LÉO RAMOSIt has been known for some time that melatonin plays a role in regulating sleep. The hormone is produced by the pineal gland, situated in the center of the brain. Now there is evidence that it also plays a key role in hunger control, in the accumulation of fats and in energy consumption. “In the absence of melatonin, mice developed metabolic diseases and became obese. Yet its replacement led to weight loss,” says José Cipolla Neto, a physiologist at the University of São Paulo (USP). He coordinated a series of animal experiments, conducted in partnership with other researchers from São Paulo, France and the United States, demonstrating that melatonin levels, which fluctuate throughout the day, affect food intake and energy expenditure, the so-called energy balance of the body.
Cipolla and his colleagues began to identify the influence of this hormone on hunger and energy accumulation using a classic strategy of physiology. According to this strategy, to know how a certain component of a system works, one must eliminate it and see what happens. They surgically removed the animals’ pineal gland, halting production of the hormone, and then they tracked the changes that occurred. Then, as the piece they removed was put back in place, they reversed the effect, restoring the melatonin orally and registering how the functioning of various organs and tissues activated by melatonin were affected. The experiments revealed that energy metabolism has a daily temporal organization synchronized by melatonin.
As it gets dark, the pineal gland begins to release melatonin until it reaches a maximum concentration, flooding the body with the hormone. From this peak, which occurs around the middle of the night, its concentration decreases and remains low during the morning and the afternoon; these levels are 10 times lower than at night. In the case of humans and other mammals active during the day, the lower concentrations coincide with the period of greatest activity. Humans and other mammals eat during the day—or at least eat more than at night—and store more energy than they expend.
The energy stored as fat or sugar stocks during the day ensures that the body continues to function at night, usually the rest period when melatonin levels are high and the body spends hours fasting. A significant portion of this energy is used by brown adipose tissue—this type of fat expends energy, while white fat is stored—to produce heat and keep the body warm at a time when there is little muscle contraction (another heat source). Energy consumption by brown fat is so high at night that, on balance, it offsets what was stored during the day. As a result, there is almost no change in weight.
“From an evolutionary standpoint, this temporal organization of energy metabolism must have been fundamental to the survival of mammals,” says Cipolla, a Brazilian pioneer in chronobiology studies, an area of science that investigates how biological phenomena change over time. Producing energy reserves during activity, he says, makes it possible to survive safely at night, at a time of fasting and sleeping, usually in a separate environment that is less susceptible to predators.
In laboratory tests, Cipolla observed that after a certain period of time, mice that did not produce melatonin presented metabolic disorders associated with the development of obesity. Sugar levels (glucose) and fats (lipids) in the blood were higher than normal, which led to energy storage in the form of fat in white adipose tissue and in the liver. In addition to having more energy available to store, the animals also began eating more and at odd hours, in addition to expending less energy. Cipolla believes these changes are the direct result of reduced melatonin, a hormone that, as he has shown, helps control hunger and stimulates brown adipose tissue (concentrated around the neck, under the collarbone and along the spine) to expend energy.
Interruption in timing
Without melatonin, the animals lose their metabolic daily rhythmic pattern of organization. “An interruption in the internal clock occurs,” says Cipolla. As a result, the brain ceases to perceive satiety and appetite increases. And so the animals eat at odd hours. To make matters worse, their bodies use less energy. If before the animals accumulated energy when they were awake and expended it during rest, alternating periods of storage with periods of fat burning, they now begin to build energy all the time and grow fatter.
Cipolla also noted that it was possible to reverse the effects of the interruption in the internal clock by administering melatonin orally to the animals. The phenomenon also occurs in humans who experience excessive exposure to light (especially the bluish light of computer screens, tablets, cell phones and LED TVs) and in those who work nightshifts. “The mice receiving the melatonin hormone replacement lost weight,” he says. Those treated with melatonin shortly after removal of the pineal gland showed no changes in energy metabolism.
Administering the hormone also had a protective effect on older and obese mice, which produce less melatonin than young and healthy animals. In one of the tests, the mice that received melatonin for eight weeks gained the equivalent of 1.3% of body weight, while those receiving only water and their normal diet gained 4.7%. The longer the treatment, the more pronounced the differences. For example, the group treated for 12 weeks with a mixture of water and melatonin lost 2% of their body weight, while the group receiving only water weighed on average almost 8% more at the end of the period, according to a study published in 2013 in the Journal of Pineal Research.
Cipolla is working in partnership with colleagues from USP, the Federal University of São Paulo (Unifesp), the Butantan Institute and the United States. Their work indicates that a significant reduction in melatonin levels, as observed in mice, increases hunger and leads to weight gain in two direct ways and one indirect way. Higher levels of melatonin, such as those released at night, act directly on a region of the brain called the hypothalamus to inhibit hunger. Therefore, less melatonin means an increased appetite. Another direct effect of the decrease of this hormone is a reduction of energy burning by brown fat tissue.
Indirectly, melatonin reduction deregulates the production and action of the insulin hormone and reduces leptin production by adipose tissue—two hormones that also act on the hypothalamus to inhibit hunger. Without melatonin, or with very low levels of it, two of the brain’s curbs on appetite are lost and less energy is expended. Experimental studies also indicate that in the absence of melatonin, the body produces more ghrelin, a hormone that induces hunger.
It is suspected that this change in the production and action of insulin initiates a feedback process and generates a vicious circle. Animals that produce less insulin also secrete less melatonin. This was shown in an experiment using mice with Type 1 diabetes, a disease that causes a significant decrease in insulin production. The reduction in insulin levels, however, only explained 20% of the decrease in melatonin production. Cipolla and his colleagues found that what most influenced the decrease in sleep hormone levels were high blood glucose concentrations (hyperglycemia), a common indicator of uncontrolled diabetes. Tests done on human subjects have shown that the smaller the production of melatonin at night, the higher the fasting glucose.
This result also raises the possibility that something similar may occur in Type 2 diabetes, a much more frequent form of the disease. It is estimated that about 10% of adults will develop Type 2 diabetes, one of the consequences of obesity and now considered an epidemic in the western world. Tests done with mice that had Type 1 diabetes and mice that had Type 2 diabetes showed that melatonin supplementation helped to synchronize metabolism in the activity and rest phases, improved insulin action and helped to regulate the intake and metabolism of lipids.
In studies soon to be published, Cipolla and his team showed that using insulin and melatonin to treat animals with Type 1 diabetes regulated the rhythm of their daily variations in body temperature. This was an indirect indication that the interruption in timing had been overcome while the general health of the animals also improved. This set of results, Cipolla believes, indicates that melatonin supplementation may, in certain cases, play an important role in preventing and improving these metabolic problems. “Especially if they are at an early stage,” he says.
A fundamental contribution of the group was to elucidate how melatonin helps the body to maintain temporal synchrony with the environment. It was already known that the retina, the light-sensitive tissue that lines the back of the eye, sends signals to the biological clock in the hypothalamus. This, in turn, stimulates the pineal gland to produce melatonin at night and inhibits synthesis during the day. But how does melatonin synchronize metabolism throughout the 24 hours of the day, if it is only secreted at night?
Cipolla and his colleagues found that, once melatonin is released in the blood, it activates a set of genes—the so-called clock genes— in the cells of different parts of the body that act as peripheral synchronizers. They transmit the information from the central clock to all the cells in the body.
In the cells, these genes trigger a chain of molecular events that last about 24 hours and signal the time at which the various metabolic reactions must occur. This mechanism can help us to understand the pattern of how various organs and body tissues work.
Setting the hands of the clock
“Melatonin is already used to treat sleep disorders and could be administered to help restore the circadian pattern for releasing other hormones,” says Marcio Mancini, an endocrinologist at the USP School of Medicine. As a matter of fact it regulates the production cycle of hormones such as cortisol, released in stressful situations; leptin and ghrelin, which regulate hunger; and the growth hormone, which helps repair cell damage. “But it is still necessary to demonstrate that what we observed in mice also occurs in humans,” says Mancini.
Evidence that melatonin may help control blood glucose and lipid and cholesterol levels in humans has begun to appear in recent years. A clinical study done in the U.S. and published in 2011 in the journal Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy indicated that in patients with Type 2 diabetes and insomnia, melatonin improved sleep after three weeks and helped control blood glucose after five months. Another clinical test, described in the Journal of Pineal Research, also in 2011, showed that after two months of treatment with melatonin, people with metabolic disturbances were able to reduce both their blood pressure and cholesterol levels.
Even with these findings, Cipolla is cautious and points out that there is no easy solution to metabolic problems. “Melatonin can become an adjunct to the treatment of these disorders and may play an especially important role in their prevention,” he says. “After so many years of experimental studies, the time has come to carry out well-designed and adequately controlled clinical studies to test the role of melatonin in human metabolic pathophysiology.”
There is still much work to be done. The efficacy and safety of melatonin to treat these problems in humans must first be determined. In the event that it does work, regulations governing the sale of this hormone in Brazil must also be changed. Because of widespread misuse in the 1990s, the Brazilian Health Surveillance Agency (ANVISA) prohibited the sale of melatonin, although its use may be permitted. Cipolla himself imports a salt supplement from the United States and uses it here for his experiments—and also purchases some tablets for personal use.
The role of melatonin in the control of energy metabolism: central and peripheral actions and the circadian timing of the metabolic function. Pineal, diabetes, obesity and aging (2009/ 52920-0); Grant mechanism: Thematic Project; Principal investigator: José Cipolla Neto (ICB-USP); Investment: R$1,849,483.52 (FAPESP).
CIPOLLA-NETO, J. et al. Melatonin, energy metabolism and obesity: a review. Journal of Pineal Research. V. 56, p. 371-81. 2014.
AMARAL, F.G. et al. Environmental control of biological rhythms: effects on development, fertility and metabolism. Journal of Neuroendocrinology. V. 26, p. 603-12. 2014.
AMARAL, F.G. et al. Melatonin synthesis impairment as a new deleterious outcome of diabetes-derived hyperglycemia. Journal of Pineal Research. V. 57, p. 67-79. 2014.