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Washington DC: Scientists have identified a key biological system that helps brown fat burn energy by building the networks it needs to function.
A protein called SLIT3 splits into two parts, with each piece guiding the growth of blood vessels and nerves inside brown fat. These structures allow the tissue to pull in nutrients and rapidly convert them into heat instead of storing them as fat.
Researchers have discovered how a crucial protein switches on brown fat by helping it build the blood vessels and nerve connections needed for heat production.
The findings, published in Nature Communications, suggest a new way to tackle obesity that focuses on increasing how much energy the body burns instead of reducing appetite.
Brown Fat and How It Burns Calories
Most fat in the body is white fat, which stores excess energy and can contribute to obesity when it accumulates. In contrast, brown fat is present in smaller amounts and plays a specialised role in controlling body temperature and supporting metabolic health.
When exposed to cold, brown fat uses glucose and lipids to produce heat through a process called thermogenesis.
“During thermogenesis, all of that chemical energy is dissipated as heat instead of being stored in the body as white fat,” said Farnaz Shamsi, assistant professor of molecular pathobiology at NYU College of Dentistry and the study’s senior author.
“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,” added Farnaz Shamsi.
Brown fat relies on dense networks of nerves and blood vessels to do its job. Nerves allow it to receive signals from the brain, which activate the tissue when the body senses cold.
Blood vessels deliver oxygen and nutrients needed to generate heat and help distribute that heat throughout the body. While previous studies have mainly focused on how fat cells produce heat, less attention has been given to how these supporting networks develop and function.
SLIT3 Protein Builds Brown Fat Infrastructure
Earlier research from Shamsi’s lab used single-cell RNA sequencing to identify SLIT3, a protein released by brown fat cells that may help them communicate. Once produced, SLIT3 is split into two separate pieces.
In the new study, scientists used experiments in both human and mouse cells to identify the enzyme BMP1, which cuts SLIT3 into these two fragments. Each fragment has a different role. One promotes the growth of blood vessels, while the other supports the expansion of nerve networks.
“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,” noted Shamsi.
The researchers also identified a receptor called PLXNA1 that binds to one of the SLIT3 fragments and helps regulate nerve development in brown fat.
In mouse studies, removing SLIT3 or the PLXNA1 receptor made the animals more sensitive to cold and less able to maintain their body temperature. Further analysis showed that their brown fat lacked proper nerve structure and an adequate network of blood vessels.
Links to Obesity and Metabolic Health
To determine whether the same mechanism exists in humans, the team analysed fat tissue samples from more than 1,5000 individuals, including people with obesity. They focused on the gene responsible for producing SLIT3, which previous studies have linked to obesity and insulin resistance.
Their results suggest that SLIT3 activity may influence fat tissue health, inflammation, and insulin sensitivity in people with obesity.
“That really got our attention, as it suggests that this pathway could be relevant in human obesity and metabolic health,” said Shamsi.
A New Approach to Obesity Treatment
Most weight loss medications, including GLP-1s, work by suppressing appetite and reducing how much people eat. In contrast, targeting brown fat could increase how much energy the body uses.
The new findings, including how SLIT3 splits into two parts and interacts with receptors to shape nerve and blood vessel networks, point to several potential targets for future treatments.
“Our research shows that just having brown fat isn’t enough — you need the right infrastructure within the tissue for heat production,” said Shamsi.
