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Brown adipose tissue sympathetic nerves. Credit: Shamsi Lab, NYU College of Dentistry<\/p>\nSummary: While current weight-loss blockbusters like GLP-1s focus on suppressing appetite, researchers have uncovered a completely different strategy: increasing energy expenditure by \u201cbuilding out\u201d the body\u2019s natural heat-generating tissue.<\/p>\n
The study reveals how a protein called SLIT3 acts as a \u201csplit signal\u201d to grow the essential nerve and blood vessel networks within brown fat. Without this infrastructure, brown fat cannot receive the brain\u2019s \u201cget warm\u201d signals or the nutrients it needs to burn calories. This discovery suggests that obesity could be treated by enhancing the body\u2019s internal \u201cmetabolic sink\u201d rather than just eating less.<\/p>\n
Key Facts<\/p>\n
The \u201cSplit Signal\u201d: When brown fat cells secrete SLIT3, an enzyme called BMP1 cleaves it into two fragments. One fragment grows the blood vessels (supplying fuel), while the other expands the nerves (supplying the \u201con\u201d switch).The Metabolic Sink: Activated brown fat acts as a \u201csink,\u201d drawing in glucose and lipids from the bloodstream to generate heat (thermogenesis) instead of storing them as white fat.The PLXNA1 Receptor: Researchers identified PLXNA1 as the specific docking station for SLIT3 that controls nerve density. Mice lacking this receptor couldn\u2019t maintain their body temperature in the cold because their brown fat lacked the \u201cwiring\u201d to hear the brain\u2019s signals.Human Evidence: Analyzing fat samples from over 1,500 people, the team found that SLIT3 gene expression is closely linked to metabolic health, inflammation, and insulin sensitivity in individuals with obesity.<\/p>\n
Source: NYU<\/p>\n
Researchers have determined how a key protein activates brown fat by expanding blood vessels and nerves in the heat-generating tissue.\u00a0<\/p>\n
The findings,\u00a0published in\u00a0Nature Communications, point to a potential strategy for treating obesity that deviates from the current approach of suppressing appetite.\u00a0<\/p>\n
Most of the fat in our bodies is white fat, which stores excess energy and, at too high of levels, can lead to obesity. Humans and other mammals also have a smaller amount of brown fat, a specialized tissue that regulates body temperature and is closely linked to weight loss and metabolic health. When activated by exposure to cold, brown fat uses the body\u2019s resources like glucose and lipids to generate heat, a process called thermogenesis.<\/p>\n
Brown adipose tissue sympathetic nerves. Credit: Shamsi Lab, NYU College of Dentistry<\/p>\n
\u201cDuring thermogenesis, all of that chemical energy is dissipated as heat instead of being stored in the body as white fat,\u201d said\u00a0Farnaz Shamsi, assistant professor of molecular pathobiology at NYU College of Dentistry and the study\u2019s senior author.<\/p>\n
\u201cBy 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.\u201d<\/p>\n
Brown fat has intricate, dense networks of nerves and blood vessels that are critical for its functioning. Nerves enable brown fat to communicate with the brain; when the brain senses cold, it rapidly signals to activate brown fat.<\/p>\n
Blood vessels supply brown fat with oxygen and nutrients to generate heat, and then distribute this heat throughout the body. While research on brown fat has largely focused on stimulating fat cells to generate heat, less is known about how these underlying networks function.<\/p>\n
Shamsi\u2019s lab previously used single-cell RNA sequencing to identify SLIT3, a protein secreted by brown fat cells, which they thought may play a role in how fat cells communicate. When produced, SLIT3 gets cleaved into two different fragments.<\/p>\n
In the\u00a0Nature Communications\u00a0study, using a combination of approaches in human and mouse cells, the researchers discovered the enzyme, BMP1, that is responsible for cleaving SLIT3 into two. They also determined that the two SLIT3 fragments control different processes: one grows the network of blood vessels, while the other expands the network of nerves.\u00a0<\/p>\n
\u201cIt 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,\u201d noted Shamsi.\u00a0<\/p>\n
In addition, the researchers identified the receptor, PLXNA1, that binds to one of the SLIT3 fragments to control brown fat\u2019s network of nerves. In studies in mice\u2014which typically have very active brown fat and can tolerate cold temperatures for long periods of time\u2014removing SLIT3 or the PLXNA1 receptor from brown fat resulted in mice becoming sensitive to cold and having difficulty maintaining their body temperatures. A closer look at brown fat tissue missing SLIT3 or its receptor revealed that it lacks the proper nerve structure and density of blood vessels.\u00a0<\/p>\n
To see if their findings translate to humans, the researchers examined samples of fat tissue from more than 1,5000 people, some of whom had obesity. Focusing on the gene that produces SLIT3, which prior studies show is associated with obesity and insulin resistance, they found that SLIT3 gene expression may regulate fat tissue health, inflammation, and insulin sensitivity in people with obesity.\u00a0<\/p>\n
\u201cThat really got our attention, as it suggests that this pathway could be relevant in human obesity and metabolic health,\u201d said Shamsi.\u00a0<\/p>\n
While most weight loss drugs\u2014including GLP-1s\u2014suppress appetite, decreasing the amount of food people eat and therefore the amount of energy stored, treatments that involve brown fat have the potential to increase energy expenditure.<\/p>\n
This new understanding of what\u2019s happening inside brown fat\u2014including how SLIT3 splits into two and binds to receptors to control nerves and blood vessels\u2014highlights several processes that could potentially be harnessed for their therapeutic potential.\u00a0<\/p>\n
\u201cOur research shows that just having brown fat isn\u2019t enough\u2014you need the right infrastructure within the tissue for heat production,\u201d said Shamsi.\u00a0<\/p>\n
Additional study authors include Tamires Duarte Afonso Serdan, Heidi Cervantes, Benjamin Frank, Akhil Gargey Iragavarapu, Qiyu Tian, Daniel Hope, and Halil Aydin of NYU College of Dentistry; Chan Hee Choi and Paul Cohen of Rockefeller University; Anne Hoffmann and Matthias Bl\u00fcher of the University of Leipzig; Adhideb Ghosh and Christian Wolfrum of ETH Zurich; Matthew Greenblatt of Weill Cornell Medical College; and Gary Schwartz of Albert Einstein College of Medicine.<\/p>\n
Funding: The 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), the Einstein-Mount Sinai Diabetes Center, the NYU Dentistry Department of Molecular Pathobiology, and the Boettcher Foundation.<\/p>\n
Key Questions Answered:Q: If I have brown fat, why am I not losing weight automatically?<\/p>\n
A: As senior author Farnaz Shamsi points out, \u201cjust having brown fat isn\u2019t enough.\u201d If your brown fat doesn\u2019t have the right \u201cinfrastructure\u201d\u2014meaning enough nerves to hear the brain\u2019s signals and enough blood vessels to get oxygen\u2014it stays dormant. It\u2019s like having a high-performance engine with no fuel line or ignition switch.<\/p>\n
Q: How is this different from drugs like Ozempic or Wegovy?<\/p>\n
A: Most current drugs (GLP-1s) work by telling your brain you aren\u2019t hungry, which reduces the energy going in. This SLIT3 pathway is about increasing the energy going out. By \u201cupgrading\u201d your brown fat, you are essentially turning up your body\u2019s internal thermostat to burn through stored white fat and blood sugar.<\/p>\n
Q: Does this mean we can \u201cgrow\u201d more weight-loss tissue?<\/p>\n
A: We may not need to grow more brown fat, but rather optimize what we already have. By harnessing the SLIT3-PLXNA1 pathway, scientists hope to develop therapies that \u201crenovate\u201d existing brown fat, making it more efficient at drawing in and burning off excess nutrients.<\/p>\n
Editorial Notes:This article was edited by a Neuroscience News editor.Journal paper reviewed in full.Additional context added by our staff.About this neurology and aging research news<\/p>\n
Author:\u00a0Rachel Harrison<\/a>
Source:\u00a0NYU<\/a>
Contact:\u00a0Rachel Harrison \u2013 NYU
Image:\u00a0The image is credited to Shamsi Lab, NYU College of Dentistry<\/p>\n