Researchers report that a protein signal called SLIT3 helps brown fat ramp up heat production by coordinating the growth of blood vessels and sympathetic nerves. In experiments using mouse models and human cells and tissue datasets, the team found SLIT3 is cut into two fragments with distinct roles—one linked to vessel growth and the other to nerve expansion—pointing to possible future obesity-treatment strategies aimed at boosting energy expenditure.
Brown fat differs from white fat in that it can burn fuels such as glucose and lipids to generate heat through thermogenesis, a process that helps maintain body temperature.
Farnaz Shamsi, an assistant professor of molecular pathobiology at NYU College of Dentistry and the study’s senior author, said that in thermogenesis, “all of that chemical energy is dissipated as heat instead of being stored in the body as white fat.” She added that brown fat can act “like a metabolic sink” by taking up and using fuel sources.
For brown fat to sustain high heat production, it depends on dense neurovascular “infrastructure.” Nerves help transmit cold-triggered signals that activate the tissue, and blood vessels supply oxygen and nutrients and help distribute generated heat.
In the new study, the researchers focused on SLIT3, a protein they describe as being released by brown fat cells and then split into two parts. Using experiments in mouse and human cells, they identified the enzyme BMP1 as the factor that cuts SLIT3 into two fragments. The team reported that the fragments have different functions: one promotes the growth of blood vessels, while the other supports the expansion of nerve networks. Shamsi described this as “a split signal, which is an elegant evolutionary design in which two components of a single factor independently regulate distinct processes that must be tightly coordinated in space and time.”
The researchers also reported identifying a receptor called PLXNA1 that binds one of the SLIT3 fragments and helps regulate nerve development. In mouse experiments described in the report, removing SLIT3 or PLXNA1 made animals more sensitive to cold and less able to maintain body temperature; their brown fat also showed impaired nerve structure and a less robust blood-vessel network.
To assess whether the pathway could be relevant in people, the team analyzed fat-tissue samples from more than 1,500 individuals, including people with obesity, focusing on the gene responsible for producing SLIT3. According to the report, the results linked SLIT3-related activity to measures associated with fat-tissue health, inflammation, and insulin sensitivity in obesity. “That really got our attention, as it suggests that this pathway could be relevant in human obesity and metabolic health,” Shamsi said.
The researchers framed the findings as a potential complement to weight-loss approaches that primarily reduce food intake. “Most weight loss medications, including GLP-1s, work by suppressing appetite,” the report said, while targeting brown fat could, in principle, increase how much energy the body uses. Shamsi emphasized that “just having brown fat isn’t enough—you need the right infrastructure within the tissue for heat production.”
The study was published in Nature Communications. Additional authors listed in the report are from NYU College of Dentistry, Rockefeller University, the University of Leipzig, ETH Zurich, Weill Cornell Medical College, and Albert Einstein College of Medicine.
