Researchers have discovered how a key protein turns on brown fat by helping build blood vessels and nerve connections needed for heat production.
The survey results are nature communicationsproposes a new way to tackle obesity that focuses on increasing the body’s energy expenditure rather than reducing appetite.
Brown fat and how it burns calories
Most of the fat in the body is white fat, which stores excess energy and can cause obesity when accumulated. In contrast, brown fat exists in small amounts and plays a specialized role in regulating body temperature and supporting metabolic health. When exposed to cold, brown fat uses glucose and lipids to generate heat through 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,” said Farnaz Shamsi, assistant professor of molecular pathology at New York University School of Dentistry and senior author of the study. “Brown fat acts like a metabolic sink that draws in nutrients and prevents them from accumulating by rapidly taking up and using fuel sources from our bodies and the food we eat.”
Brown fat relies on a dense network of nerves and blood vessels to function. Nerves allow the body to receive signals from the brain and activate tissues when the body senses cold. Blood vessels carry the oxygen and nutrients needed to generate heat and help distribute that heat throughout the body. Previous research has mainly focused on how adipocytes generate heat, but how these support networks develop and function has received less attention.
SLIT3 protein builds brown fat infrastructure
Previous research by Shamsi’s lab used single-cell RNA sequencing to identify SLIT3, a protein released by brown adipocytes that may aid in brown adipocyte communication. When SLIT3 is generated, it is split into two separate parts.
In the new study, scientists conducted experiments on both human and mouse cells and identified the enzyme BMP1 that cuts SLIT3 into these two fragments. Each fragment has a different role. One promotes blood vessel growth and the other supports the expansion of nerve networks.
“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.
The researchers also identified a receptor called PLXNA1 that binds to one of the SLIT3 fragments and helps regulate neurodevelopment in brown fat. In a mouse study, removing the SLIT3 or PLXNA1 receptors made the animals more sensitive to cold and unable to maintain body temperature. Further analysis revealed that their brown fat lacked proper neural structure and a proper network of blood vessels.
Links to obesity and metabolic health
To determine whether the same mechanism exists in humans, the research team analyzed adipose tissue samples from more than 1,5000 people, including obese people. 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 adipose tissue health, inflammation, and insulin sensitivity in obese individuals.
“This caught our attention because it suggests that this pathway may be related to obesity and metabolic health in humans,” Shamsi said.
A new approach to obesity treatment
Most weight loss drugs containing GLP-1 work by suppressing your appetite and making you eat less. In contrast, targeting brown fat can increase the amount of energy your body uses. New discoveries, such as how SLIT3 splits into two parts and interacts with receptors to form neural and vascular networks, point to some potential targets for future treatments.
“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.
