Prof. Natália Ferreira Mendes’ research reveals how different fields of science can come together to unravel one of today’s greatest public health challenges: obesity. Through projects that connect neuroscience, immunology, metabolism, and vascular biology, the researcher investigates how high-fat diets trigger inflammation in the hypothalamus, the brain region responsible for controlling hunger, energy expenditure, and hormonal functions. In the future, her studies may pave the way for new therapeutic strategies against obesity.
The Scientist Connecting Brain, Metabolism, and Inflammation
Prof. Natália’s academic journey began with a degree in Nutrition at the Federal University of São Paulo. She also completed part of her undergraduate studies in Portugal, attending the Portuguese Catholic University and undertaking an internship in Experimental Nutrition at the University of Porto. She later completed her master’s and doctoral degrees at Unicamp. During her PhD, she carried out part of her research at Beth Israel Deaconess Medical Center, an institution affiliated with Harvard Medical School.
Currently, she works as a researcher in the Department of Translational Medicine at the School of Medical Sciences (FCM) and at the Obesity and Comorbidities Research Center (OCRC) at Unicamp, while also serving as a faculty member in the Graduate Program in Pharmacology at FCM/Unicamp. Today, she coordinates research projects funded by FAPESP.
Prof. Natália’s projects are particularly ambitious. They connect obesity, hormonal regulation, inflammation, and neuroscience. As she explains: “My academic background gradually led me to different fields that gave me knowledge in distinct areas. That’s why I designed a project that brought together all the experience I had accumulated.”
Prof. Natália investigates several aspects involved in hypothalamic inflammation associated with a high-fat diet: changes in blood vessels, the formation of new neurons, the recruitment of immune cells, and how all of this ultimately impacts metabolism. She explains: “I seek to understand how these structural changes in the hypothalamus are involved in regulating hypothalamic inflammation.”
When Fat Inflames the Brain
Prof. Natália’s projects are particularly complex because they involve many fields of knowledge. So buckle up, because understanding her research will be a long journey. Let’s start at the beginning: what happens when a person or animal consumes a high-fat diet?
One consequence of this diet, which is the focus of Prof. Natália’s studies, is hypothalamic inflammation. The hypothalamus is a brain region that plays an important role in controlling hunger, sleep, energy expenditure, and several other functions. Therefore, the hypothalamus is directly linked to obesity, especially when inflammation occurs in this region.
This is because hypothalamic inflammation causes several structural and functional changes in the hypothalamus. These include insulin and leptin resistance, involving hormones that act on the hypothalamus to regulate hunger and energy expenditure. If you feel hungrier and expend less energy, your body will store excess energy from food as fat, ultimately leading to obesity.
In the case of inflammation caused by the consumption of a high-fat diet, these alterations intensify over time. In other words, the longer an unbalanced diet is maintained, the greater the consequences become.
Another consequence observed in mice is apoptosis, the death of hypothalamic neurons that should regulate food intake. When these neurons die, the person or animal may develop binge eating behavior, meaning a loss of control over food intake, resulting in episodes of consuming large amounts of food in a short period of time.
Today, there are research lines focused on neurogenesis, the process of forming new neurons. Neurogenesis could potentially reverse the effects of apoptosis by replacing neurons that have died. Prof. Natália comments: “That’s why there are research lines like mine. We try to understand how these neurons can be formed again.”
How the Hypothalamus Creates New Neurons
To better understand all the consequences of hypothalamic inflammation, we first need to learn a bit more about the anatomy of the central nervous system, where the hypothalamus is located.
The central nervous system contains a fluid called cerebrospinal fluid (CSF), which helps protect, nourish, and transport important substances to neurons. CSF circulates through structures called ventricles, of which there are four in total. The hypothalamus surrounds the third ventricle. Prof. Natália explains: “It’s as if the hypothalamus were a ball with a pipe running through its center.”
In the “wall of this pipe” are cells called tanycytes. These cells are in contact both with what is circulating in the CSF and with the hypothalamus itself. Tanycytes are also present in a region below the hypothalamus called the median eminence. Prof. Natália comments: “It’s where the pipe ends, so to speak. The median eminence is a very small portion that is not technically part of the hypothalamus.” There, tanycytes also make contact with blood vessels in addition to the CSF.
By sensing changes in substances present in the CSF and blood, tanycytes can communicate this information to the hypothalamus. One of the signals sent by tanycytes is responsible for coordinating the formation of new neurons. This occurs especially in the hypothalamic region that regulates hunger and energy expenditure, known as the arcuate nucleus.
This is only possible because progenitor cells are found around tanycytes. These cells are capable of transforming into other cell types, such as neurons. Through tanycyte signaling, these progenitor cells are instructed on what they should become and where they should migrate.
The Brain’s “Sieve”
Another way the central nervous system protects itself is through the blood-brain barrier. This barrier acts like a filter in the walls of blood vessels, controlling what can leave the bloodstream and enter the nervous system. However, the blood-brain barrier is not present in the median eminence mentioned earlier.
Prof. Natália explains: “It’s as if the endothelial cells were full of tiny holes, like a sieve. We say these cells are fenestrated. This allows many substances to quickly move from the bloodstream into the median eminence.”
When a high-fat diet is consumed, the blood-brain barrier becomes more “leaky.” As a result, there is an increased entry of fatty acids (fats and oils) and other substances that ideally should not enter. Prof. Natália comments: “It’s like an avalanche of substances reaching the hypothalamus.”
When fatty acids enter, glial cells take them up in order to metabolize them. In other words, glial cells function as the brain’s cleanup and recycling team, attempting to process this excess fat. However, during this process, these cells release inflammatory cytokines, molecules that act as “warning signals” that initiate hypothalamic inflammation.
In addition, glial cells also produce chemokines. Chemokines act like a “chemical GPS,” guiding immune system cells to the site where inflammation is occurring. At this point, the story becomes even more complex, as new protagonists enter the scene: monocytes, immune system cells that are attracted to the hypothalamus during inflammation.
Monocytes Enter the Scene
Monocytes are defense cells of the immune system. Many monocytes circulate in the bloodstream, but they are also present in the spinal cord. This is because, during gestation, when we are still embryos, these monocytes are directed to the spinal cord, where they remain until they are “called into action.”
I say “called into action” because monocytes function as the body’s “patrolling soldiers.” When they detect signs of inflammation somewhere in the body, they migrate to that location to participate in the inflammatory process. These “signs of inflammation” are precisely the release of chemokines mentioned earlier.
In the context of hypothalamic inflammation, monocytes rich in CCR2 are involved. CCR2 is a receptor located on the surface of monocytes that can detect chemokines. When CCR2 detects a chemokine, it tells the monocyte where it needs to go. In other words, where inflammation and chemokine release are occurring. It is as if chemokines were a perfume and CCR2 were the monocytes’ nose, tracking that scent and identifying where it is strongest (in this case, the inflamed hypothalamus).
Chemokines, however, bind very specifically. It is as if there were several different perfumes (different types of chemokines) and several specialized noses trained to detect each scent (the receptors). Thus, for example, only the CCR2 receptor can detect the chemokine CCL2.
In her research, Prof. Natália observed that one specific receptor–chemokine combination is particularly important in hypothalamic inflammation: the CXCR4 receptor and the chemokine CXCL12. Interestingly, CXCR4 receptors are mainly found in tanycytes, the cells previously discussed that are important for signaling the formation of new neurons. Meanwhile, the chemokine CXCL12 is mainly present in endothelial cells, which form the inner walls of blood vessels.
In other words, tanycytes and endothelial cells likely interact in some way through the CXCR4/CXCL12 pathway. In the hippocampus (another brain region), this pathway has already been shown to be involved in the formation of new neurons. For this reason, Prof. Natália decided to investigate the importance of this pathway for the formation of new neurons in the hypothalamus as well.
Prof. Natália comments on the importance of this study: “Let’s suppose we are actually able to demonstrate that CXCR4 participates in neurogenesis in the hypothalamus. If you can block or stimulate CXCR4, you can modulate this receptor and, consequently, neurogenesis. If we find that this neurogenesis is beneficial for obesity treatment, we can increase it. Or, conversely, reduce it if it turns out to be harmful.”
In other words, understanding the importance of the CXCR4/CXCL12 pathway in the formation of new neurons in the hypothalamus may open the door to new obesity treatments. However, as Prof. Natália pointed out, it is first necessary to understand exactly how these new cells are formed, because the process may not be entirely beneficial.
Not Every New Neuron Is Good News
Today, it is already known that the hypothalamus has the ability to form new neurons, but there is a major problem: it is still unclear whether the newly formed cells will actually become neurons. They may also differentiate into other cell types, some of which could even intensify the negative effects of inflammation. Understanding exactly what is happening is essential.
Prof. Natália explains: “When we administer a high-fat diet, one of the things that happens is a process we call gliosis.” Gliosis occurs when the brain’s immune cells, such as glial cells, become highly reactive. These cells multiply and enlarge, forming what can be described as a “scar in the brain.”
Prof. Natália adds: “So, when we think about neurogenesis, we may also be talking about the formation of new cells that are not necessarily neurons, but rather these immune cells.”
In other words, we need to understand how neurogenesis occurs and whether it is beneficial or harmful to the patient. Once this is understood, it will be possible to determine the best therapeutic approach: stimulating or inhibiting neurogenesis. And, as mentioned earlier, the CXCR4/CXCL12 pathway may represent a promising route for such treatments. This is precisely the focus of the projects conducted by master’s students Igor Vinicius Sousa Cavalheiro and Vinicius Stefanini Mantovan.
A New Generation Investigating Obesity
Both Igor and Vinicius earned degrees in Biomedical Sciences from São Francisco University (Campinas campus) and met before joining Prof. Natália’s research team.
Igor joined the group first, during his undergraduate research internship. He describes part of this journey. Initially, he worked with metabolic programming, investigating how hypothalamic alterations that lead to obesity are established as early as gestation.
Today, Igor works with adult animals. He explains some of the differences between his undergraduate and master’s research projects: “I worked with the hypothalamus and became very interested in how many processes it orchestrates in metabolism itself. So, during my master’s, we wanted to investigate more deeply the alterations in this region and how they are sustained throughout adult life.”
Vinicius joined the group somewhat later. He explains: “I came from another laboratory, in a completely different field. Nothing related to obesity. I wanted to change fields. I was already very interested in immunology, so I discovered Prof. Natália through Igor and other colleagues. She introduced me to the undergraduate research project, and I really liked it. It combined my desire to conduct scientific research with my interest in the immune system.”
The Genetic Engineering Behind the Research
Today, both of their projects complement one another, as Vinicius explains: “He works with the receptor, and I work with the ligand.” This is because Igor’s focus is on the CXCR4 receptor in tanycytes, while Vinicius focuses on the chemokine CXCL12 in endothelial cells.
In this context, in some of their experiments, Igor and Vinicius prevent their target cells (tanycytes and endothelial cells) from expressing these receptors, chemokines, and other components. This is only possible thanks to a highly intricate approach known as the Cre-Lox system.
The Cre-Lox system is a genetic engineering technique used to modify specific genes in a controlled manner. Through this approach, researchers can alter the DNA in specific regions of an animal, preventing the cells in that region from producing a particular component.
This system receives its name because it combines Cre enzymes with “Lox markers.” It is as if DNA were a book. The Lox “markers” are like two bookmarks indicating the beginning and end of a specific passage in that book. The Cre enzyme acts like an intelligent pair of scissors that knows exactly where to cut between the “Lox” markers.
However, this process cannot occur in every cell in the body. In Igor’s case, for example, he only wants to “cut” the DNA in tanycytes. That is where viruses come into play. They guide the Cre enzymes specifically to tanycytes, ensuring that they act only there. It is as if those intelligent scissors were delivered by drones to a specific shelf of books in a library with the instruction: “Only cut the marked pages in the books located here.”
Igor and Vinicius reveal that this technique presents some of the greatest challenges in their projects. In addition to the difficulty of mastering the technique itself, there is extensive bureaucracy regulating the purchase and use of both viruses and genetically modified animals. Igor comments: “We started the whole process even before my master’s degree so that, by the time I began, I would already have the animals, the virus, and everything else. Just obtaining the animal lineage took about a year.”
Working with the Cre-Lox system presents yet another obstacle: many steps are required before researchers can collect any results from their studies. After receiving mice from the specific lineage, researchers must inoculate the virus, wait for the animals to reach adulthood, and then feed them a high-fat diet for the appropriate period of time. Altogether, this means it can take up to four months for researchers to obtain their results.
Males, Females, and Differences in Obesity
In addition to Igor and Vinicius’s projects, Prof. Natália’s group also investigates other aspects of obesity. In this context, one of Prof. Natália’s interests is sexual dimorphism, that is, the differences observed between male and female animals.
In her experiments, differences have already been observed in the pattern of monocytes (the “patrolling soldiers” discussed earlier) recruited to the hypothalamus during inflammation. Because of this and other findings, Prof. Natália always seeks to determine whether her results indicate sex-related differences.
Prof. Natália explains that similar differences are also observed in humans: “In general, women have a higher percentage of body fat. And they also often tend to be more susceptible to weight gain and to alterations triggered by excessive fat consumption.”
She points to a possible explanation: “My bet is on hormones. That’s why I also have projects studying the influence of female sex hormones on these hypothalamic modulations. The hypothalamus not only regulates weight and energy balance, but also reproductive functions.”
She adds: “Women have menstrual cycles, and these cycles are directly regulated by hormones. The neurons responsible for this regulation are located in the hypothalamus. And these same neurons connect with other hypothalamic neurons that regulate hunger, sleep, and so on.”
In addition, Prof. Natália also investigates obesity in humans. She comments: “We also have a project at Women’s Comprehensive Healthcare Center of Unicamp (CAISM) in which we collect umbilical cord blood from newborns of mothers with obesity and mothers without obesity in order to evaluate the differences.” The researchers also assess these mothers’ eating habits.
From Unicamp to Canada
Prof. Natália also maintains an international collaboration with Université Laval in Canada, particularly with Prof. Caroline Ménard. This partnership is funded by the São Paulo Research Foundation (FAPESP) through the SPRINT program (São Paulo Researchers in International Collaboration).
Prof. Natália explains how this collaboration began: “One day, after reading one of her papers, I decided to send Prof. Caroline an email to ask about a technique. She replied very quickly and kindly. Then an opportunity arose to apply for FAPESP’s SPRINT program. Since Prof. Caroline is highly experienced in vascular biology in the central nervous system, I contacted her, and she was extremely helpful.”
Prof. Natália describes the work that will be carried out in Canada: “We have this project involving CXCL12 in the endothelium. We will perform this analysis there because they have super-resolution microscopes, and Prof. Caroline will help me with that. Her work is actually more focused on psychiatry. She studies vascular alterations, but also behavioral aspects.”
The project includes a 45-day research stay in Canada for Prof. Natália.
What Drives a Researcher
At the end of the interview, Prof. Natália shared more about what motivates her to work in scientific research: “It’s something I truly enjoy doing. Because I think only people who genuinely like science pursue scientific research. Financially, everything is very uncertain. And we do not receive the recognition we should.”
She mentions another reason: “Another thing that makes me very happy is seeing how I can contribute to people’s professional growth. It’s very rewarding to watch students develop. You see a student arriving for undergraduate research with no experience, someone who has never spoken in public or even held a pipette. And then you see them today presenting their work, speaking English, and teaching one another.”
She adds: “I’m very happy to be able to do that. To encourage them to have a positive experience with science. Over the years, I’ve accumulated both good and bad experiences with supervisors, so I always try to filter what I think is valuable to pass on to my students.”
More than understanding obesity, the researcher’s trajectory also highlights how science is built collectively: through curiosity, collaboration, and the training of new generations of scientists.
The research presented in this article received funding from FAPESP (grant numbers 23/07393-0, 24/18774-7, 24/09484-5, 24/00572-9, 25/11576-8, 25/12765-9, 22/06282-7, 25/11437-8, 25/00121-0, and 26/02312-0).
This article was produced with support from the São Paulo Research Foundation (FAPESP), Brazil. Grant number 25/17158-3. The opinions, hypotheses, conclusions, and recommendations expressed in this material are the responsibility of the author(s) and do not necessarily reflect the views of FAPESP.
To Learn More
Hypothalamic Inflammation in Obesity
Article 1 – in English (DOI: 10.1159/000153423)
Article 2 – in Portuguese (DOI: 10.1590/S0004-27302012000600001)
Neurogenesis in the Hypothalamus
Article in English (DOI: 10.1186/s12974-021-02242-8)
Recruitment of Immune Cells to the Inflamed Hypothalamus
Article 1 – in English (DOI: 10.7554/eLife.95044)
Article 2 – in English (DOI: 10.3390/ijms22052256)
Prof. Natália’s doctoral thesis
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.