Researchers have uncovered how a key protein activates brown fat by dilating blood vessels and nerves in the heat-producing tissue.
The survey results are nature communicationspoints to the possibility of obesity treatment strategies that deviate from current approaches to suppressing appetite.
Most of the fat in our bodies is white fat, which stores excess energy and can lead to obesity if levels are too high. Humans and other mammals also have low amounts of brown fat, a specialized tissue that regulates body temperature and is closely associated with weight loss and metabolic health. When brown fat is activated by exposure to cold, it uses the body’s resources such as glucose and lipids to generate heat. This is a process called thermogenesis.
During thermogenesis, all of that chemical energy is dissipated as heat rather than being stored in the body as white fat. Brown fat acts like a metabolic sink, drawing in nutrients and preventing them from accumulating by rapidly taking up and using fuel sources from our bodies and the food we eat. ”
Farnaz Shamsi, assistant professor of molecular pathology at New York University School of Dentistry and senior author of the study
Brown fat has a complex and dense network of nerves and blood vessels that are essential to its function. Nerves allow brown fat cells to communicate with the brain. When the brain senses cold, it rapidly sends signals to activate brown fat. Blood vessels supply oxygen and nutrients to brown fat, generate heat, and distribute this heat throughout the body. Research on brown fat has primarily focused on stimulating adipocytes to generate heat, but less is known about how these underlying networks function.
Shamsi’s lab previously used single-cell RNA sequencing to identify SLIT3, a protein secreted by brown adipocytes that may play a role in adipocyte communication. Once SLIT3 is generated, it is cleaved into two different fragments.
in nature communications Using a combined approach in human and mouse cells, researchers discovered the enzyme BMP1, which cleaves SLIT3 in two. They also found that the two SLIT3 fragments control different processes. One grows the vascular network and the other expands the neural network.
“This acts as a splitting signal, an elegant evolutionary design in which the two components of a single element independently control different processes that need to be tightly coordinated in space and time,” Shamsi said.
Additionally, the researchers identified a receptor, PLXNA1, that binds to one of the SLIT3 fragments and controls the brown fat neural network. Studies using mice, which normally have highly active brown fat and can tolerate long periods of cold temperatures, found that removing SLIT3 or PLXNA1 receptors from brown fat made the mice more sensitive to cold and had a harder time maintaining body temperature. A closer look at brown adipose tissue lacking SLIT3 or its receptor revealed a lack of proper neural architecture and vascular density.
To see if their findings applied to humans, the researchers examined samples of adipose tissue from more than 1,5000 people. Among them was obesity. Focusing on the gene that produces SLIT3, which previous studies have shown to be associated with obesity and insulin resistance, the researchers found that SLIT3 gene expression may regulate adipose tissue health, inflammation, and insulin sensitivity in obese people.
“This caught our attention because it suggests that this pathway may be related to obesity and metabolic health in humans,” Shamsi said.
Most weight loss drugs containing GLP-1 suppress appetite, reducing the amount of food eaten and thereby reducing the amount of energy stored, whereas treatments containing brown fat may increase energy expenditure. This new understanding of what happens inside brown fat, including how SLIT3 splits in two and binds to receptors to control nerves and blood vessels, highlights several processes that could be harnessed for therapeutic potential.
“Our study shows that just having brown fat is not enough; you need the right infrastructure in your tissues to produce heat,” Shamsi said.
Additional study authors include Tamirez Duarte Afonso Cerdan, Heidi Cervantes, Benjamin Frank, Akhil Gergei Ilagavarap, Qiyu Tian, Daniel Hope, and Khalil Aydin of New York University School of Dentistry. Chan Hee Choi and Paul Cohen of Rockefeller University. Anne Hoffmann and Matthias Breuer from the University of Leipzig. Adideb Ghosh and Christian Wolfram of ETH Zurich. Matthew Greenblatt of Weill Cornell Medical College. Gary Schwartz of Albert Einstein College of Medicine;
This research was supported in part by the National Institutes of Health (K01DK125608, R03DK135786, R01DK136724, RC2DK129961, R35GM150942), the G. Harold and Leila Y. Mathers Charitable Foundation, the American Heart Association (24CDA1271852), and the Einstein Mount Sinai. Diabetes Center, New York University School of Dentistry Department of Molecular Pathobiology, and Boettcher Foundation.
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Reference magazines:
Cerdan, TDA, others. (2026). SLIT3 fragment coordinates neurovascular dilation and thermogenesis in brown adipose tissue. Nature Communications. DOI: 10.1038/s41467-026-70310-9. https://www.nature.com/articles/s41467-026-70310-9
