A compound known as TOFA appears to fight metabolic disease by pushing cells to use more energy rather than suppressing appetite.

Unlike GLP-1 drugs, which suppress appetite and reduce energy intake, a newly identified molecular compound helps cells burn more energy without changing food intake or exercise and has shown promise in mouse models.

The most successful new obesity drugs largely work by helping people eat less. Researchers at UC Berkeley are exploring a different strategy: increasing how much energy the body uses, rather than reducing how much energy comes in.

Over the past five years, GLP-1 medications such as Ozempic, Wegovy, Mounjaro, and Zepbound have transformed treatment for obesity, diabetes, and fatty liver diseases by helping people lose weight and control blood sugar. But some patients experience nausea and other gastrointestinal problems, and because the drugs suppress appetite and reduce food intake, they can also contribute to nutritional deficiencies and loss of muscle, potentially increasing frailty and other long-term health problems.

The Berkeley researchers identified a potential treatment for obesity and diabetes that instead raises energy expenditure, effectively increasing the body’s metabolic rate.

In a study published in Science Advances, they investigated 5-tetradecyloxy-2-furoic acid (TOFA), a molecular compound that both suppresses production of lipids such as cholesterol and triglycerides and activates genes that help cells burn fat and produce energy.

In mice, TOFA improved insulin sensitivity and glucose control, reduced triglycerides, and improved features of fatty liver disease. Obese mice treated with the compound lost fat without a significant reduction in lean muscle mass.

Rachelle Stark, a Ph.D. student and co-author of the new study, in the Anders Näär lab at Berkeley. Credit: Mathew Burciaga/UC Berkeley

“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.”

TOFA boosts energy use without raising triglycerides

TOFA was originally discovered in the 1970s and belongs to a group of compounds called ACC inhibitors, which interfere with lipid production in the body. Several ACC inhibitors have advanced to mid-stage clinical trials, but none has been approved for metabolic disease, in large part because many can increase triglyceride levels and potentially raise cardiovascular risk.

The researchers found that TOFA behaves differently. In addition to inhibiting ACC, it activates PPARα and PPARδ, cellular receptors that switch on genes involved in taking up fat and burning it for energy. In mice, this increased energy expenditure by as much as 18% without changes in physical activity or body temperature. TOFA also avoided the rise in triglycerides seen with other ACC inhibitors, possibly because of this dual action.

Graduate student Rachelle Stark (left), Professor Anders Näär and postdoctoral fellow Chu Zhu in the Anders Näär lab at Berkeley. Credit: Mathew Burciaga/UC Berkeley

“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.”

To test whether the two effects could simply be reproduced separately, the researchers gave mice one compound that blocked lipid production and another that increased energy expenditure. That combination did not improve overall metabolic health as effectively as TOFA alone.

TOFA strengthened GLP-1 effects in mice

The researchers also tested TOFA alongside GLP-1 medications, including semaglutide, sold as Ozempic and Wegovy, and tirzepatide, sold as Mounjaro and Zepbound. In mice, combining TOFA with these drugs produced greater improvements in body weight, glucose control, insulin levels, and triglycerides than either treatment used by itself.

“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.

TOFA has so far been studied only in animals, and researchers caution that its safety and effectiveness in people remain unknown. With support from Berkeley’s life sciences entrepreneurship ecosystem, including Nucleate and Berkeley SkyDeck, the researchers founded ReRx Therapeutics to pursue further development of the approach.

Reference: “A multi-functional oral small molecule targeting energy and lipid metabolism to treat obesity and related metabolic disorders” by Justin Y. Lee, Chi Zhu, Melissa A. Boldridge, Rachelle L. Stark, Gracia Bonilla, Kosuke Watari, Christina Papa, Lei Xu, Federico Gonzalez, Xin Tang, Kaitlyn T. Dang, Kook Son, Kashish Chetal, Prabha Ibrahim, Ruslan I. Sadreyev, Bilal N. Sheikh, Michael Karin and Anders M. Näär, 21 August 2026, Science Advances.
DOI: 10.1126/sciadv.aed3119

The work was supported by discretionary funds from UC Berkeley, with assistance from the UCSF Liver Center and the University of Michigan Animal Phenotyping Core.

Disclosure: Anders Näär, Justin Lee and Prabha Ibrahim are co-founders or officers and equity holders of ReRx Therapeutics, which has optioned UC Berkeley intellectual property related to this work.

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