A recent publication from researchers at the University of Iowa, Vanderbilt University, and the University of California, Los Angeles, in Proceedings of the National Academy of Sciences (PNAS) identifies a protein as a key contributor in metabolism and the body’s ability to produce heat.
Brown adipose tissue, or brown fat, helps the body stay warm by burning calories to produce heat instead of storing energy. This process, known as thermogenesis, depends on healthy mitochondria, fat breakdown, and precisely controlled calcium signaling. Although calcium is known to regulate brown fat activity, how these signals are organized has remained unclear.
Led by Long-Sheng Song, MD, MS, professor in Cardiovascular Medicine, the researchers’ new study identifies Junctophilin-2 (JP2)—a protein previously recognized for its role in heart muscle—as a key organizer of calcium signaling in brown fat. Using genetically engineered mice and cultured brown fat cells, researchers measured JP2 levels, removed the protein from brown fat, and examined the effects on calcium signaling, mitochondrial function, heat production, and metabolism.
JP2 was found at much higher levels in brown fat than in white fat, but its expression declined during obesity and nutrient overload. Mice lacking JP2 in brown fat became less tolerant of cold, burned less energy, and gained more weight on a high-fat diet, showing that the protein is essential for normal thermogenesis.
Without JP2, calcium signaling became disorganized. Resting calcium levels increased, activating the enzyme calpain, which degraded proteins needed for calcium regulation and fat breakdown, including STIM1 and hormone-sensitive lipase. This disrupted mitochondrial function, reduced oxygen consumption, and impaired the cells’ ability to generate heat.
Song and his team propose that JP2 acts as a molecular scaffold that maintains specialized calcium signaling needed for brown fat to function efficiently. Loss of JP2 triggers a cascade of calcium dysregulation, impaired fat metabolism, mitochondrial dysfunction, and reduced heat production.
Their findings extend JP2’s known role beyond the heart and suggest that maintaining its presence and its ability in calcium signaling is critical for healthy brown fat. Although the research was conducted primarily in mice and does not show that increasing JP2 can reverse obesity, it identifies a potential new target for therapies aimed at improving brown fat activity and metabolic health.
Song extends his sincere thanks to his team, led by Biyi Chen, MD, PhD, at the University of Iowa for their contributions to this publication, including the university’s Metabolic Phenotyping Core and the Fraternal Order of Eagles Diabetes Research Center (FOEDRC). He also gratefully acknowledges the pilot grant from the FOEDRC, which supported much of this work, as well as the Department of Veterans Affairs Merit Award for its funding.
Feature image: Representative confocal images of Rhod-2 fluorescence in BODIPY-positive cultured BAT adipocytes at baseline, during application of 1 µM norepinephrine (NE), and after NE washout [Song, et. al. Junctophilin-2-orchestrated calcium signalosome regulates brown adipocyte thermogenesis and energy metabolism, Proc. Natl. Acad. Sci. U.S.A. 123 (27)]