Studies in mice have shown that a hormone produced in the gut can send signals to the brain and influence how much energy the body uses. This hormone, called FGF19 (fibroblast growth factor 19), activates processes that help the body use more energy, utilize stored fat as fuel and improve weight control and blood sugar levels in overweight animals.
The researchers linked these effects to the action of FGF19 in the hypothalamus, an important region of the brain that receives information from the rest of the body and the environment to coordinate energy metabolism. They found that FGF19 signaling in the hypothalamus increases the activity of thermogenic adipocytes (i.e. fat cells that burn energy to generate heat). These are specialized fat cells that help the body generate heat instead of storing calories.
New Ways to Treat Obesity and Diabetes
Based on these findings, the scientists believe that FGF19 could serve as inspiration for new drugs to treat obesity, diabetes and other metabolic diseases. The idea is to develop compounds that mimic the behavior of natural substances in the body and mimic the action of endogenous compounds (i.e. compounds produced by the body itself). This strategy is similar to the way some of the latest drugs for diabetes and obesity work. Ozempic, for example, contains semaglutide, an active ingredient that activates receptors that mimic the hormone GLP-1. In this way, it sends satiety signals to the brain and helps patients to feel full with less food.
According to the study, FGF19 did more than just change appetite or fat storage. The hormone also reduced peripheral inflammation and improved the animals’ cold tolerance. However, when the researchers blocked the sympathetic nervous system, these benefits disappeared. In further experiments, they observed that exposure to cold increased the expression of FGF19 receptors in the hypothalamus. Since the hypothalamus is critical for maintaining body temperature, these results suggest that FGF19 may help the body adapt by coordinating energy balance and thermoregulation.
FGF19, Thermogenesis and the Brain’s Control of Energy Balance
“FGF19 has already been associated with a reduction in food intake. Our work has provided new insights by showing that it also plays an important role by acting on the hypothalamus and stimulating an increase in energy expenditure in white and brown adipose tissue. In other words, it not only controls appetite but also stimulates thermogenesis. So in terms of therapies related to obesity, it would be very useful,” explains Professor Helena Cristina de Lima Barbosa of the Obesity and Comorbidities Research Center (OCRC) of the State University of Campinas (UNICAMP).
The OCRC is a Research, Innovation and Dissemination Center (RIDC) of FAPESP, which also funded the project through scholarships for PhD student Lucas Zangerolamo, the first author of the study, under the direction of Barbosa. The work was described in detail in an article published in the American Journal of Physiology – Endocrinology and Metabolism, where it was highlighted as the top article in May.
Global Obesity Crisis and Urgent Health Targets
The World Atlas of Obesity 2025 warns that global health targets for this year will not be met if current trends continue. These targets include halting the rise in diabetes and obesity and reducing premature deaths from cardiovascular disease, chronic respiratory disease and cancer by 25% compared to the 2010 baseline.
The Atlas estimates that more than 1 billion people worldwide are currently living with obesity. Obesity is a chronic condition in which excessive body fat accumulates and affects health. It is usually caused by a long-term imbalance between energy intake and expenditure, but is influenced by many factors, including genetic predisposition, hormonal regulation, lifestyle, psychological stress and social conditions. Obesity increases the risk of numerous secondary diseases such as type 2 diabetes, cardiovascular problems, certain types of cancer and joint problems.
If no effective measures are taken, this figure could rise to over 1.5 billion by 2030. Obesity is already associated with around 1.6 million premature deaths per year from non-communicable diseases. In Brazil, around 31% of the population is obese. In addition, between 40% and 50% of adults do not reach the recommended levels of physical activity in terms of frequency or intensity.
Where FGF19 Comes from and How it Works
FGF19, which is involved in the control of energy metabolism, is mainly produced in the small intestine. In the liver, it regulates the production of bile acids and also influences the synthesis of glucose and fats. While its primary functions in the liver have been extensively studied in the scientific literature, its effects on the brain have received far less attention. “In the lab, we work with bile acids, which are also the subject of my Master’s degree, and which regulate the release of FGF-19. Our initial studies led us down this path,” Zangerolamo told Agência FAPESP.
At eight weeks of age, the mice used in the study were randomly divided into two groups. One group was fed a standard diet (control) and the other was fed a high-fat diet to induce obesity. The researchers then administered FGF19 directly into the brains of the obese animals. All mice were kept under carefully controlled conditions in terms of temperature, lighting and access to water.
In the article, the scientists report that central FGF19 signaling improved energy homeostasis. This was done by increasing sympathetic nervous system activity and stimulating thermogenesis in adipose tissue, causing the tissue to use more energy in the form of heat. “The brain plays an extremely important role in controlling the body’s obesity. It triggers commands at the same time as it receives information from peripheral tissues. These commands, which appear to use the sympathetic nervous system, seem to be an interesting way to think about energy expenditure,” adds Barbosa.
Diving Deeper into Brain Cells and FGF19 Receptors
To better understand which brain cells respond to FGF19, the authors compiled and analyzed public scRNA-seq data from several studies on the hypothalamus. This method allows RNA from individual cells to be sequenced, revealing which genes are active in each cell type. In total, the team assessed the transcription of more than 50,000 individual cells to identify hypothalamic cell populations expressing FGF19 receptors.
The researchers note that a key question now is how to stimulate the body to produce more FGF19 itself. They are also working to relate these findings to what is already known about the neural circuits that regulate eating behavior. “We want to expand this understanding. We are studying the hypothalamus to assess the inflammation that often occurs with a high-fat diet and to determine if FGF19 plays a role in this area,” says Zangerolamo, who did part of the work during an internship at Harvard Medical School’s Joslin Diabetes Center with Professor Yu-Hua Tseng, also an author on the paper.
A Hidden Regulatory System Helps Determine How Much Fat the Body Stores or Loses
When it comes to maintaining healthy adipose tissue, a certain protein plays an important role. Our fat cells, also known as adipocytes, do much more than just store excess body weight. They serve as an important energy reserve for the body. In each adipocyte, the fat is packaged in lipid droplets that can be used as fuel when needed – for example in the hours between meals. To release this stored energy, the body uses a protein called HSL, which works like a switch. When energy runs low, hormones such as adrenaline activate HSL and cause it to release fat, which can then fuel various organs. Without HSL, it would be expected that fat would accumulate as if the body no longer had access to its energy supply. Surprisingly, however, this is not the case. Studies on mice and patients with mutations in the HSL gene show that the lack of this protein does not lead to excessive fat or obesity. Instead, those affected experience a loss of fat mass, a condition known as lipodystrophy. Although obesity and lipodystrophy are seemingly opposing conditions, both involve fat cells that are not functioning properly. As a result, each of these conditions can contribute to metabolic disorders and cardiovascular problems.
To understand this surprising behavior, a team led by Dominique Langin, professor at the University of Toulouse within the I2MC, took a closer look at where HSL is found in adipocytes. The protein is known for its role on the surface of lipid droplets, where it supports the breakdown of stored fat. However, the study found that HSL is also found in the nucleus of adipocytes. “In the nucleus of adipocytes, HSL can combine with many other proteins and participate in a program that maintains an optimal amount of adipose tissue and keeps the adipocytes ‘healthy’,” explains Jérémy Dufau, co-author of the study, who completed his doctoral thesis on the subject.
The researchers also found that the concentration of HSL in the cell nucleus is strictly regulated. Adrenaline, which activates the form of HSL found on the lipid droplets, also stimulates the protein to leave the nucleus. This process occurs naturally during fasting. In contrast, obese mice have increased levels of HSL in the nucleus, indicating a shift in this regulatory system. “HSL has been known as a fat-mobilizing enzyme since the 1960s. However, we now know that it also plays an important role in the nucleus of adipocytes, where it contributes to the maintenance of healthy adipose tissue,” says Dominique Langin. This additional function explains why the absence of HSL leads to lipodystrophy and provides new insights into metabolic disorders such as obesity and related health complications. Continuous scientific research is crucial for improving preventive measures and patient care.