ArticlePDF AvailableLiterature Review


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.
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
, F. G. Amaral
S. C. Afeche
, D. X. Tan
R. J. Reiter
Department of Physiology and Biophysics,
Institute of Biomedical Sciences, University of
ao Paulo, S~
ao Paulo, Brazil;
Laboratory of
Pharmacology, Institute Butantan, S~
ao Paulo,
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
ao Paulo, Av. Lineu Prestes, 1524, Bldg 1,
05508000 S~
ao Paulo, SP, Brazil.
Received March 15, 2014;
Accepted March 17, 2014.
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
and a
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
J. Pineal Res. 2014; 56:371–381
©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
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
-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
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,
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
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
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.
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.
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.
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.
1. STEHLE JH, SAADE A, RAWASHDEH O et al. A survey of
molecular details in the human pineal gland in the light of
phylogeny, structure, function and chronobiological dis-
eases. J Pineal Res 2011; 51:1743.
2. GOMEZ FJ, RABA J, CERUTTI S et al. Monitoring melatonin
and its isomer in Vitis vinifera cv. Malbec by UHPLC-MS/
MS from grape to bottle. J Pineal Res 2012; 52:349355.
3. BYEON Y, PARK S, KIM YS et al. Light-regulated melatonin
biosynthesis in rice during the senescence process in
detached leaves. J Pineal Res 2012; 53:107111.
variation in melatonin synthesis and arylalkylamine N-ace-
tyltransferase activity in the nematode Caenorhabditis ele-
gans. J Pineal Res 2012; 53:3846.
5. ROOPIN M, LEVY O. Temporal and histological evaluation
of melatonin patterns in a ‘basal’ metazoan. J Pineal Res
2012; 53:259269.
6. OZAKI Y, LYNCH HJ. Presence of melatonin in plasma and
urine or pinealectomized rats. Endocrinology 1976; 99:
cerebrospinal fluid melatonin and possible function in the
integration of photoperiod. Reprod Suppl 2003; 61:311321.
8. SIMONNEAUX V, RIBELAYGA C. Generation of the melatonin
endocrine message in mammals: a review of the complex
regulation of melatonin synthesis by norepinephrine, pep-
tides, and other pineal transmitters. Pharmacol Rev 2003;
9. REITER RJ, TAN DX, KIM SJ et al. Delivery of melatonin to
the brain and SCN: role of canaliculi, cerebrospinal fluid,
tanycytes and Virchow- Robin perivascular spaces. Brain
Str Funct 2014. doi: 10.1007/s00429-014-0719-7.
10. CARDINALI DP, LYNCH HJ, WURTMAN RJ. Binding of mela-
tonin to human and rat plasma proteins. Endocrinology
1972; 91:12131218.
11. PARDRIDGE WM, MIETUS LJ. Transport of albumin-bound
melatonin through the blood-brain barrier. J Neurochem
1980; 34:17611763.
12. MORIN D, SIMON N, DEPRES-BRUMMER P et al. Melatonin
high-affinity binding to alpha-1-acid glycoprotein in human
serum. Pharmacology 1997; 54:271275.
13. DUBOCOVICH ML, MARKOWSKA M. Functional MT1 and
MT2 melatonin receptors in mammals. Endocrine 2005;
national Union of Basic and Clinical Pharmacology.
LXXV. nomenclature, classification, and pharmacology of
g protein-coupled melatonin receptors. Pharmacol Rev
2010; 62:343380.
et al. Pineal gland hormone melatonin binds and activates
an orphan of the nuclear receptor superfamily. J Biol Chem
1994; 269:2853128534.
16. SMIRNOV AN. Nuclear melatonin receptors. Biochemistry
(Mosc) 2001; 66:1926.
nuclear receptors involved in pituitary responsiveness to
melatonin? Mol Cell Endocrinol 1996; 123:5359.
18. AFECHE SC, AMARAL FG, VILLELA DCM et al. Melatonin
and the Pineal Gland. In: New Research on Neurosecretory
Systems. ROMANO E, DELS, ed., Nova Biomedical Books,
New York, 2008; pp. 151177.
Angiotensin-melatonin axis. Inter. J Hypertension 2013;
of melatonin in the cells of the innate immunity: a review.
J Pineal Res 2013; 55:103120.
review of the multiple actions of melatonin on the immune
system. Endocrine 2005; 27:189200.
22. TOMAS-ZAPICO C, COTO-MONTES AA. Proposed mechanism
to explain the stimulatory effect of melatonin on antioxida-
tive enzymes. J Pineal Res 2005; 39:99104.
23. TAN DX, CHEN LD, POEGGLER B et al. Melatonin: a potent,
endogenous hydroxyl radical scavenger. Endocr J 1993;
24. KILIC U, YILMAZ B, UGUR M et al. Evidence that mem-
brane-bound G protein-coupled melatonin receptors MT1
and MT2 are not involved in the neuroprotective effects of
melatonin in focal cerebral ischemia. J Pineal Res 2012;
25. GALANO A, TAN DX, REITER RJ. On the free radical scav-
enging activities of melatonin’s metabolites, AFMK and
AMK. J Pineal Res 2012; 54:245257.
26. KAPPERS JA. The development, topographical relations and
innervation of the epiphysis cerebri in the albino rat. Z
Zellforsch Mikrosk Anat 1960; 52:163215.
27. REITER RJ. Neuroendocrine effects of light. Int J Biometeo-
rol 1991; 35:169175.
28. REITER RJ. Melatonin: the chemical expression of darkness.
Mol Cell Endocrinol 1991; 79:C153C158.
pression of pineal melatonin content and N-acetyltransfer-
ase activity by different light irradiances in the Syrian
hamster: a dose-response relationship. Endocrinology 1983;
of the human circadian melatonin rhythm to resetting by
short wavelength light. J Clin Endocrinol Metab 2003;
responses of the human circadian system depend on the
irradiance and duration of exposure to light. Sci Transl
Med 2010; 2:3133.
al responses to simultaneous presentation of blue and
red monochromatic light. J Biol Rhythms 2012; 27:
Melatonin, energy metabolism, and obesity
33. SAHIN L, FIGUEIRO MG. Alerting effects of short-wave-
length (blue) and long-wavelength (red) lights in the after-
noon. Physiol Behav 2013; 117:17.
34. WEHR TA. The durations of human melatonin secretion
and sleep respond to changes in daylength (photoperiod).
J Clin Endocrinol Metab 1991; 73:12761280.
rachiasmatic control of melatonin synthesis in rats: inhibi-
tory and stimulatory mechanisms. Eur J Neurosci 2003;
36. PERREAU-LENZ S, KALSBEEK A, van der VLIET J et al. In
vivo evidence for a controlled offset of melatonin synthesis
at dawn by the suprachiasmatic nucleus in the rat. Neuro-
science 2005; 130:797803.
subjective night and season of the year. Physiol Res 2000;
49(Suppl 1):S1S10.
38. REITER RJ. Pineal control of a seasonal reproductive
rhythm in male golden hamsters exposed to natural day-
light and temperature. Endocrinology 1973; 92:423430.
39. CARTER DS, GOLDMAN BD. Antigonadal effects of timed
melatonin infusion in pinealectomized male Djungarian
hamsters (Phodopus sungorus sungorus): duration is the crit-
ical parameter. Endocrinology 1983; 113:12611267.
40. BARRETT P, BOLBOREA M. Molecular pathways involved in
seasonal body weight and reproductive responses governed
by melatonin. J Pineal Res 2012; 52:376388.
41. DAWSON D, ARMSTRONG SM. Chronobioticsdrugs that
shift rhythms. Pharmacol Ther 1996; 69:1536.
nin and the circadian entrainment of metabolic and hor-
monal activities in primary isolated adipocytes. J Pineal
Res 2008; 45:422429.
sleep disrupts circadian regulation of the human transcrip-
tome. Proc Natl Acad Sci USA 2014; 111:E682E691.
44. ARENDT J, SKENE DJ. Melatonin as a chronobiotic. Sleep
Med Rev 2005; 9:2539.
45. SAARELA S, REITER RJ. Function of melatonin in thermo-
regulatory processes. Life Sci 1994; 54:295311.
epiphysis; influence of aqueous pineal extract on some
aspects of carbohydrate metabolism in healthy and eucrine
subjects. Arch Maragliano Patol Clin 1956; 12:11051113.
47. MILCU I, NANU L, MARCEAN R et al. The effect of epiphy-
sectomy on the metabolism of carbohydrates. studies with
rats. Stud Cercet Endocrinol 1965; 16:1723.
48. MILCU I, NANU L, MARCEAN R et al. The action of pineal
extract and epiphysectomy on hepatic and muscular glyco-
gen after prolonged infusion of glucose. Stud Cercet Endo-
crinol 1963; 14:651655.
49. CSABA G, BARATH P. Are Langerhan’s islets influenced by
the pineal body? Experientia 1971; 27:962.
50. DIAZ B, BLAZQUEZ E. Effect of pinealectomy on plasma glu-
cose, insulin and glucagon levels in the rat. Horm Metab
Res 1986; 18:225229.
51. RODRIGUEZ V, MELLADO C, ALVAREZ E et al. Effect of pine-
alectomy on liver insulin and glucagon receptor concentra-
tions in the rat. J Pineal Res 1989; 6:7788.
52. MELLADO C, RODRIGUEZ V, de DIEGO JG et al. Effect of
pinealectomy and of diabetes on liver insulin and glucagon
receptor concentrations in the rat. J Pineal Res 1989;
53. LIMA FB, MACHADO UF, BARTOL I et al. Pinealectomy
causes glucose intolerance and decreases adipose cell
responsiveness to insulin in rats. Am J Physiol 1998; 275:
melatonin induces night-time hepatic insulin resistance and
increased gluconeogenesis due to stimulation of nocturnal
unfolded protein response. Endocrinology 2011; 152:
55. SIMKO F, REITER RJ, PECHANOVA O et al. Experimental
models of melatonin-deficient hypertension. Front Biosci
2013; 18:616625.
restriction reduces pinealectomy-induced insulin resistance
by improving GLUT4 gene expression and its translocation
to the plasma membrane. J Pineal Res 2003; 35:141148.
57. MENDES C, LOPES AM, AMARAL FG et al. Adaptations of
the aging animal to exercise: role of daily supplementation
with melatonin. J Pineal Res 2013; 55:229239.
et al. Reduced lipolysis and increased lipogenesis in adipose
tissue from pinealectomized rats adapted to training.
J Pineal Res 2005; 39:178184.
SM et al. Pinealectomy impairs adipose tissue adaptability
to exercise in rats. J Pineal Res 2005; 38:278283.
alectomy reduces hepatic and muscular glycogen content
and attenuates aerobic power adaptability in trained rats.
J Pineal Res 2007; 43:96103.
melatonin administration at middle age suppresses male rat
visceral fat, plasma leptin, and plasma insulin to youthful
levels. Endocrinology 1999; 140:10091012.
62. KARLSSON B, KNUTSSON A, LINDAHL B. Is there an associa-
tion between shift work and having a metabolic syndrome?
Results from a population based study of 27,485 people.
Occup Environ Med 2001; 58:747752.
63. NISHIDA S, SATO R, MURAI I et al. Effect of pinealectomy
on plasma levels of insulin and leptin and on hepatic lipids
in type 2 diabetic rats. J Pineal Res 2003; 35:251256.
64. FONKEN LK, WORKMAN JL, WALTON JC et al. Light at
night increases body mass by shifting the time of food
intake. Proc Natl Acad Sci USA 2010; 107:1866418669.
65. FONKEN LK, WEIL ZM, NELSON RJ. Dark nights reverse
metabolic disruption caused by dim light at night. Obesity
(Silver Spring) 2013; 21:11591164.
melatonin consumption prevents obesity-related metabolic
abnormalities and protects the heart against myocardial
ischemia and reperfusion injury in a prediabetic model of
diet-induced obesity. J Pineal Res 2011; 50:171182.
67. de OLIVEIRA AC, ANDREOTTI S, FARIAS SM et al. Metabolic
disorders and adipose tissue insulin responsiveness in
neonatally STZ-induced diabetic rats are improved by
long-term melatonin treatment. Endocrinology 2012;
68. AGIL A, ROSADO I, RUIZ R et al. Melatonin improves glu-
cose homeostasis in young Zucker diabetic fatty rats.
J Pineal Res 2012; 52:203210.
melatonin receptor type 1 induces insulin resistance in the
mouse. Obesity (Silver Spring) 2010; 18:18611863.
Cipolla-Neto et al.
70. SERAPHIM PM, BARTOL I, CIPOLLA-NETO J et al. Quantifica-
tion of GLUT4 transporter in insulin-sensitive tissues from
pinealectomized rats. In: Pineal Update. WEBB SM, PUIG-
EVET P, eds., PJD Publica-
tions Limited, Westbury, NY, 1997; pp. 99106.
71. DAS UN. A defect in the activity of Delta6 and Delta5 de-
saturases may be a factor predisposing to the development
of insulin resistance syndrome. Prostaglandins Leukot Es-
sent Fatty Acids 2005; 72:343350.
72. GHOSH G, DEK, MAITY S et al. Melatonin protects against
oxidative damage and restores expression of GLUT4 gene
in the hyperthyroid rat heart. J Pineal Res 2007; 42:7182.
73. SRIVASTAVA RK, KRISHNA A. Melatonin modulates glucose
homeostasis during winter dormancy in a vespertilionid
bat, Scotophilus heathi. Comp Biochem Physiol A Mol In-
tegr Physiol 2010; 155:392400.
vivo activation of insulin receptor tyrosine kinase by mela-
tonin in the rat hypothalamus. J Neurochem 2004; 90:
75. HAE, YIM SV, CHUNG JH et al. Melatonin stimulates glu-
cose transport via insulin receptor substrate-1/phosphati-
dylinositol 3-kinase pathway in C2C12 murine skeletal
muscle cells. J Pineal Res 2006; 41:6772.
tion of insulin and IGF-1 signaling pathways by melatonin
through MT1 receptor in isolated rat pancreatic islets.
J Pineal Res 2008; 44:8894.
77. LIMA FB, MATSUSHITA DH, HELL NS et al. The regulation
of insulin action in isolated adipocytes. Role of the period-
icity of food intake, time of day and melatonin. Braz J Med
Biol Res 1994; 27:9951000.
78. BRYDON L, PETIT L, DELAGRANGE P et al. Functional
expression of MT2 (Mel1b) melatonin receptors in human
PAZ6 adipocytes. Endocrinology 2001; 142:42644271.
Intermittent and rhythmic exposure to melatonin in pri-
mary cultured adipocytes enhances the insulin and dexa-
methasone effects on leptin expression. J Pineal Res 2006;
ectomy alters adipose tissue adaptability to fasting in rats.
Metabolism 2004; 53:500506.
81. ZALATAN F, KRAUSE JA, BLASK DE. Inhibition of isoprote-
renol-induced lipolysis in rat inguinal adipocytes in vitro by
physiological melatonin via a receptor-mediated mecha-
nism. Endocrinology 2001; 142:37833790.
82. DAUCHY RT, BLASK DE, SAUER LA et al. Physiologic mela-
tonin concentration, omega-3 fatty acids, and conjugated li-
noleic acid inhibit fatty acid transport in rodent hind limb
skeletal muscle in vivo. Comp Med 2003; 53:186190.
differentiation is inhibited by melatonin through the regula-
tion of C/EBPbeta transcriptional activity. J Pineal Res
2009; 47:221227.
84. PESCHKE E, PESCHKE D, HAMMER T et al. Influence of mela-
tonin and serotonin on glucose-stimulated insulin release
from perifused rat pancreatic islets in vitro. J Pineal Res
1997; 23:156163.
85. PESCHKE E, FAUTECK JD, MUSSHOFF U et al. Evidence for a
melatonin receptor within pancreatic islets of neonate rats:
functional, autoradiographic, and molecular investigations.
J Pineal Res 2000; 28:156164.
(MT(1)) mediated influence of melatonin on cAMP concen-
tration and insulin secretion of rat insulinoma cells INS-1. J
Pineal Res 2002; 33:6371.
inhibits insulin secretion and decreases PKA levels without
interfering with glucose metabolism in rat pancreatic islets.
J Pineal Res 2002; 33:156160.
88. MUHLBAUER E, PESCHKE E. Evidence for the expression of
both the MT1- and in addition, the MT2-melatonin recep-
tor, in the rat pancreas, islet and beta-cell. J Pineal Res
2007; 42:105106.
89. STUMPF I, MUHLBAUER E, PESCHKE E. Involvement of the
cGMP pathway in mediating the insulin-inhibitory effect of
melatonin in pancreatic beta-cells. J Pineal Res 2008;
inhibits insulin secretion in rat insulinoma beta-cells (INS-
1) heterologously expressing the human melatonin receptor
isoform MT2. J Pineal Res 2011; 51:361372.
91. KULKARNI RN, BRUNING JC, WINNAY JN et al. Tissue-spe-
cific knockout of the insulin receptor in pancreatic beta
cells creates an insulin secretory defect similar to that in
type 2 diabetes. Cell 1999; 96:329339.
92. KULKARNI RN. Receptors for insulin and insulin-like
growth factor-1 and insulin receptor substrate-1 mediate
pathways that regulate islet function. Biochem Soc Trans
2002; 30:317322.
93. BURKS DJ, WHITE MF. IRS proteins and beta-cell function.
Diabetes 2001; 50(Suppl 1):S140S145.
94. DELIMA LM, DOS REIS LC, DELIMA MA. Influence of the
pineal gland on the physiology, morphometry and mor-
phology of pancreatic islets in rats. Braz J Biol 2001;
95. KOSA E, MAUREL D, SIAUD P. Effects of pinealectomy on
glucagon responsiveness to hypoglycaemia induced by insu-
lin injections in fed rats. Exp Physiol 2001; 86:617620.
96. BAHR I, MUHLBAUER E, SCHUCHT H et al. Melatonin stimu-
lates glucagon secretion in vitro and in vivo. J Pineal Res
2011; 50:336344.
rhythm of glucose-induced insulin secretion by isolated
islets from intact and pinealectomized rat. J Pineal Res
2002; 33:172177.
et al. A variant near MTNR1B is associated with increased
fasting plasma glucose levels and type 2 diabetes risk. Nat
Genet 2009; 41:8994.
in MTNR1B influence fasting glucose levels. Nat Genet
2009; 41:7781.
100. GARCIA RA, AFECHE SC, SCIALFA JH et al. Insulin modu-
lates norepinephrine-mediated melatonin synthesis in
cultured rat pineal gland. Life Sci 2008; 82:108114.
temporal sensitivity and its signaling pathway in the rat
pineal gland. Life Sci 2010; 87:169174.
melatonin programs the daily pattern of energy metabolism
in adult offspring. PLoS ONE 2012; 7:e38795.
103. SCHEER FA, HILTON MF, MANTZOROS CS et al. Adverse met-
abolic and cardiovascular consequences of circadian mis-
alignment. Proc Natl Acad Sci USA 2009; 106:44534458.
Melatonin, energy metabolism, and obesity
104. REITER RJ, TAN DX, KORKMAZ A et al. Obesity and meta-
bolic syndrome: association with chronodisruption, sleep
deprivation, and melatonin suppression. Ann Med 2012;
105. GREEN CB, TAKAHASHI JS, BASS J. The meter of metabo-
lism. Cell 2008; 134:728742.
106. LAPOSKY AD, BASS J, KOHSAKA A et al. Sleep and circadian
rhythms: key components in the regulation of energy
metabolism. FEBS Lett 2008; 582:142151.
107. HUANG W, RAMSEY KM, MARCHEVA B et al. Circadian
rhythms, sleep, and metabolism. J Clin Invest 2011;
108. SAHAR S, SASSONE-CORSI P. Circadian rhythms and memory
formation: regulation by chromatin remodeling. Front Mol
Neurosci 2012; 5:37.
109. PAULY JE, SCHEVING LE. Circadian rhythms in blood glu-
cose and the effect of different lighting schedules, hypophy-
sectomy, adrenal medullectomy and starvation. Am J Anat
1967; 120:627636.
fasting on the circadian rhythm of serum insulin levels.
Chronobiologia 1976; 3:2026.
111. PAULY JE. Chronobiology: anatomy in time. Am J Anat
1983; 168:365388.
112. KALSBEEK A, STRUBBE JH. Circadian control of insulin
secretion is independent of the temporal distribution of
feeding. Physiol Behav 1998; 63:553558.
113. SHI SQ, ANSARI TS, MCGUINNESS OP et al. Circadian dis-
ruption leads to insulin resistance and obesity. Curr Biol
2013; 23:372381.
114. la FLEUR SE, KALSBEEK A, WORTEL J et al. Role for the
pineal and melatonin in glucose homeostasis: pinealectomy
increases night-time glucose concentrations. J Neuroendo-
crinol 2001; 13:10251032.
115. CAILOTTO C, la FLEUR SE, van HEIJNINGEN C et al. The sup-
rachiasmatic nucleus controls the daily variation of plasma
glucose via the autonomic output to the liver: are the clock
genes involved? Eur J Neurosci 2005; 22:25312540.
116. WHICHELOW MJ, STURGE RA, KEEN H et al. Diurnal varia-
tion in response to intravenous glucose. Br Med J 1974;
117. GIBSON T, STIMMLER L, JARRETT RJ et al. Diurnal variation
in the effects of insulin on blood glucose, plasma non-esteri-
fied fatty acids and growth hormone. Diabetologia 1975;
118. GIBSON T, JARRETT RJ. Diurnal variation in insulin sensitiv-
ity. Lancet 1972; 2:947948.
119. JARRETT RJ, BAKER IA, KEEN H et al. Diurnal variation in
oral glucose tolerance: blood sugar and plasma insulin lev-
els morning, afternoon, and evening. Br Med J 1972;
120. JARRETT RJ, KEEN H, BAKER IA. Diurnal variation in oral
glucose tolerance. Clin Sci 1971; 40:28P.
121. BEN-DYKE R. Diurnal variation of oral glucose tolerance in
volunteers and laboratory animals. Diabetologia 1971;
ations in insulin secretion and K+permeability in isolated
rat islets. Clin Exp Pharmacol Physiol 1999; 26:505510.
Light/dark cycle-dependent metabolic changes in adipose
tissue of pinealectomized rats. Horm Metab Res 2004;
124. ERREN TC, REITER RJ. Defining chronodisruption. J Pineal
Res 2009; 46:245247.
enhances leptin expression by rat adipocytes in the presence
of insulin. Am J Physiol Endocrinol Metab 2005; 288:
126. BARTNESS TJ, WADE GN. Photoperiodic control of seasonal
body weight cycles in hamsters. Neurosci Biobehav Rev
1985; 9:599612.
127. BARTNESS TJ, WADE GN. Body weight, food intake and
energy regulation in exercising and melatonin-treated Sibe-
rian hamsters. Physiol Behav 1985; 35:805808.
128. PUCHALSKI W, KLIMAN R, LYNCH GR. Differential effects of
short day pretreatment on melatonin-induced adjustments
in Djungarian hamsters. Life Sci 1988; 43:10051012.
129. ELLIOTT JA, BARTNESS TJ, GOLDMAN BD. Effect of melato-
nin infusion duration and frequency on gonad, lipid, and
body mass in pinealectomized male Siberian hamsters.
J Biol Rhythms 1989; 4:439455.
130. BARTNESS TJ, DEMAS GE, SONG CK. Seasonal changes in
adiposity: the roles of the photoperiod, melatonin and other
hormones, and sympathetic nervous system. Exp Biol Med
(Maywood) 2002; 227:363376.
cance and application of melatonin in the regulation of
brown adipose tissue metabolism: relation to human obes-
ity. Obes Rev 2011; 12:167188.
tonin reduces body weight gain in Sprague Dawley rats
with diet-induced obesity. Endocrinology 2003; 144:
133. SARTORI C, DESSEN P, MATHIEU C et al. Melatonin
improves glucose homeostasis and endothelial vascular
function in high-fat diet-fed insulin-resistant mice. Endocri-
nology 2009; 150:53115317.
134. RASKIND MA, BURKE BL, CRITES NJ et al. Olanzapine-
induced weight gain and increased visceral adiposity is
blocked by melatonin replacement therapy in rats. Neuro-
psychopharmacology 2007; 32:284288.
effects on metabolism independent of gonad function.
Endocrine 2003; 21:169173.
dependent changes in the effect of daily melatonin supple-
mentation on rat metabolic and behavioral responses.
J Pineal Res 2001; 31:8994.
melatonin administration to middle-aged male rats sup-
presses body weight, intraabdominal adiposity, and plasma
leptin and insulin independent of food intake and total
body fat. Endocrinology 2000; 141:487497.
tonin reduces body weight gain and increases nocturnal
activity in male Wistar rats. Physiol Behav 2013; 118C:
139. HELDMAIER G, HOFFMANN K. Melatonin stimulates growth
of brown adipose tissue. Nature 1974; 247:224225.
140. SINNAMON WB, PIVORUN EB. Melatonin induces hypertro-
phy of brown adipose tissue in Spermophilus tridecemlinea-
tus. Cryobiology 1981; 18:603607.
141. VISWANATHAN M, HISSA R, GEORGE JC. Effects of short
photoperiod and melatonin treatment on thermogenesis in
the Syrian hamster. J Pineal Res 1986; 3:311321.
Cipolla-Neto et al.
et al. Melatonin specifically stimulates type-II thyroxine 5’-
deiodination in brown adipose tissue of Syrian hamsters.
J Endocrinol 1989; 122:553556.
et al. Melatonin induces browning of inguinal white adi-
pose tissue in Zucker diabetic fatty rats. J Pineal Res 2013;
144. RICHARD D, PICARD F. Brown fat biology and thermogene-
sis. Front Biosci 2011; 16:12331260.
145. TOWNSEND KL, TSENG YH. Brown fat fuel utilization and
thermogenesis. Trends Endocrinol Metab 2014; 25:168177.
adipose tissue regulates glucose homeostasis and insulin
sensitivity. J Clin Invest 2013; 123:215223.
147. LICHTENBELT WV, KINGMA B, van der LANS A et al. Cold
exposure - an approach to increasing energy expenditure in
humans. Trends Endocrinol Metab 2014; 25:165167.
148. CYPESS AM, LEHMAN S, WILLIAMS G et al. Identification
and importance of brown adipose tissue in adult humans.
N Engl J Med 2009; 360:15091517.
tonin improves insulin sensitivity independently of weight
loss in old obese rats. J Pineal Res 2013; 55:156165.
Melatonin, energy metabolism, and obesity
... Melatonin is present in almost every living organism to regulate the circadian rhythm of these organisms (149). In vertebrates, the direct release of melatonin into the blood and CSF by the pineal gland is the major source of circulating melatonin, however, it is also generated in a variety of cells, tissues, and organs primarily for local consumption (autocrine and paracrine activities) (150,151). ...
... Melatonin is primarily responsible for establishing an optimal energy balance by controlling the flow of energy to and from the reserves, as well as directly regulating energy expenditure by activating brown adipose tissue and browning of white adipose tissue. Melatonin levels fall as a result of aging, shift work, or light settings at night, which also causes insulin resistance, glucose intolerance, sleep disturbances, and metabolic circadian disorganization, a condition known as chrono disruption (149). Melatonin regulates energy balance and metabolism, which have a distinct 24-hour rhythm (169). ...
... This is a period characterized by increased adipose tissue lipogenesis and adiponectin production, as well as elevated insulin secretion, high glucose uptake by insulin-sensitive tissues, hepatic and muscular glycogen synthesis and glycolysis, and high central and peripheral sensitivity to insulin and glucose tolerance. The normal fasting phase necessitates the utilization of stored energy for the maintenance of cellular functions, which distinguishes the rest/sleep phase of the day, in contrast with insulin resistance, enhanced hepatic gluconeogenesis and glycogenolysis, adipose tissue lipolysis, and leptin release are all present throughout this portion of the daily cycle (149) thus it also regulates brain metabolism in that way. Melatonin interacts with molecules and signalling networks such as insulin-like growth factor 1 (IGF-1), Forkhead box O (FoxOs), sirtuins, and the mammalian target of rapamycin (mTOR) signalling pathways and all of them affect energy consumption (170). ...
Full-text available
Energy metabolism is the biochemical pathway of converting macronutrients (carbohydrates, protein, and fat) to cellular energy for the maintenance of cell homeostasis. The brain is an organ that consumes unproportional energy compared to its size. Glucose (glycogen, in storage form of glucose) is the principal source of brain energy. Impairment in brain energy metabolism results in neuronal loss and subsequent neurodegenerative diseases including AD, PD, amyotrophic lateral sclerosis, Huntington’s disease, etc. However, metabolic disorders such as chronic hyperglycemia, and insulin resistance are also linked with neuronal activity. Dysregulation in neuronal transmission is associated with oxidative stress and brain insulin resistance. Diabetes mellitus jeopardizes brain function through various mechanisms including glucose toxicity, BBB damage, neuroinflammation, and gliosis. B vitamins as antioxidants and neuroprotective agents, can improve brain glucose metabolism. Melatonin is a potent free radical scavenger and it can also modulate cellular cytokine levels and prevent insulin resistance. The neuroprotective and antihyperglycemic effects of melatonin improve the brain's antioxidant defense system, decrease brain NOS activity, and prevent glucose toxicity. Hence this review suggests a therapeutic use of a combination of melatonin and B vitamins to improve brain functioning disrupted by diabetes.
... Furthermore, some studies have reported a U-shaped association between sleep duration and MetS as both short and long sleeping hours were associated with the risk of MetS 58 [61][62][63] , sleep restriction can reduce leptin and increase ghrelin levels, leading to increased hunger and appetite specifically for carbohydrate-dense food 63 . The deficiency in melatonin secretion, as in shift-work associated with reductions in blood melatonin levels 64 .Recent studies indicates that melatonin has potential benefits for cardiovascular health and metabolic syndrome by influencing on blood pressure regulation, lipid metabolism, and glucose homeostasis 64,65 . In addition, chronic sleep insufficiency can cause an increase in both in advanced glycation end products (AGEs) 66 and pro-inflammatory cytokines, both of which can contribute to an increase in insulin resistance 67 . ...
... Furthermore, some studies have reported a U-shaped association between sleep duration and MetS as both short and long sleeping hours were associated with the risk of MetS 58 [61][62][63] , sleep restriction can reduce leptin and increase ghrelin levels, leading to increased hunger and appetite specifically for carbohydrate-dense food 63 . The deficiency in melatonin secretion, as in shift-work associated with reductions in blood melatonin levels 64 .Recent studies indicates that melatonin has potential benefits for cardiovascular health and metabolic syndrome by influencing on blood pressure regulation, lipid metabolism, and glucose homeostasis 64,65 . In addition, chronic sleep insufficiency can cause an increase in both in advanced glycation end products (AGEs) 66 and pro-inflammatory cytokines, both of which can contribute to an increase in insulin resistance 67 . ...
Full-text available
Many factors can lead to an increase in the prevalence of metabolic syndrome (MetS) in different populations. Using an advanced structural equation model (SEM), this study is aimed to determine the most important risk factors of MetS, as a continuous latent variable, using a large number of males and females. We also aimed to evaluate the interrelations among the associated factors involved in the development of MetS. This study used data derived from the Fasa PERSIAN cohort study, a branch of the PERSIAN cohort study, for participants aged 35 to 70 years with 10,138 males and females. SEM was used to evaluate the direct and indirect effects, as well as gender effects of influencing factors. Results from the SEM showed that in females most changes in MetS are described by waist circumference (WC), followed by hypertension (HP) and triglyceride (TG), while in males most changes in MetS are described by WC, followed by TG then fasting blood glucose (FBG). Results from the SEM confirmed the gender effects of social status on MetS, mediated by sleep and controlled by age, BMI, ethnicity and physical activity. This study also shows that the integration of TG and WC within genders could be useful as a screening criterion for MetS in our study population.
... Melatonin decreases the risk of cardiovascular illnesses Patients with diabetes mellitus were found to have lower levels of melatonin (21). ...
Full-text available
Background & Aim: Melatonin is primarily involved in the regulation of circadian rhythm and sleep and
... However, the decreased amplitude of the nocturnal pineal melatonin peak has been described in obese rodents [70], and altered leptin production has also been attributed to a lack of circadian control, having an impact on appetite and energy balance [24,25]. Indeed, melatonin deficiency has been demonstrated to correlate with obesity [71,72], and the absence of melatonin leads to leptin resistance [65], making leptin treatments ineffective. Then, one can ask whether melatonin supplementation at night normalizes some of the obesity-related metabolic alterations described here. ...
Full-text available
Leptin is critically compromised in the major common forms of obesity. Skeletal muscle is the main effector tissue for energy modification that occurs as a result of the effect of endocrine axes, such as leptin signaling. Our study was carried out using skeletal muscle from a leptin-deficient animal model, in order to ascertain the importance of this hormone and to identify the major skeletal muscle mechanisms affected. We also examined the therapeutic role of melatonin against leptin-induced muscle wasting. Here, we report that leptin deficiency stimulates fatty acid β-oxidation, which results in mitochondrial uncoupling and the suppression of mitochondrial oxidative damage; however, it increases cytosolic oxidative damage. Thus, different nutrient-sensing pathways are disrupted, impairing proteostasis and promoting lipid anabolism, which induces myofiber degeneration and drives oxidative type I fiber conversion. Melatonin treatment plays a significant role in reducing cellular oxidative damage and regulating energy homeostasis and fuel utilization. Melatonin is able to improve both glucose and mitochondrial metabolism and partially restore proteostasis. Taken together, our study demonstrates melatonin to be a decisive mitochondrial function-fate regulator in skeletal muscle, with implications for resembling physiological energy requirements and targeting glycolytic type II fiber recovery.
... Гормон эпифиза МТ осуществляет смену физиологических процессов в организме и инициирует восстановительные процессы в органах и тканях человека, обладая выраженным антиоксидантным эффектом [10][11][12]. Ограниченное воздействие света в дневное время, повышенная освещенность ночью, работа в ночное время могут приводить к нарушению циркадных ритмов, снижению выработки МТ и неблагоприятным последствиям для здоровья [13][14][15]. ...
Introduction Metabolic syndrome is a complex of disorders including abdominal obesity, impaired glucose tolerance, dyslipidemia, and arterial hypertension. Antioxidant and anti-inflammatory properties of the pineal hormone melatonin are of great importance for preserving body homeostasis, and potentially melatonin can be a a safe and effective agent in the complex treatment of menopausal women with metabolic syndrome. The aim of the study is to determine the prospects of using the epiphysis hormone melatonin in the complex treatment of menopausal metabolic syndrome based on the analysis of scientific publications. Material and methods The review includes data from studies on the effect of melatonin (MT) on the components of metabolic syndrome in periand postmenopausal women. Sources were searched for the period 2016–2023 in the international databases Medline, Scopus, Web of Science and the Russian scientific electronic library eLibrary by search words and phrases: melatonin, menopause, perimenopause, metabolic syndrome, obesity, insulin resistance, dyslipidemia, arterial hypertension. Results and Discussion The analysis of the literature data showed a number of advantages of the effect of exogenous MT preparations on individual components of metabolic syndrome, but some results were contradictory. Scientific evidence of MT influence on anthropometric indices, markers of glucose homeostasis, hemodynamic parameters and signs of body's inflammatory response, as well as multidirectional effects on lipid profile was found. Conclusion Given the multifunctionality and safety of exogenous MT preparations, its use in the complex therapy of menopausal metabolic syndrome should be considered.
... 2 Circadian rhythm disorders are regarded to be associated with reproductive system disorders or diseases, cardiovascular diseases, metabolic syndrome, gut microbiota disorders and increased cancer. [3][4][5] Melatonin is an important hormone needed to regulate circadian rhythm and cope with oxidative stress. Its depletion or lack will clearly lead to circadian rhythm disorders, oxidative stress and other problems. ...
Full-text available
Objective To reveal whether gut microbiota and their metabolites are correlated with oocyte quality decline caused by circadian rhythm disruption, and to search possible approaches for improving oocyte quality. Design A mouse model exposed to continuous light was established. The oocyte quality, embryonic development, microbial metabolites and gut microbiota were analyzed. Intragastric administration of microbial metabolites was conducted to confirm the relationship between gut microbiota and oocyte quality and embryonic development. Results Firstly, we found that oocyte quality and embryonic development decreased in mice exposed to continuous light. Through metabolomics profiling and 16S rDNA‐seq, we found that the intestinal absorption capacity of vitamin D was decreased due to significant decrease of bile acids such as lithocholic acid (LCA), which was significantly associated with increased abundance of Turicibacter . Subsequently, the concentrations of anti‐Mullerian hormone (AMH) hormone in blood and melatonin in follicular fluid were reduced, which is the main reason for the decline of oocyte quality and early embryonic development, and this was rescued by injection of vitamin D3 (VD3). Secondly, melatonin rescued oocyte quality and embryonic development by increasing the concentration of lithocholic acid and reducing the concentration of oxidative stress metabolites in the intestine. Thirdly, we found six metabolites that could rescue oocyte quality and early embryonic development, among which LCA of 30 mg/kg and NorDCA of 15 mg/kg had the best rescue effect. Conclusion These findings confirm the link between ovarian function and gut microbiota regulation by microbial metabolites and have potential value for improving ovary function.
... Melatonin reduces vasoconstriction and blood pressure, and it is proposed as an adjunct drug in the treatment of hypertension [78]. Melatonin has also a significant impact on metabolism, being an important protective factor against obesity and the development of diabetes mellitus [37,79,80]. Melatonin also plays a role in modulating the inflammatory response, having noticeable anti-inflammatory potential, as it can prevent cell death caused by pyroptosis [81,82]. ...
Full-text available
Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. The brain is one of the organs involved in sepsis, and sepsis-induced brain injury manifests as sepsis-associated encephalopathy (SAE). SAE may be present in up to 70% of septic patients. SAE has a very wide spectrum of clinical symptoms, ranging from mild behavioral changes through cognitive disorders to disorders of consciousness and coma. The presence of SAE increases mortality in the population of septic patients and may lead to chronic cognitive dysfunction in sepsis survivors. Therefore, therapeutic interventions with neuroprotective effects in sepsis are needed. Melatonin, a neurohormone responsible for the control of circadian rhythms, exerts many beneficial physiological effects. Its anti-inflammatory and antioxidant properties are well described. It is considered a potential therapeutic factor in sepsis, with positive results from studies on animal models and with encouraging results from the first human clinical trials. With its antioxidant and anti-inflammatory potential, it may also exert a neuroprotective effect in sepsis-associated encephalopathy. The review presents data on melatonin as a potential drug in SAE in the wider context of the pathophysiology of SAE and the specific actions of the pineal neurohormone.
... Finally, the present study revealed that no association between body weight and serum melatonin levels in contrast to other previous studies [37,38] . ...
Full-text available
Caffeine intake reduces sleep quality and melatonin secretion, the hormone responsible for regulating sleep. Chewing gum increases alertness and improves concentration. This study aims to investigate the impact of coffee consumption and gum chewing on serum melatonin levels in a study population of 40 Jordanian subjects (mean age, 21.15±3.21 years), including 23 males and 17 females. A total of 40 participants volunteered and met the inclusion criteria and were divided into four groups; a control group did not consume espresso coffee and chewed gum during the study period, a second group consumed two cups of espresso coffee (240 ml), and the third group chewed Gum constantly throughout the procedure; finally, the fourth group consumed two cups of espresso coffee and chewed Gum constantly throughout the process. Melatonin serum levels were measured one hour before and one hour after the completion of the study; the duration was five hours. The findings revealed that the coffee plus chewing gum participants had the lowest serum levels of melatonin (13.1± 2.0). Among the intervention groups, the coffee group and the last group regarding melatonin levels were the chewing gum group, 15.3± 1.2 and 19.2± 2.2, respectively. In conclusion, Significant differences existed between the interventions and control groups (P < 0.05). Furthermore, there were significant differences between coffee plus chewing gum and the coffee group and the chewing gum group (P < 0.002, P < 0.02, P < 0.004, respectively).
Dimethyl sulfoxide is one of the most commonly applied organic solvents in many organic reactions. It is known that DMSO/SOCl2 is the efficient system for the intramolecular cyclization of 2-alkenylanilines. The interaction of N-tosyl derivatives of 2-(cyclo)(alken-2-yl)- and 2-(cyclo)(alken-1-yl)anilines with thionyl chloride was studied in the DMSO/SOCl2 system. It was established that the structure of the obtained products depends on the structure of the alkenyl fragment and the reaction conditions. As a result of these reactions, methylsulfanyl(cyclo)alkyl products, indole, carbazole, or oxazepine were formed. The structure of new compounds was confirmed by IR, heteronuclear NMR spectroscopy, and high resolution mass spectrometry.
Full-text available
Achieving synchronization between the central and peripheral body clocks is essential for ensuring optimal metabolic function. Meal timing is an emerging field of research that investigates the influence of eating patterns on our circadian rhythm, metabolism, and overall health. This narrative review examines the relationship between meal timing, circadian rhythm, clock genes, circadian hormones, and metabolic function. It analyzes existing literature and experimental data to explore the connection between mealtime, circadian rhythms, and metabolic processes. The available evidence highlights the importance of aligning mealtime with the body’s natural rhythms to promote metabolic health and prevent metabolic disorders. Specifically, studies show that consuming meals later in the day is associated with an elevated prevalence of metabolic disorders, while early time-restricted eating, such as having an early breakfast and an earlier dinner, improves levels of glucose in the blood and substrate oxidation. Circadian hormones, including cortisol and melatonin, interact with mealtimes and play vital roles in regulating metabolic processes. Cortisol, aligned with dawn in diurnal mammals, activates energy reserves, stimulates appetite, influences clock gene expression, and synchronizes peripheral clocks. Consuming meals during periods of elevated melatonin levels, specifically during the circadian night, has been correlated with potential implications for glucose tolerance. Understanding the mechanisms of central and peripheral clock synchronization, including genetics, interactions with chronotype, sleep duration, and hormonal changes, provides valuable insights for optimizing dietary strategies and timing. This knowledge contributes to improved overall health and well-being by aligning mealtime with the body’s natural circadian rhythm.
Full-text available
Nuclear orpan receptors are members of the superfamily of structurally related, ligand-inducible transcription factors for which no ligand has yet been identified. Over the past few years many nuclear orphan receptors have been cloned, but only for the retinoid X receptor (RXR) has a natural ligand (9-cis-retinoic acid) been found. Here we report the identification of melatonin as a ligand for the recently cloned orphan receptor retinoid Z receptor beta (RZR beta). We found RZR beta expression in the rat brain nearly coincident with binding sites for the pineal gland hormone melatonin (5-methoxy-N-acetyltryptamine). We show here binding and activation of RZR beta by melatonin with Kd and EC50 values in the low nanomolar range. A nuclear signaling pathway for melatonin may contribute to some of the diverse and profound effects of this hormone, for example, in the context of circadian rhythmicity.
Full-text available
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.
Full-text available
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.
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.
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 ...
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.
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.
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.