Mouse Study Finds Compound That Burns Fat Without Losing Muscle

GLP-1 medications sold as Ozempic, Wegovy, Mounjaro and Zepbound have transformed obesity and diabetes treatment, but they work mainly by reducing appetite and food intake, which can also cause nausea, nutritional deficiencies and loss of muscle. Researchers at UC Berkeley are investigating a different approach: raising the amount of energy the body uses rather than cutting the amount it takes in.

In a study published August 21 in the journal Science Advances, the team reports that a compound called 5-tetradecyloxy-2-furoic acid (TOFA) interferes with the production of lipids such as cholesterol and triglycerides while activating genes that push cells to burn fat for fuel. In mice, TOFA improved insulin sensitivity and glucose control, reduced triglyceride levels, and reduced fat without significantly shrinking lean muscle mass. "Body weight responds to two levers: taking in fewer calories, or spending more energy," said Anders Näär, a UC Berkeley professor of metabolic biology and nutrition and senior author of the study. "GLP-1s work almost entirely on the first, so we went after the second."

TOFA was first discovered in the 1970s and belongs to a group of compounds that block a lipid-producing enzyme; earlier compounds in this class raised triglyceride levels, a cardiovascular risk. The Berkeley team found TOFA also activates two cellular receptors called PPAR (peroxisome proliferator-activated receptor), specifically PPARα and PPARδ, that switch on fat-burning genes, and it increased energy use in mice by as much as 18% without raising their body temperature or activity levels, while avoiding the triglyceride rise seen with earlier compounds of its type.

When the researchers combined TOFA with GLP-1 drugs such as semaglutide (Ozempic, Wegovy) and tirzepatide (Mounjaro, Zepbound) in mice, the combination produced larger improvements in body weight, glucose control, insulin levels and triglycerides than either treatment alone. The researchers say TOFA has so far been tested only in animals, and its safety and effectiveness in humans remain unknown and need future study.