How TOFA Increases Energy Expenditure in Obesity Models

How TOFA Differs From GLP-1 Medications Like Ozempic and Wegovy

Over the past five years, medications like Ozempic, Wegovy, Mounjaro, and Zepbound have revolutionized metabolic disorder treatments. Sold under these brand names, GLP-1s help patients manage blood sugar levels and lose weight effectively. However, suppressing appetite and reducing food intake can sometimes cause nutritional deficiencies and muscle loss, potentially leading to long-term frailty. According to Anders Näär, a professor of metabolic biology and nutrition at UC Berkeley and senior author of the study, body weight responds to two distinct levers. “Body weight responds to two levers: taking in fewer calories, or spending more energy,” Näär said. “GLP-1s work almost entirely on the first, so we went after the second.”

The Dual Mechanism of TOFA in Cellular Energy Expenditure

Originally discovered in the 1970s, TOFA belongs to a class of compounds known as ACC inhibitors, which block the production of lipids in the body. While earlier ACC inhibitors stalled in mid-stage clinical testing because they raised triglycerides and threatened heart health, TOFA behaves differently. The UC Berkeley research team found that TOFA activates cellular receptors PPARα and PPARδ alongside its ACC-inhibiting functions. These receptors turn on genes that enable cells to take up fat and burn it for fuel. In mouse experiments, this dual mechanism caused cells to burn up to 18% more energy without any alteration in physical activity or body temperature. “TOFA appears to engage a coordinated metabolic response,” said study first author Justin Y. Lee, a postdoctoral student at UCSF who conducted the research as a Ph.D. student at Berkeley. “It is not simply blocking lipid synthesis. It is also activating energy expenditure pathways that may help the body handle excess lipid and glucose more effectively.”

Combining TOFA With GLP-1 Drugs for Enhanced Weight Loss

When researchers tested TOFA on obese mice, the animals lost weight from fat without experiencing significant losses in lean muscle mass. Furthermore, the compound improved insulin sensitivity, glucose control, and lowered triglycerides while addressing features of fatty liver disease. Interestingly, when scientists administered two separate compounds—one blocking lipid production and another boosting energy expenditure—the combination proved less effective than TOFA alone. When investigating potential combination therapies, the team administered TOFA alongside GLP-1 medications like semaglutide (sold as Ozempic or Wegovy) and tirzepatide (sold as Mounjaro and Zepbound). According to the findings, combining TOFA with these appetite-suppressing drugs produced greater improvements in body weight, glucose control, insulin levels, and triglycerides than either treatment administered independently. “In our combination experiments, TOFA worked additively or synergistically with the GLP-1 appetite suppressing drugs, so we view it as complementary rather than as a replacement,” Näär noted.

Frequently Asked Questions

What is TOFA?

TOFA (5-tetradecyloxy-2-furoic acid) is a molecular compound originally discovered in the 1970s that blocks lipid production while simultaneously activating genes that help cells burn fat for energy.

How does TOFA differ from Ozempic and other GLP-1 drugs?

While GLP-1 medications like Ozempic, Wegovy, Mounjaro, and Zepbound work primarily by suppressing appetite and reducing calorie intake, TOFA targets energy expenditure by increasing the body’s metabolic rate and forcing cells to burn stored fat.

Has TOFA been tested in humans?

No. Researchers emphasize that TOFA has only been studied in animals, and its safety and efficacy in humans remain untested. To help carry this work toward clinical application, the researchers have founded a new company named ReRx Therapeutics with support from Berkeley’s entrepreneurship ecosystem, including Nucleate and Berkeley SkyDeck.