Scientists have uncovered a critical biological mechanism that switches on brown fat — the type of fat that burns energy rather than storing it — by building the blood vessel and nerve networks the tissue needs to function.
The findings, published in Nature Communications, could point toward a new approach to treating obesity that focuses on increasing how much energy the body burns, rather than simply reducing appetite.
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Most fat in the human body is white fat, which stores excess energy and contributes to obesity when it builds up in large amounts. Brown fat, present in smaller quantities, works very differently — it burns glucose and lipids to generate heat through a process called thermogenesis.
"By rapidly taking up and using fuel sources from our bodies and the food that we eat, brown fat acts like a metabolic sink that draws in nutrients and prevents them from being stored," said Farnaz Shamsi, assistant professor of molecular pathobiology at NYU College of Dentistry and the study's senior author.
To do its job, brown fat depends on dense networks of nerves and blood vessels. Nerves carry signals from the brain that activate the tissue when the body senses cold, while blood vessels deliver the oxygen and nutrients needed to generate and distribute heat.
Earlier research from Shamsi's lab used single-cell RNA sequencing to identify SLIT3, a protein released by brown fat cells. Once produced, the protein is cut into two separate fragments by an enzyme called BMP1.
Each fragment has a distinct role — one promotes the growth of blood vessels, while the other supports the development of nerve networks within the tissue.
"It works 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," Shamsi noted.
The researchers also identified a receptor called PLXNA1, which binds to one of the SLIT3 fragments and helps regulate nerve development in brown fat.
In mouse studies, animals with SLIT3 or PLXNA1 removed became more sensitive to cold and struggled to maintain body temperature — and their brown fat was found to lack both proper nerve structure and adequate blood vessel networks.
To test whether the same mechanism operates in humans, the team analysed fat tissue samples from more than 1,500 individuals, including people with obesity. They found that the gene responsible for producing SLIT3 — previously linked to obesity and insulin resistance — may influence fat tissue health, inflammation, and insulin sensitivity.
"That really got our attention, as it suggests that this pathway could be relevant in human obesity and metabolic health," said Shamsi.
Most current weight loss medications, including GLP-1 drugs, work by suppressing appetite. Targeting brown fat's internal infrastructure could offer a complementary approach — one that increases how much energy the body uses rather than limiting how much goes in.
"Our research shows that just having brown fat isn't enough — you need the right infrastructure within the tissue for heat production," Shamsi said.
The study's findings on how SLIT3 splits, interacts with receptors, and shapes both nerve and blood vessel networks identify several possible targets for future obesity therapies.