Researchers at the University of California, Berkeley have investigated an experimental molecular compound that targets obesity by increasing energy expenditure rather than suppressing appetite. The study, published in Science Advances, tested the compound 5-tetradecyloxy-2-furoic acid (TOFA) on obese male mice fed a high-fat diet.
University of California, Berkeley Researchers Test TOFA in Obese Mice
While popular metabolic medications like GLP-1 receptor agonists—including semaglutide and tirzepatide—promote weight loss primarily by reducing food intake, they can also cause side effects and muscle loss. In contrast, TOFA was administered by mouth twice a day for four weeks without changing how much the animals ate, yet it produced an average weight loss of 18 percent.
Dual Cellular Mechanism Boosts Energy Expenditure
According to the study, TOFA engages a coordinated metabolic response through a dual mechanism. First, it acts as an ACC inhibitor, blocking the production of lipids such as cholesterol and triglycerides. Second, it activates cellular receptors known as PPARα and PPARδ, which switch on genes that encourage cells to take up fat and burn it for energy.
Senior author Anders Näär, a professor of metabolic biology and nutrition at UC Berkeley, noted that whole-body energy expenditure increased by as much as 18 percent in the treated mice, with no changes in physical activity or body temperature. Food intake was unchanged, physical activity was unchanged, and body temperature did not rise, yet whole-body energy expenditure increased by as much as 18 percent,
Näär told Sciencealert.
Furthermore, most of the weight lost came from body fat, while muscle and other lean tissues were largely preserved. The treatment also improved insulin sensitivity, glucose control, and features of fatty liver disease while lowering triglyceride levels.
Reviving a 1970s Compound to Avoid Previous Hurdles
TOFA was initially discovered in the 1970s and has long been used in laboratory research as an ACC inhibitor. Although several other ACC inhibitors advanced to mid-stage clinical trials in the past, none were approved for metabolic disease because many such compounds raised triglyceride levels and posed cardiovascular risks.
The UC Berkeley team found that TOFA did not raise triglycerides, likely due to its ability to simultaneously activate fat-burning pathways. When researchers attempted to replicate TOFA’s results using two separate compounds—one to suppress lipid production and another to increase energy expenditure—the combination did not produce the same metabolic improvements, indicating that having both activities in a single molecule is significant.
Combination Therapy With GLP-1 Medications
The researchers also explored pairing TOFA with existing GLP-1 medications, including semaglutide (sold under brand names like Ozempic and Wegovy) and tirzepatide (sold as Mounjaro and Zepbound). Because GLP-1 drugs reduce energy intake while TOFA increases energy expenditure, the mechanisms acted on different sides of the body’s energy balance.
According to the study, combining TOFA with GLP-1 drugs produced greater improvements in body weight, glucose control, insulin levels, and triglycerides than any of the treatments used alone. In a separate experiment, TOFA-treated mice maintained their weight for longer after treatment ended, whereas mice given semaglutide rapidly regained weight as food intake rose. Researchers noted that these combination experiments were short and involved small groups of mice.
