A collaborative research team, including bioanalytical neurochemist Alexander G. Zestos of American University, has identified a key signaling pathway that spurs beige fat cells to burn energy, revealing a possible target for obesity therapies in humans. The team, whose findings published today in Nature Medicine, conducted mouse studies to identify the brain receptor known as the CHRNA2 signaling pathway.
Zestos helped to develop the method that detected acetylcholine, fundamental to the pathway. The method detected acetylcholine and over 20 other neurotransmitters over a four-minute time period. Since many neurotransmitters play important roles in the brain, it is important to monitor them simultaneously and measure their concentration levels relative to one another.
The finding reveals insights into the communication taking place between the body's immune system and beige fat cells. Understanding this communication will be critical to developing therapies targeting beige fat to curb obesity. An additional discovery that nicotine causes the energy-burning process in beige fat, too, could answer questions about associations between weight and smoking.
"This is a very exciting discovery for this pathway. Until recently, we thought this pathway primarily existed in brain cells, the neuromuscular junction, and affected neuronal signaling, and we didn't know it was prevalent in certain fat cells," Zestos said. "It raises all sorts of new questions. Is it the density of the receptors that a person has, or is it the way the receptors are activated, that contributes to one's ability to gain or lose weight? What is the connection between smoking and weight loss or weight gain?"
Scientific understanding of beige fat is in its early stages. Many aspects of how the cells function are not yet known. It's only recently that scientists found beige fat cells in human adults and noted their role in burning energy, resulting in improved metabolic health.
Beige fat cells help organisms defend against severe cold. As part of the immune response to cold, beige fat gets made by the brown fat mixing with small concentrations of white fat. The new research verifies the CHRNA2 signaling pathway is active when brown fat gets converted into energy to protect against cold. In mice, beige fat allows them to shiver to ward off cold. When the team deactivated CHRNA2 in mice, they weren't able to protect against cold and they gained weight.
The chemistry played a pivotal role in the research. Working with biologists, Zestos measured acetylcholine in the fat cells. Zestos verified that acetylcholine was inducing the pathway. As part of the method developed, Zestos came up with a way to separate the acetylcholine from other fat cells.
The next step of the research will be to examine other neurochemicals and their pathways for the roles they could play in activating beige fat cells, as well as to test for possible therapeutics for weight loss and obesity prevention by targeting the CHRNA2 pathway.
Additional author contributors include Heejin Jun, Hui Yu, Jianke Gong, Juan Jiang, Xiaona Qiao, Eric Perkey, Dong-il Kim, Margo P. Emont, Jung-Sun Cho, Jianfeng Liu, Robert T. Kennedy, Ivan Maillard, X.Z. Shawn Xu, and Jun Wu.
American University is a leader in global education, enrolling a diverse student body from throughout the United States and nearly 130 countries. Located in Washington, D.C., the university provides opportunities for academic excellence, public service, and internships in the nation's capital and around the world. AU's Center for Behavioral Neuroscience brings together psychologists, biologists, chemists, and other scientists who seek to understand the relationship between nervous system behavior and disease.