TOFA Shows Promise as a New Treatment for Obesity and Metabolic Diseases

Scientists have identified a decades-old compound called TOFA as a promising potential treatment for obesity, diabetes, fatty liver disease, and other metabolic disorders.

Over the past five years, GLP-1 medications have transformed the treatment of obesity and related metabolic conditions, including type 2 diabetes and fatty liver disease.

Sold under brand names such as Ozempic, Wegovy, Mounjaro, and Zepbound, these medications can help people lose weight and improve blood sugar control. However, GLP-1 drugs can also cause side effects, including nausea and other gastrointestinal problems.

Because GLP-1 medications primarily work by suppressing appetite and reducing food intake, some researchers are exploring alternative approaches that increase the body’s energy expenditure. Reduced food intake may also contribute to nutritional deficiencies and muscle loss in some patients, potentially increasing the risk of frailty over time.

“Weight responds to two levers: either you take in fewer calories, or you expend more energy,” said Anders Naar, a professor at the University of California, Berkeley, and lead author of the study.

“GLP-1 works almost perfectly with the first one, so we considered the second one.”

For the new study, the researchers investigated an orally bioavailable compound known as 5-tetradecyloxy-2-furoic acid, or TOFA.

TOFA was first studied during the 1970s and 1980s as an inhibitor of enzymes involved in fat production. However, its broader effects on obesity and metabolic disease had not been fully investigated, and the compound had not been evaluated in humans.

In experiments involving mice, TOFA led to an average weight loss of 18%, improved blood sugar control, and significant improvements in fatty liver disease. These benefits occurred without appetite suppression or a reduction in muscle mass.

Importantly, TOFA did not cause the potentially dangerous increase in blood triglycerides associated with some other compounds that target fat metabolism.

The researchers also identified an unexpected mechanism of action. In addition to blocking lipid synthesis, TOFA activated proteins known as PPAR receptors, which help regulate energy use and metabolism.

“TOFA appears to be involved in coordinated metabolic reactions,” said lead author Dr. Justin Lee, a researcher at the University of California, Berkeley.

“It doesn’t just block lipid synthesis; it also activates energy-consuming pathways and may help the body process excess lipids and glucose more effectively.”

When TOFA was combined with the weight-loss medications semaglutide and tirzepatide, the mice experienced greater weight loss than animals treated with either medication alone.

The mice treated with TOFA also maintained their weight loss for longer after treatment ended than mice treated with semaglutide. The researchers believe this may be linked to TOFA’s ability to increase energy expenditure rather than simply reduce food intake.

Although the findings suggest that TOFA could become a future treatment for obesity and related metabolic disorders, additional studies are needed. Human safety, appropriate dosage, and potential side effects must be established before clinical trials can begin.

“In our combination experiments, TOFA acted additively or synergistically with GLP-1 appetite suppressants, so we consider them to be complementary rather than substitutes,” Professor Naar said.

The findings appear in the journal Science Advances.

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Justin Y. Lee et al. 2026. Multifunctional oral small molecules targeting energy and lipid metabolism to treat obesity and related metabolic disorders. Science Advances 12(34); doi: 10.1126/sciadv.aed3119