Researchers at the University of California, Berkeley, report that a decades-old compound called TOFA reduces body fat in high-weight mice without curbing appetite. Published August 21 in Science Advances, the findings offer an alternative strategy to blockbuster GLP-1 drugs by increasing metabolic energy expenditure instead of suppressing food intake.
Reviving a 1970s Lipid Compound to Target Energy Expenditure
Blockbuster weight-loss medications such as semaglutide, sold as Ozempic and Wegovy, and tirzepatide, sold as Mounjaro and Zepbound, have transformed the treatment of obesity, type 2 diabetes, and fatty liver disease over recent years. These drugs work primarily by reducing appetite and limiting food intake. But because patients eat significantly less, they can also experience nutritional deficiencies and a notable loss of lean muscle mass, raising concerns about frailty and long-term metabolic slowdown. In a study published August 21 in Science Advances, researchers investigated a very different strategy.
Instead of restricting calorie consumption, the research team focused on increasing the amount of energy the body uses. Scientists at UC Berkeley examined 5-(tetradecyloxy)-2-furoic acid, or TOFA, a small molecule first studied in the 1970s as a lipid-lowering compound. TOFA belongs to a class of drugs known as ACC inhibitors, which interfere with acetyl coenzyme A carboxylases 1 and 2—enzymes involved in fatty acid synthesis. While other ACC inhibitors have advanced into clinical trials, they often trigger a rise in circulating triglycerides, fats in the blood that elevate cardiovascular risks. TOFA behaves differently because it was originally designed to lower blood lipids, avoiding that dangerous liability.
“I was struck by the fact that it was a unique ACC inhibitor.”
Anders Näär, metabolic biologist at the University of California, Berkeley
How TOFA Activates Cellular Receptors and Burns Fat Without Curbing Appetite
Because TOFA’s chemical structure resembles a fatty acid, metabolic biologist Anders Näär and former graduate student Justin Lee suspected the compound might interact with peroxisome proliferator-activated receptors, a family of proteins that regulate genes involved in fat metabolism and energy use. When tested on mice fed a high-fat diet for several weeks, the animals lost body weight without eating less. The compound interfered with the production of lipids like cholesterol and triglycerides while simultaneously activating genes that prompt cells to burn fat for fuel.
In metabolic cage experiments, mice treated with TOFA expended up to 18 percent more energy than untreated mice under specific conditions. Follow-up analyses showed that TOFA binds directly to and partially activates two members of the receptor family, PPARα and PPARδ, engaging a coordinated metabolic response without overstimulating downstream pathways or causing dangerous increases in body temperature. Obese mice given the compound lost fat while showing no significant reduction in lean muscle mass, according to the study.
Combination Potential With Blockbuster GLP-1 Medications
Researchers also explored whether TOFA could complement existing treatments rather than replace them. When administered alongside semaglutide or tirzepatide in animal models, the combined therapies produced larger improvements in body weight, glucose control, insulin levels, and triglycerides than any single treatment achieved on its own. The two-pronged approach pairs an appetite-suppressing lever with an energy-expending lever, offering a potential path toward combination treatments in human medicine.
Despite the promising preclinical results, the study authors emphasize that the findings remain strictly preliminary. TOFA has so far been evaluated only in animal models, and its safety and efficacy in humans are still unknown.