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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 [1–5]. 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 [6–9].
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
[10–12], 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 [15–17]. Melatonin’s mem-
brane receptor-mediated mechanisms of action and its
physiological effects via those receptors have been defined
[18–20]. 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 [23–25].
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 [29–33]. 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 [34–36]. 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 [38–40]. 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 [48–52] 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 [53–55]. This dramatic pathological picture can be
reverted by melatonin replacement therapy or restricted
feeding [54, 56, 57], but not by physical training [58–60].
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 [61–68]. 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, 70–73]. 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) [74–76].
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 3–5 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,
81–83].
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 [84–90].
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, 91–93].
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 [105–108] (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 [109–111], 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 [116–120] 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
[126–130], 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, 134–137], 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
[139–143]. 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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