Unlocking the Power of TOFA: Boosting Energy Expenditure in Obesity Models with a Novel Dietary Approach for Weight Loss and Improved Metabolic Health

How TOFA Targets Energy Expenditure Differently Than GLP-1s

Over the past five years, drugs like Ozempic, Wegovy, Mounjaro, and Zepbound have transformed how clinicians approach metabolic conditions, helping millions manage blood sugar and drop pounds. Yet these treatments carry notable downsides, including stubborn gastrointestinal side effects like nausea. More critically, because they work by suppressing appetite and slashing food intake, patients often face the risk of nutritional deficiencies and dangerous muscle loss that can trigger long-term frailty. Seeking an alternative approach that bypasses calorie restriction entirely, a team at UC Berkeley focused on boosting the body’s natural metabolic rate instead. Their findings were published in the journal Science Advances in the article titled “A multi-functional oral small molecule targeting energy and lipid metabolism to treat obesity and related metabolic disorders” (Sci Adv. 2026;12(34):eaed3119. doi: 10.1126/sciadv.aed3119).

“Body weight responds to two levers: taking in fewer calories, or spending more energy,” said Anders Näär, a professor of metabolic biology and nutrition at UC Berkeley and senior author of the study. “GLP-1s work almost entirely on the first, so we went after the second.”

The Mechanism of TOFA and Its Dual Cellular Action

The research centers on a small molecule known formally as 5-tetradecyloxy-2-furoic acid, or TOFA, which was originally discovered back in the 1970s. While TOFA belongs to a class of compounds called ACC inhibitors designed to block lipid production, earlier iterations in this class stalled out before winning clinical approval because they paradoxically raised blood triglycerides and threatened heart health. The UC Berkeley team discovered that TOFA does something entirely unique: it blocks lipids while simultaneously flipping on genetic switches that burn fat. Specifically, the compound activates PPARα and PPARδ cellular receptors, which instruct cells to take up fat and incinerate it for fuel. Laboratory experiments showed that treated mice burned up to 18% more energy without any artificial spike 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.”

Animal Study Results on Weight Loss and Muscle Preservation

When put to the test in murine models, TOFA demonstrated a remarkable ability to revamp metabolic health without the muscle-wasting pitfalls seen in traditional appetite suppression. The compound successfully improved insulin sensitivity, tightened glucose control, slashed triglycerides, and reversed key markers of fatty liver disease. Most importantly, when obese mice were administered the compound, they dropped weight strictly from fat stores while keeping their lean muscle mass completely intact. Furthermore, when the investigators tested a split approach—giving mice two separate compounds to simultaneously block lipids and boost energy—the dual-drug cocktail failed to match the metabolic success of TOFA on its own.

Combining TOFA With GLP-1 Medications for Enhanced Results

Rather than positioning the new molecule as a direct competitor to existing blockbuster injectables, the research team explored what happens when the two strategies join forces. In further experiments involving mice, combining TOFA with popular GLP-1 receptor agonists like semaglutide (sold as Ozempic and Wegovy) or tirzepatide (sold as Mounjaro and Zepbound) yielded superior results compared to either intervention deployed in isolation. The hybrid approach drove even sharper improvements in body weight, glucose regulation, insulin levels, and triglycerides.

“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 said.

Pathways to Human Clinical Trials Through ReRx Therapeutics

Moving from successful animal models to human pharmacies remains a monumental hurdle, and the research team emphasizes that TOFA has not yet been tested for safety or efficacy in human patients. To bridge that gap, the scientists have launched a startup company named ReRx Therapeutics, utilizing support from Berkeley’s local life sciences entrepreneurship ecosystem, including organizations like Nucleate and Berkeley SkyDeck, to help carry this work to patients.