Introduction
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 largely provided by the pineal gland where it is produced and directly released to the blood and cerebrospinal fluid 6-9.
It is centrally produced in an endocrine 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 membrane 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 receptor‐independent effects 23-25.
Pineal melatonin production is under control of the paraventricular nucleus of the hypothalamus.
The activation/deactivation of this complex neural pathway controlling pineal melatonin synthesis is under the precise control of the master circadian clock, the suprachiasmatic 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 behavioral 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 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 conditions, the physiological system that controls melatonin synthesis allows the nocturnal profile of circulating melatonin to vary according to the duration of the daily scotoperiod reflecting therefore the season of the year and acting as a neuroendocrine mediator of the photoperiod 27, 37.
Melatonin and energy metabolism
All physiological and behavioral processes of the body are organized to balance energy intake, storage, and expenditure. The energy balance guarantees the individual's survival, 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 harvesting 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 circadian 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 metabolism, 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 perspective 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 experiments 48-52 demonstrated that infusion of pineal extracts led to hypoglycemia, increased glucose tolerance, and hepatic and muscular glycogenesis after glucose loading, while pinealectomy induced a diminished glucose tolerance 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 resistance 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 several alterations in other metabolic parameters can be seen in some physiological or pathophysiological states associated with reductions in blood melatonin levels, as aging, diabetes, shift work, and environmental high level of illumination 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 resistance and glucose intolerance is related to the cellular consequences 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 phosphorylation and activation of the tyrosine kinase β‐subunit of the insulin receptor, and mobilizing several intracellular transduction 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 functional synergism between melatonin and insulin was published 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 C14‐2‐deoxy‐D‐glucose uptake stimulated by insulin to the left. This was the first demonstration 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 adipocytes. This indicated that the adipose tissue is a peripheral target of melatonin for the regulation of the overall 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 possible to document the synergistic effect of melatonin on several other insulin actions in addition to glucose uptake. In a series of reports, Alonso‐Vale et al. 42, 79, 80 demonstrated 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 melatonin‐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 differentiation, and fatty acids uptake among others 78, 81, 82, 42, 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 content of PKCα‐subunit, in parallel to a reduction in cGMP. In addition, through MT1 activation, melatonin induces insulin receptor, IRS‐1, AKT, ERK1/2, and STAT3 phosphorylation, 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 glucagon‐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.
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 accomplished using direct or indirect neural connections and/or humoral/hormonal mediators. As mentioned above, melatonin is one of these mediators, being one of the most important internal synchronizing agents. As a consequence, 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 maintenance 103, 104.
The energy balance and energy metabolism are under control of the circadian system and exhibits a clear differential 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 glucose 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 period that requires the use of stored energy for the maintenance of cellular processes. This phase of the daily cycle exhibits insulin resistance, accentuated hepatic gluconeogenesis 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 variation 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 after awaking, the glucose tolerance and insulin sensitivity were reported as the highest of the day, and both diminished as the day progresses reaching their nadir at the time of sleep onset.
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, metabolic adaptations to activity/feeding and rest/fasting 54, 58, 59, 80, 123, and daily distribution of glycogen synthesis and lipogenesis as opposite to those of glycogenolysis and lipolysis 123 (Fig. 2). The picture of circadian metabolic chronodisruption 113, 124 in pinealectomized animals is reversed by the appropriate melatonin replacement therapy.
To emphasize this critical role of melatonin, it is documented that the adult offspring of pinealectomized dams experience a misalignment of their circadian rhythms of energy metabolism by misplacing gluconeogenesis predominance to the active/feeding daily phase. Rhythmic melatonin replacement therapy to the pregnant mothers completely eliminates this dyssynchrony 102.
Other hormones that exert powerful influences on cellular metabolism, for example, glucocorticoids, growth hormone, and catecholamines, also show circadian rhythmic fluctuations in their secretion and action. One of the putative 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 exposure 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, particularly Bmal1, Clock, and Per1. More interesting, however, was that important metabolic functions of the adipocytes were synchronized by the rhythmic addition of melatonin so that during the in vitro induced night (melatonin 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 subjective 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 expenditure. 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.
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 animal. 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 period (14 wk) and disappeared with the interruption of melatonin 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 metabolism, 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‐treated 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 expenditure rather than a reduction in the energy intake. This elevation in core body temperature is consistent with a rise in the energy expenditure dependent on the trophic and metabolism‐activating effect of melatonin in the brown adipose tissue (BAT) and in the browning of the white adipose tissue 139-143.
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 intolerance that might be partially responsible for the observed age‐associated weight gain. Related to this, we recently demonstrated 149 that the rhythmic melatonin supplementation 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, melatonin supplementation of aging rats improves considerably the metabolic and body weight reduction beneficial effects of physical training 57.
Referência :
J Pineal Res. 2014 May;56(4):371-81.
