High-Fat Diet and Hypothalamic Inflammation: What Changes Between Males and Females?

A high-fat diet does not affect male and female organisms in the same way. And the differences may begin in the brain. A new study investigated how exposure to this type of diet modifies, over time, communication between cells in the hypothalamus, a brain region involved in metabolic control.

The study was published in the scientific journal Journal of Neuroendocrinology and involved researchers from the Cellular Signaling Laboratory at the Obesity and Comorbidities Research Center (OCRC).

For this article, Farmaco em Foco spoke with Prof. Natália Ferreira Mendes, PhD, who supervised the research, and Giovanna Ariozi dos Santos, one of the study’s first authors. The researchers shared details about the findings, the hypotheses raised by the study, and the challenges involved in understanding how these responses may relate to human metabolism.

The brain also feels the effects of diet

Stop and think about the effects of a high-fat diet. You probably thought of weight gain, liver health, or even some metabolic diseases, such as diabetes. But what many people may not realize is that the brain is also affected by this type of diet, particularly a region called the hypothalamus.

Hipotálamo hypothalamus — Hypothalamus highlighted in blue.

The hypothalamus is located at the base of the brain. It acts as an important control center for several functions that help regulate food intake and energy expenditure.

When researchers study animals fed a high-fat diet, they observe that the hypothalamus of these animals can become inflamed. During this process, changes occur in cells of the nervous system and in the communication between these cells and with other cell types. These changes can interfere precisely with the hypothalamus’s ability to regulate appetite and energy expenditure.

We have previously discussed these mechanisms here at Farmaco em Foco. To better understand the function of the hypothalamus and the consequences of its inflammation, check out the article “Inflamed hypothalamus: how obesity remodels the brain”.

But there is another major question in this story. We already know that obesity develops differently in men and women, as well as in male and female animals. Could this be related to differences between the sexes in how the hypothalamus responds to diet?

Male and female animals do not respond in the same way

Women and men exhibit different patterns of obesity. Prof. Natália explains: “Women generally have more body fat due to hormonal factors. Men tend to gain less fat, but that does not mean they are more protected.”.

This is because a high-fat diet does not only cause obesity. It can also lead to other metabolic outcomes, such as diabetes and changes in cholesterol levels, which can occur in men even when they are not obese.

Prof. Natália explains that, in animals, the scenario is different from what is observed in humans: “Female mice are generally more resistant to developing obesity. For example, when we put the animal on a high-fat diet, we see that the male gets chubby much faster. The female sometimes takes one, two, three, or four months to gain a significant amount of weight.”

Given these differences, the researchers faced an unanswered question: Is hypothalamic inflammation also different between males and females?

To investigate this question, it is necessary to look at how hypothalamic inflammation develops over time. In this context, Prof. Natália’s team became particularly interested in chemokines.

During hypothalamic inflammation, chemokines are molecules responsible for signaling and recruiting immune cells. They are like a scent that attracts these cells to the hypothalamus. To do this, chemokines need to interact with receptors on these cells, which act as sensors for the chemokines.

Once these cells reach the hypothalamus, they are responsible for triggering a series of changes associated with inflammation.

In other words, chemokines are key players in the changes that occur when the hypothalamus becomes inflamed as a result of consuming high-fat foods. As mentioned above, some of these changes are closely linked to the development of obesity and other metabolic diseases.

Therefore, Prof. Natália hypothesized that differences in obesity between males and females may be related to chemokines.

She explains that her study is pioneering in this investigation: “When I looked through the literature to see if there was anything about chemokines and differences between biological sexes, I couldn’t find anything. Generally, most studies only use male animals.”

For this reason, the researchers decided to monitor, at different points during exposure to the high-fat diet, changes in chemokines and their receptors in the hypothalamus of male and female animals.

Tracking inflammation over time

To investigate all these questions, the researchers fed some mice a standard diet and others a high-fat diet. In addition, they separately observed what happened in male and female mice.

The researchers also monitored the response at different points during dietary exposure: after 1, 3, 14, and 28 days. This made it possible to observe what happened at each time point and, therefore, analyze how hypothalamic inflammation progressed over the 28-day period.

At each time point, the researchers analyzed the expression of genes related to chemokines and their receptors in the hypothalamus. This is a way of determining whether cells are producing more or less of these chemokines and their “sensors” over time.

Thus, the study evaluated three aspects: how the diet causes changes in chemokines and their receptors; how these changes evolve over time; and whether this process occurs differently in males and females.

First the change, then the adjustment

The results revealed something very interesting: the hypothalamic response to a high-fat diet does not occur in a continuous and progressive manner. In other words, the situation does not simply get worse over time.

The expression of many chemokines and their receptors initially decreased, but this effect was transient.

This indicates that the hypothalamic response depends on the duration of exposure to the high-fat diet. In other words, the effects observed after a few days of the diet are not necessarily the same as those found after several weeks.

For Dr. Natália, one possibility is that these initial changes indicate that the body is trying to adapt to the diet.

She explains: “We also see this a lot when we analyze neuropeptides, which are those molecules that regulate hunger. Generally, when we give the animal a high-fat diet, anorexigenic neuropeptides, which suppress hunger, increase. And orexigenic ones, which increase hunger, decrease. After some time, this effect disappears.”

This may be related to an effect that some people may notice. When we maintain a healthy diet but eat something very fatty on a particular day, it is common to feel less hungry the following day.

This happens because the body adapts to the sudden change in diet, releasing orexigenic hormones to reduce hunger. It is almost as if the body were saying: “We have plenty of energy. We can eat a little less for a while.”

The same effect may occur with the expression of chemokines and their receptors. When the animals’ hypothalamus encounters the sudden change in diet, it initially reduces the expression of these molecules to decrease the recruitment of immune cells to the hypothalamus. It is almost as if it were saying: “This will pass soon. Let’s not raise the alarm for now, immune system.”

Prof. Natália comments: “At first, this tries to keep the situation under control, but then it kind of loses that control.”

The researcher emphasizes, however, that the study does not allow us to definitively conclude that this effect represents an initial protective mechanism. Further experiments are needed to understand the actual function of these changes.

The results point to a complex process in which different molecular signals are modified at different points in time. But the story becomes even more interesting (and complex) when we look at the differences between males and females.

CXCR3: the molecule that drew the most attention

The study analyzed several different types of chemokines and their corresponding receptors. Among all these molecules, one chemokine receptor stood out: CXCR3.

In a previous Farmaco em Foco article, we explained that different chemokines interact only with their specific receptors. We also discussed how each cell type expresses different types of chemokine receptors. Therefore, knowing specifically which chemokines and receptors are most highly expressed during hypothalamic inflammation allows us to determine which cells are being recruited to the region.

In this context, the CXCR3 receptor stands out. In a previous study, Prof. Natália had already observed that cells expressing the CXCR3 receptor appear to protect the body against some metabolic changes caused by a high-fat diet.

Now, in this new study, Prof. Natália observed that CXCR3 expression in the hypothalamus after 14 and 28 days of a high-fat diet was higher in females than in males. This finding drew attention because it coincides with the period during which females show greater initial resistance to the effects of this diet.

However, the current study does not demonstrate that CXCR3 is directly responsible for this protection. Additional experiments are needed to determine which cells are involved in this process and what function they actually perform in the hypothalamus.

But why is CXCR3 more highly expressed in females?

Giovanna reflects on this question: “When we observed that the females seemed to be more protected, we wanted to understand why. What do they have that males don’t? We immediately thought of sex hormones.”

Where do hormones come in?

A fundamental difference between males and females is their sex hormones. For this reason, the researchers decided to investigate another aspect: the role of ovarian hormones, that is, female sex hormones.

To do so, further experiments were conducted with female mice. Some animals underwent ovarian removal surgery, known as ovariectomy. As a result, these mice no longer produced ovarian hormones. Another group of animals also had their ovaries removed but received replacement of one of the main ovarian hormones: estrogen.

All these animals were fed a high-fat diet to evaluate the same parameters discussed above. Removing the animals’ ovaries makes it possible to determine whether ovarian hormones are responsible for the protection observed in females.

Replacing estrogen in the ovariectomized animals was important to confirm that the observed effects were indeed related to the hormone and not to other effects caused by the surgery itself. In addition, this made it possible to assess the importance of estrogen in isolation, since it is the main ovarian hormone, but not the only one. There is also progesterone, for example.

Prof. Natália explains this experimental approach: “Once you remove the ovaries, let’s suppose there is an increase or decrease in some factor we’re investigating. When you replace estrogen, that factor is expected to return to normal. This allows us to actually determine what role the hormones play.”

By comparing these groups of animals, Prof. Natália’s research team found differences in the hypothalamic chemokine profile.

In the absence of ovarian hormones, CXCR3 expression increased. In the animals that received estrogen replacement, CXCR3 expression was partially restored, approaching the pattern observed in females with their ovaries intact.

These results indicate that ovarian hormones are indeed behind the difference in CXCR3 expression observed between males and females.

Nevertheless, the findings do not mean that estrogen alone explains all the differences between biological sexes. Responses to diet involve a complex network of signals that may also involve many other molecules and cells.

From Mice to Humans: What Can We Say?

The study’s findings raise an inevitable question: Does this mechanism also occur in humans? For now, the answer requires caution.

There is already evidence that obesity is associated with inflammatory changes in the human hypothalamus. However, studying what happens in this region in humans is much more difficult than in animal models.

In animals, researchers can directly analyze the hypothalamus. In humans, however, we cannot perform the same range of experiments. Much of the available information comes from imaging techniques, which make it possible to observe changes in the region but do not provide the same level of detail, such as information about the expression of chemokines and their receptors.

Post-mortem studies can provide more detailed information about tissues, but they also have an important limitation: they offer a kind of “snapshot” of that particular moment and do not allow researchers to monitor, in real time, how the hypothalamus responded to different periods of dietary exposure.

Another approach in humans is post-mortem analysis, that is, analysis conducted after death. However, these studies also have their limitations, as Prof. Natália explains: “In this case, you have something static. It is not possible to monitor, for example, the effect of a diet at different time points.”

Can We Relate the Findings to Menopause?

The role of ovarian hormones observed in the study may immediately bring menopause to mind. During this period, there is a significant reduction in the levels of these hormones, similar to what occurs in the experiments in which the ovaries were removed. It is also important to note that women going through menopause may experience metabolic changes, such as increased abdominal fat, insulin resistance, and changes in cholesterol levels.

Although the study reveals the importance of ovarian hormones, which may suggest a correlation with menopause, the findings do not allow us to establish a direct relationship between them. Further research in humans is still needed to investigate more precisely how hormonal changes, sex, age, and metabolism are related to hypothalamic inflammation.

What About That Weekend Indulgence?

The findings may also raise a very everyday question: if the hypothalamic response changes depending on the duration of dietary exposure, can a few days of eating a higher-fat diet be harmful?

Prof. Natália’s answer is straightforward: we cannot draw that conclusion from this study.

The study does not exactly reproduce the dietary pattern of a person who maintains a balanced diet during the week and indulges over the weekend. In addition, the study was conducted in mice. It is not possible to directly estimate how long it would take for a similar response to occur in humans.

“I think it is risky, based on experimental studies, to make any recommendation along the lines of: ‘Don’t worry, you can have a few days of a high-fat diet and everything will be fine afterward,’” warns Prof. Natália.

The First Contact with Scientific Research

Beyond the scientific findings, the study also represents an important experience for Giovanna. The researcher conducted the experiments as part of her undergraduate research project, during the early years of her medical degree.

“It was very different from everything I had experienced before because I started doing things here in my first year of medical school,” Giovanna says. According to her, the beginning was particularly challenging. This was her first contact with scientific research, and she had to learn everything from handling laboratory animals to the methods she developed.

The experience also meant learning a new way of thinking. For Giovanna, one of the greatest challenges was precisely understanding what was being investigated and how a scientific question could be transformed into experiments capable of producing answers.

Over time, this process became more natural. “After I adapted, I understood how I organize myself, and it became easier to get things done,” she reports. Now in the third year of her degree, she considers the experience particularly important for broadening her perspective on her own education.

For Giovanna, becoming involved with science can be especially valuable for other medical students. She comments: “It is important for other students to also have experience with approaches beyond the clinical side. This exposure broadens their horizons.”

The findings expand our understanding of the relationship between diet, inflammation, the hypothalamus, the immune system, hormones, and metabolism. One of the study’s main contributions may be reinforcing that the body’s response to obesity and to diet-induced changes is not uniform. It depends on the duration of exposure, the molecules involved, the cells participating in the response, and biological sex.

At the same time, science still needs to advance our understanding of how these responses translate to the complexity of the human body. For now, the study conducted in the laboratory offers an important clue: to better understand the metabolic changes caused by diet, we also need to look at the brain and consider that males and females may not tell exactly the same story.

The research discussed in this article was funded by FAPESP (grant numbers 2013/07607-8, 2022/06282-7, 2023/11393-5, and 2024/18774-7) and CAPES.

This article was produced with the support of the São Paulo Research Foundation (FAPESP), Brazil. Grant No. 25/17158-3. The opinions, hypotheses, conclusions, and recommendations expressed in this material are the sole responsibility of the author(s) and do not necessarily reflect the views of FAPESP.