Given the complexity of treating obesity, researchers of UNICAMP and Obesity and Comorbidities Research Center (CEPID OCRC) are investigating new alternatives. Among them is the repurposing of medications already approved for other conditions. In a multidisciplinary thematic project, the group led by Prof. Dr. Gabriel Forato Anhê is analyzing how melatonin receptor agonists, used in the treatment of sleep and mood disorders, may impact energy metabolism and eating behavior.
To learn more about the project, Farmaco em Foco spoke with Prof. Gabriel and two of his students, PhD candidates Carolina Namie Sato Cortezão and Yuri Richard Silva da Conceição.
From Physiology to Innovation
Prof. Gabriel has built his academic career by bridging physiology and pharmacology. His research focuses on the endocrine mechanisms that regulate metabolism. Over the years, he has conducted studies investigating obesity and diabetes, as well as their relationships with pregnancy, lactation, and respiratory allergies.
Prof. Gabriel holds a degree in Pharmacy-Biochemistry from the University of São Paulo. He then completed his PhD and postdoctoral training in Human Physiology at the Institute of Biomedical Sciences at the same institution, where he deepened his studies in the pathophysiology of diabetes. He is currently a professor in the Graduate Program in Pharmacology at the School of Medical Sciences of the State University of Campinas (UNICAMP).
Currently, Prof. Gabriel is one of the principal investigators of a thematic project funded by FAPESP (grant no. 23/01448-7), titled “The search for new targets for the prevention and treatment of obesity.” The project is coordinated by Prof. Dr. Licio Augusto Velloso and brings together a multidisciplinary team that, in addition to Prof. Gabriel, includes Prof. Dr. Bruno Geloneze Neto and Prof. Dr. Eliana Pereira de Araujo, All researchers from UNICAMP and the Obesity and Comorbidities Research Center (CEPID OCRC).
In this project, researchers aim to investigate new targets for the prevention and treatment of obesity. With an expected duration until 2030, the study combines research in humans and experimental models and is structured around three main axes.
The first axis investigates the role of the hypothalamus, a region of the brain, in regulating hunger and energy expenditure. The second axis evaluates the function of brown adipose tissue (a specialized type of body fat) as a modulator of metabolism. Finally, the third axis examines how metabolism is programmed from gestation, influencing the future risk of obesity.
Overall, the project integrates multiple approaches to expand current knowledge on obesity and, ultimately, pave the way for more effective therapeutic strategies against the disease and its complications.
Why Doesn’t Every Treatment Work?
Obesity is a complex disease, which makes it difficult to treat. It can have causes of different natures. For example, it may result from hypothyroidism, other disorders affecting energy expenditure, binge eating, genetic factors, among others.
Therefore, there is no single treatment for obesity. Prof. Gabriel comments: “Today we are experiencing a revolution of ‘weight-loss pens.’ They act through a pathway that seems common to most cases of obesity, but even so, there is a portion of people who are non-responsive.”
Studies show that approximately 1 in 5 people do not respond to treatment with these “weight-loss pens,” such as Ozempic, Mounjaro, and Wegovy. This highlights the importance of discovering new treatments for obesity.
Obesity is often associated with psychological and psychiatric disorders. These conditions can affect a person’s eating patterns, leading to eating disorders. Such cases contribute to forms of obesity that are more difficult to treat, especially those associated with a condition known as night eating syndrome (NES).
This syndrome is characterized by a major imbalance in the distribution of calorie intake throughout the day. If 25% of daily caloric intake occurs between 8:00 p.m. and 5:00 a.m., the condition is considered present. In addition to increased nighttime eating, morning anorexia (lack of appetite in the morning) is also observed. Although less common, even lean individuals may present this syndrome.
Prof. Gabriel explains: “In this syndrome, the person craves foods with high caloric density and high levels of sodium, sugar, and saturated fat. You never wake up at night craving an apple. ‘Oh, I feel like eating a salad, I can’t sleep.’”
Finding treatments specifically for these cases of obesity has long been a challenge in medicine. These are precisely the cases on which Prof. Gabriel’s research group is focusing its efforts.
The Potential of Melatonin Receptor Agonists
Prof. Gabriel explains his role within the thematic project: “There are several pharmacological alternatives being studied. I, in particular, will focus on drugs that are already approved for other purposes.” These drugs are melatonin receptor agonists. They act mainly in the hypothalamus, activating the same pathways that melatonin naturally activates in the brain.
Using these drugs to treat obesity may seem unusual, but this approach has a long history. Prof. Gabriel has been studying the effects of melatonin for years, with a focus on energy metabolismo, that is, the processes the body uses to convert food into energy.
Prof. Gabriel is investigating the potential of two melatonin receptor agonists: ramelteon and agomelatine.
Ramelteon is the first selective agonist of the MT1 and MT2 melatonin receptors. It is indicated exclusively for sleep disorders. Ramelteon is more potent and has a longer half-life than melatonin. This means that lower doses are required compared to melatonin, and its effects last longer.
Agomelatine, on the other hand, is also an agonist of MT1 and MT2 receptors but acts as an antagonist of serotonin 5-HT2C receptors. In other words, it blocks the effects of serotonin on these receptors (one of the many pathways through which serotonin acts). Agomelatine is an older drug than ramelteon and is approved for the treatment of mood disorders, such as depression.
Prof. Gabriel is studying the repurposing of these medications for the treatment of obesity. He explains how this idea emerged: “I chose to study agomelatine because there are some phase 3 clinical trials with a small number of participants showing that depressed and diabetic patients who used agomelatine as an antidepressant had some improvement in glycemic control markers, especially glycated hemoglobin.”
In other words, researchers conducted studies to confirm that agomelatine was effective for treating depression (phase 3 clinical trials). Although this was the primary goal, improvements in diabetes-related parameters were also observed. Diabetes and obesity are closely linked, and “weight-loss pens” are used to treat both conditions. These findings suggest that agomelatine may have additional effects beyond mood regulation that are worth exploring.
On the other hand, clinical trials with ramelteon did not demonstrate relevant metabolic outcomes. Even so, since it is also a melatonin receptor agonist, investigating its effects on obesity remains of interest.
When the Biological Clock Is Disrupted
But why specifically investigate melatonin receptor agonists? Prof. Gabriel has observed a strong correlation between eating disorders, obesity, and melatonin production. This is particularly relevant when considering that the most difficult cases of obesity to treat are those associated with night eating syndrome.
Together with his former student, Dr. Juliana de Almeida Faria, Prof. Gabriel developed an animal model that simulates night eating syndrome, in which they observed intriguing results related to melatonin production.
The first point to understand about this model is that mice and rats operate in antiphase relative to humans. This means that while humans are more active and eat more during the day, these rodents do so at night (dark phase). Conversely, humans rest at night, whereas these animals rest during the day (light phase).
In the experimental model, during the daytime, the animals’ water is replaced with a 10% fructose solution. This concentration similar to that found in most commercial soft drinks. Prof. Gabriel explains: “Normally, the animal wakes up a few times during the day. When it drinks water, it actually consumes fructose. Because it is sweet, fructose stimulates the reward system and keeps the animal awake.”
He adds: “Over time, the animal stays awake during the day, when it should be sleeping. While awake, it also eats chow, moves around, and increases its energy expenditure.”
This approach makes it possible to simulate night eating syndrome in animals. In this condition, humans remain awake at night and consume more food than during the rest of the day. A similar pattern occurs in the animals, but during the daytime, when they should be resting.
In this model, researchers observed that the animals developed several metabolic alterations, such as glucose intolerance, which is associated with type 2 diabetes and obesity. In addition, a reduction in melatonin production was observed. When melatonin was supplemented, part of these metabolic alterations was reversed.
Considering the condition in humans, a similar mechanism may occur. At night, light exposure (especially blue and white light) inhibits melatonin production. Individuals with the syndrome remain awake, eating, and often active. During this period, the main sources of light are electronic screens and artificial lighting. As a result, melatonin production is suppressed while the person eats at times that are misaligned with the body’s natural rhythms.
New Generations in Research
Currently, two PhD candidates supervised by Prof. Gabriel are working with melatonin receptor agonists: Carolina Cortezão and Yuri da Conceição. Both investigate how metabolism can be programmed.
Although neither of them worked directly with obesity during their master’s studies, both already had some proximity to the topic. For them, curiosity about the field was the main motivation for joining the lab.
Yuri comments: “During my master’s, I started developing research on behavioral alterations in diabetes. But I wanted to see something more applied to disease treatment. While searching, I came across Prof. Gabriel’s CV.”
In Carolina’s case, her interest arose after a conversation with Prof. Gabriel, who served on the evaluation committee for her master’s qualification. She reflects on her previous experience and connection to the field: “I didn’t work exactly with obesity during my master’s, but I worked with POMC neurons, which are important for inhibiting food intake and increasing energy expenditure.”
The Impact of Maternal Diet on the Brain
Yuri has been in his PhD program for over three years. He explains his project: “I investigate the modulation of the reward system by maternal consumption of a high-fat diet.” In other words, he studies the offspring of mothers that became obese due to a high-fat diet. In particular, he aims to understand whether the reward system in these offspring is altered. This system is a network of brain regions that makes us feel pleasure when we engage in activities that promote well-being, such as eating. An altered reward system can lead to eating disorders.
In this context, Yuri also investigates the effects of ramelteon treatment in these offspring, comparing results between males and females. Interestingly, he observes that the drug produces different responses depending on sex.
Prof. Gabriel highlights the importance of this approach: “Classical pharmacology used to investigate only the effects in males and extrapolate the results to the entire population, including females. However, the prevalence of night eating syndrome is not the same between men and women, nor is that of psychiatric disorders related to binge eating.” Therefore, it is important to break with this outdated tradition in pharmacological research.
Yuri’s project has particular aspects that make it especially challenging. He explains: “The hardest part is that the experiments are long. To know if it worked, I have to wait about six months. I need to induce obesity in the animals, then carry out mating and wait for the offspring to be born. In the process, I have to deal with uncertainties. For example, fertility is lower in obese females. Sometimes I expect a number of animals that I don’t end up getting.”
The Developing Hypothalamus
Carolina has just begun her project. She will focus on the hypothalamus of neonatal mice (newborns), particularly on the hypothalamic nuclei that regulate energy expenditure and food intake. She will evaluate the effects of melatonin and melatonin receptor agonists on these nuclei, observing neurogenesis (the formation of new neurons) and neuronal death.
Carolina explains her approach: “We know that melatonin plays a role in stimulating neurogenesis. Using melatonin, ramelteon, and agomelatine, I will investigate the role of MT1 and MT2 receptors in neurogenesis. It is still unclear which of these receptors is involved in this process.”
Thus, Carolina will examine another parameter of metabolic regulation. In some of her experiments, she will simulate an event that may occur during or after pregnancy: hypoxic-ischemic encephalopathy, that is, when the brain does not receive sufficient blood and oxygen. Carolina explains: “For example, when the umbilical cord ends up wrapped around the fetus’s neck.” This injury may affect the hypothalamus and, consequently, modulate metabolism.
Melatonin or Agonists?
But why investigate the repurposing of melatonin receptor agonists instead of using melatonin itself? Even for sleep disorders, where many people commonly use melatonin, agonists may be a more suitable option.
Today, melatonin is widely used for sleep disorders. Prof. Gabriel comments: “Melatonin helps you fall asleep. But it has no effect on sleep duration or quality.” Strong marketing around melatonin often creates the impression that it improves sleep overall. However, issues such as frequent awakenings or poor sleep quality may still persist.
In addition, many individuals with chronic sleep disorders begin using melatonin on their own and report the same frustration: it “loses its effect” over time. This phenomenon is common, as Prof. Gabriel explains: “The problem is that more than 90% of orally ingested melatonin is metabolized through the first-pass effect. And this process is inducible.”
The first-pass effect is an event that occurs when a drug is taken orally. After ingestion, the compound enters the bloodstream but is not immediately distributed throughout the body. Instead, it follows a specific route.
Blood vessels from the digestive tract first carry the drug to the liver and only then to the rest of the body. It is like taking a bus that must stop at a terminal before you transfer to another one that takes you to your final destination.
In the liver, the drug undergoes metabolism. During this process, enzymes modify its molecules, facilitating excretion (for example, through urine) and reducing its effects. This is a natural mechanism the body uses to handle foreign substances and eliminate them safely.
As Prof. Gabriel explained, almost all melatonin undergoes this process when taken orally, leaving only about 10% available to exert an effect. Moreover, this process is inducible, meaning the body adapts over time, becoming more efficient at metabolizing the substance. As a result, the more melatonin is consumed and the longer it is used, the greater its degradation, explaining the loss of effect over time.
There are also other issues associated with melatonin use. Prof. Gabriel comments: “There are studies showing that high doses of melatonin are teratogenic, so it should not be used during pregnancy.” A teratogenic substance is one that can cause developmental abnormalities in the fetus.
For these reasons, melatonin may not be the best option for treating sleep disorders and, consequently, may also not be the most suitable approach in the context of obesity. An alternative is melatonin receptor agonists, which can activate the same pathways as melatonin in the body but without the limitations associated with first-pass metabolism.
At the end of the interview, Prof. Gabriel shares a message for those struggling with obesity: “Do not feel guilty. People with hypertension do not feel guilty for being hypertensive. People with hypothyroidism do not feel guilty for it. Culturally, there is a tendency to assign blame to being obese, but this becomes a barrier to treatment. Obesity has complex causes. Regardless of the cause, the individual is not to blame. Even if a person wakes up at night to eat. Even if they are addicted to eating. Addiction is a disease.”
This article was produced with the support of the São Paulo Research Foundation (FAPESP), Brazil. Grant No. 25/17158-3. The opinions, hypotheses, conclusions, or recommendations expressed in this material are the responsibility of the author(s) and do not necessarily reflect the views of FAPESP.
Learn more:
Weight-loss injections (DOI: 10.1136/bmjopen-2024-089477)
Night eating syndrome (DOI: 10.1038/sj.ijo.0802186)
Animal model of night eating syndrome (DOI: 10.3390/nu9040332)
Agomelatine in patients with depression and diabetes (DOI: 10.3390/ijms252312631)
Agomelatine in obesity and metabolic parameters (DOI: 10.1016/j.biopha.2021.111807)
Melatonin and metabolic syndrome (DOI: 10.9789/2175-5361.rpcfo.v17.14086)
Written by:
Mia Schezaro Ramos
Pharmacist. Ph.D. in Pharmacology. Science journalist, illustrator, trans, Nintendo enthusiast, K-pop fan, and dependent on physical exercise to stay sane.