 7.46 ± 1.58 fmol/mg protein and a Kd of 457 ± 5 pm. Both melatonin and the MT2 receptor-selective antagonist, 4-phenyl-2-propionamidotetraline, competed with 2-[¹²⁵I]iodomelatonin binding, with respective Ki values of 3 × 10⁻¹¹ and 1.5 × 10⁻¹¹m. Functional expression of melatonin receptors in PAZ6 adipocytes was indicated by the melatonin-induced, dose-dependent inhibition of forskolin-stimulated cAMP levels and basal cGMP levels with IC50 values of 2 × 10⁻⁹ and 3 × 10⁻¹⁰m, respectively. Modulation of the cGMP pathway by melatonin further supports functional expression of MT2 receptors, as this pathway was shown to be specific for that subtype in humans. In addition, long-term melatonin treatment of PAZ6 adipocytes was found to decrease the expression of the glucose transporter Glut4 and glucose uptake, an important parameter of adipocyte metabolism. These results suggest that melatonin may act directly at MT2 receptors on human brown adipocytes to regulate adipocyte physiology.
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The reactions of N 1‐acetyl‐N 2‐formyl‐5‐methoxykynuramine (AFMK) and N 1‐acetyl‐5‐methoxykynuramine (AMK) with •OH, •OOH, and •OOCCl3 radicals have been studied using the density functional theory. Three mechanisms of reaction have been considered: radical adduct formation (RAF), hydrogen transfer (HT), and single electron transfer (SET). Their relative importance for the free radical scavenging activity of AFMK and AMK has been assessed. It was found that AFMK and AMK react with •OH at diffusion‐limited rates, regardless of the polarity of the environment, which supports their excellent •OH radical scavenging activity. Both compounds were found to be also very efficient for scavenging •OOCCl3, but rather ineffective for scavenging •OOH. Regarding their relative activity, it was found that AFMK systematically is a poorer scavenger than AMK and melatonin. In aqueous solution, AMK was found to react faster than melatonin with all the studied free radicals, while in nonpolar environments, the relative efficiency of AMK and melatonin as free radical scavengers depends on the radical with which they are reacting. Under such conditions, melatonin is predicted to be a better •OOH and •OOCCl3 scavenger than AMK, while AMK is predicted to be slightly better than melatonin for scavenging •OH. Accordingly it seems that melatonin and its metabolite AMK constitute an efficient team of scavengers able of deactivating a wide variety of reactive oxygen species, under different conditions. Thus, the presented results support the continuous protection exerted by melatonin, through the free radical scavenging cascade.
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Obesity is a consequence of positive energy balance, which can be counterbalanced by eating less, increasing physical activity, or pharmacological approaches. However, weight maintenance is generally disappointing, and long-term use of pharmaceuticals has been limited because of lack of efficacy, poor long-term adherence rates, and serious adverse effects. These limitations indicate that, given our current knowledge and available technologies, insights from other fields of research will be necessary to permit exploration of new ideas and develop effective applications.