José Cipolla Neto talks about his group's research, showing how melatonin controls insulin synthesis and the organism's response to physical activity (images: personal file and Wikipedia)

Research shows lack of melatonin causes obesity and diabetes

Besides regulating sleep, melatonin controls food intake, energy expenditure, energy accumulation in adipose tissue, insulin synthesis, and the organism's response to physical activity.

Research shows lack of melatonin causes obesity and diabetes

Besides regulating sleep, melatonin controls food intake, energy expenditure, energy accumulation in adipose tissue, insulin synthesis, and the organism's response to physical activity.


José Cipolla Neto talks about his group's research, showing how melatonin controls insulin synthesis and the organism's response to physical activity (images: personal file and Wikipedia)


By Karina Toledo

Agência FAPESP – Research conducted at the University of São Paulo’s Biomedical Science Institute (ICB-USP) in Brazil shows that melatonin can be an important ally in combating metabolic disturbances such as diabetes, hypertension and obesity.

A research group led by medical doctor José Cipolla Neto recently completed their third FAPESP Thematic Project on the role of melatonin in energy metabolism. Their findings suggest that melatonin is responsible for far more than regulating sleep; it also controls food intake, energy expenditure, the accumulation of energy in adipose tissue, and insulin synthesis and action in cells.

Furthermore, the hormone is a key anti-hypertensive agent, regulates the organism’s response to aerobic physical activity, and participates in the formation of neurons during fetal and post-natal development.

Partial findings from the latest Thematic Project were published in the Journal of Neuroendocrinology in September 2014 and in the Journal of Pineal Research in May and August 2014.

In an interview with Agência FAPESP, Cipolla Neto commented on the main experiments performed, the factors that may impair melatonin synthesis, and how melatonin supplementation can help in the treatment of disease.

Agência FAPESP – What findings from your group’s research on the role of melatonin in energy metabolism regulation would you highlight?
José Cipolla Neto – Our data confirm the importance of melatonin for the control of food intake, energy expenditure by the organism, and the storage of energy at sites such as adipose tissue and the liver. The final result of this energy balance is body weight. We can say that melatonin plays a fundamental role in regulating body weight. This is the main conclusion of these years of work funded by FAPESP.

Agência FAPESP – How does this regulation work?
Cipolla Neto – In several ways. Above all, melatonin is a powerful regulator of insulin secretion and action. As a pro-insulin and anti-diabetogenic hormone, it performs many functions in the organism. One of the most important of these functions is regulating the diversion of ingested energy to energy stores as well as withdrawing energy from stores for use in day-to-day activities. Thus, melatonin can be considered as a possible assistant in the treatment of type 2 diabetes, which derives from insulin resistance. Even in type 1 diabetes, which involves underproduction of insulin, melatonin could improve the action of this pancreatic hormone. It’s also a powerful anti-hypertensive agent. Another key point about melatonin, already well established in the literature, is that it’s an important chronobiotic, meaning that it regulates the organism’s rhythm. At certain times of day, we wake up, expend energy while interacting with the environment, and acquire energy from food. At other times, we don’t interact with the environment but rest and consume stored energy. This daily energy balance and metabolism are basically regulated by melatonin. When melatonin is removed from animals in experiments, we observe a reduction in insulin action and deregulation of the circadian cycle. This also happens to anyone who produces less melatonin for some reason. Underproduction of melatonin leads to a metabolic disturbance, resulting in obesity, insulin resistance and high blood pressure.

Agência FAPESP – What kind of experiments did you do to reach these conclusions?
Cipolla Neto – The basic experiment involved performing a pinealectomy [surgical removal of the pineal gland, which produces melatonin] in rats and observing the effects of the lack of melatonin on metabolically important tissue, such as fat, muscle, the liver, the central nervous system and the pancreas. Two or three months later, without any other changes to routine or diet, the animal already displayed insulin resistance, hypertension and the beginnings of obesity. When melatonin was replenished, the situation was completely reversed. In groups in which replenishment began on the same day as removal of the pineal gland, the animals didn’t develop any metabolic disturbances at all. In parallel, we performed studies with aging animals, which are known to produce less melatonin. Melatonin replenishment eliminated the metabolic changes typically found in aging animals. We also demonstrated that melatonin is essential to the organism’s response to aerobic exercise. In animals from which the pineal gland had been removed, the beneficial metabolic adaptations promoted by exercise disappeared. In another study, we showed definitively that melatonin production is lower in rats with experimental type 1 diabetes and in patients with type 1 diabetes who produce little or no insulin. Thus, these individuals suffer all of the metabolic consequences relating to a lack of melatonin. We also showed that the cause of falling melatonin production in this case is hyperglycemia, which alters the functioning of certain enzymes in the pineal gland that are responsible for synthesizing melatonin. Type 1 diabetics are therefore strong candidates for melatonin supplementation.

Agência FAPESP – Besides hyperglycemia, what else can impair melatonin production?
Cipolla Neto – The main cause of reduced nocturnal melatonin production is photostimulation. Most people start producing this hormone around 8 p.m. When an individual is exposed to light after sunset by watching television or using a smartphone or computer, the melatonin synthesis that should be occurring during this period is blocked. This may be one of the factors behind the epidemic of obesity in contemporary society. There are also factors linked to medical intervention. Several drugs used in clinical medicine alter melatonin production. They include beta blockers, calcium channel blockers and angiotensin-converting enzyme inhibitors, all of which are used to control high blood pressure. The most powerful factors are unquestionably nocturnal light pollution and night-shift work.

Agência FAPESP – Does the time at which melatonin synthesis begins vary between morning and evening types?
Cipolla Neto – It starts around 8 p.m. in about 75% of the population. In evening types, melatonin production starts later, and in morning types, it starts earlier. There’s a variation according to chronotype that also determines the time at which blood levels of melatonin are low enough for the individual to wake up.

Agência FAPESP – But nowadays, a lot of people are woken up by a bedside alarm.
Cipolla Neto – This is another potentially harmful factor. Evening types produce melatonin for a longer period in the morning and are more deprived of this hormone when they need to wake up early and are exposed to daylight sooner.

Agência FAPESP – How should daily routine be made less harmful for people who can’t go to sleep early or wake up late?
Cipolla Neto – One suggestion that’s been made is eliminating the wavelength of blue light, around 480 nanometers, which controls circadian rhythms and melatonin production. Display manufacturers and bulb suppliers are working on this. Studies have shown that if the intensity of blue light in the nocturnal environment is low, people can go on working without significantly impairing their circadian rhythm and melatonin production. But this is precisely the wavelength of light emitted by the blue LEDs used in computers, TV sets and smartphones. There are firms that sell blue-blocking film for display screens. That’s one way of addressing the problem.

Agência FAPESP – What would be recommended for children?
Cipolla Neto – Children’s melatonin production profiles and circadian rhythms are completely different from those of adults, but the effects of nocturnal lighting are the same and even more harmful. Children with less melatonin and with sleep disturbances are strong candidates for metabolic disturbances in adult life. A very sharp increase in insulin resistance has been observed in adolescents. Until puberty, the circadian rhythm is being structured, and any factor that impairs melatonin synthesis will affect a number of functions in the organism, including pubertal development.

Agência FAPESP – In what cases is melatonin supplementation indicated?
Cipolla Neto – There’s already international support from several medical associations for melatonin supplementation to treat certain kinds of insomnia as well as jet lag, which is a circadian rhythm disorder. We also have very strong evidence that melatonin can be a major therapeutic agent against cancer and hypertension and an energy metabolism regulator, but the most suitable treatment for these three conditions is still being studied.

Agência FAPESP – Do you believe doctors will soon prescribe melatonin for patients with obesity, high blood pressure and diabetes?
Cipolla Neto – Yes, undoubtedly. Treatment with beta blockers, for example, removes a physiological component that’s important to combat hypertension. It would be a good idea for these patients to take a melatonin supplement. Cardiologists are currently discussing this.

Agência FAPESP – Might continuous ingestion of a melatonin supplement lead to a reduction in endogenous production?
Cipolla Neto – No. Exogenous melatonin ingested by individuals is a powerful synchronizer of circadian rhythms and therefore helps normalize endogenous production. However, it’s crucial to note that in all circumstances, the consumption of melatonin should occur only at night, about an hour or half an hour before going to sleep.

Agência FAPESP – Does melatonin supplementation have side effects even when taken correctly?
Cipolla Neto – According to the literature, melatonin is an agent with no toxic effects. The only possible problem is circadian rhythm alteration if taken at the wrong time or dose. It should be used even more carefully by children. Depending on use and quantity, it could delay puberty. Nevertheless, the substance is prescribed to treat several childhood diseases with associated sleep disturbances, such as restless leg syndrome, Smith-Magenis syndrome, and even autism. By consolidating sleep, melatonin makes wakefulness more efficient and acts as a neuroprotective agent.

Agência FAPESP – Is the dose calculated according to weight?
Cipolla Neto – No. Melatonin is a capricious hormone. Every individual produces a different amount. Ideally, the physician should perform a prior assessment of the patient’s production level, but that isn’t always possible. My recommendation would be to do a sort of clinical trial. The smallest possible dose would be administered, and it could be increased later, depending on how the patient’s condition evolves, and stopped when the patient feels well and the signs and symptoms have been eliminated.

Agência FAPESP – If melatonin isn’t hazardous, why has it been banned in Brazil?
Cipolla Neto – Anvisa [the National Public Health Surveillance Agency] banned it about 20 years ago because it was being improperly used. Television commercials were being aired at the time with celebrities saying, “I’ve taken my melatonin today.” That was harmful. Melatonin is a hormone, and there must be very tightly controlled rules for its administration. Today, there’s sufficient evidence in the international literature for melatonin to be sold legally in Brazil as long as it’s prescribed by a physician.

Agência FAPESP – Do you plan to continue studying the action of melatonin?
Cipolla Neto – We’ve submitted a new project for evaluation, in which we intend to study the consequences of everything that we’ve discovered so far. From the experimental standpoint, we’re going to investigate how melatonin regulates the energy expenditure promoted by brown adipose tissue, a very distinct phenomenon evidenced by our previous research. We observed that animals that don’t produce melatonin expend less energy. We also demonstrated that during pregnancy, melatonin regulates the fetus’s metabolic programming. The offspring of animals deprived of melatonin during gestation develop a metabolic condition characterized by insulin resistance and insufficient insulin secretion. We want to find out exactly how melatonin interferes in this programming. There’s a huge amount of work showing that melatonin is important to neurogenesis in the central nervous system. We want to find out what happens in the hypothalamic circuits that regulate hunger, satiety and energy expenditure and to determine the stages of fetal and post-natal development in which melatonin is most important to neurogenesis. The second main part of the project consists of clinical studies. We plan to begin a large-scale multicenter study – involving researchers from the University of São Paulo (USP), the Federal University of São Paulo (UNIFESP), the University of Campinas (UNICAMP) and the Albert Einstein Jewish Hospital in São Paulo – on the role of melatonin in the regulation of the human energy metabolism. In a third part, we intend to study the social repercussions of manipulating melatonin production. This will involve studying the metabolic profile of the children of women who worked at night while pregnant. This new Thematic Project that we’re proposing will have as its external supervisor Professor Russel J. Reiter, of the University of Texas in the United States. He’s just been included in the Thomson Reuters list of The World’s Most Influential Scientific Minds.




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