Scientists found a compound that made mice burn more energy and lose fat without significant muscle loss.
- Date:
- August 23, 2026
- Source:
- University of California - Berkeley
- Summary:
- A decades-old compound may point to a new way of treating obesity by making the body burn more energy rather than simply reducing appetite. In mice, TOFA increased energy use by as much as 18%, reduced body fat without significant muscle loss, and improved blood sugar, triglycerides, and fatty liver disease. It also produced stronger results when combined with GLP-1 drugs such as Ozempic, Wegovy, Mounjaro, and Zepbound.
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GLP-1 medications have transformed the treatment of obesity, diabetes, and fatty liver disease over the past several years. Drugs sold as Ozempic, Wegovy, Mounjaro, and Zepbound can produce substantial weight loss while helping patients control blood sugar.
But these medications can also cause problems. Some patients experience nausea and other gastrointestinal side effects. Because GLP-1 drugs reduce appetite and food intake, they may also contribute to nutritional deficiencies and loss of muscle, potentially increasing the risk of frailty and other long-term health issues.
Researchers at UC Berkeley are now investigating a very different strategy for treating obesity and diabetes. Instead of reducing the amount of energy a person consumes, their approach is designed to increase the amount of energy the body uses by raising metabolic activity.
A Different Way to Target Weight Loss
In a study published August 21 in Science Advances, the team reports that a molecular compound called 5-tetradecyloxy-2-furoic acid (TOFA) can interfere with the production of lipids such as cholesterol and triglycerides. At the same time, it activates genes that encourage cells to use fat for fuel and produce more energy.
In experiments with mice, TOFA improved insulin sensitivity and glucose control, reduced triglyceride levels, and improved signs of fatty liver disease. Obese mice treated with the compound lost fat while showing no significant reduction in lean muscle mass.
"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."
Reviving a Compound First Discovered Decades Ago
TOFA was initially discovered in the 1970s and belongs to a group of compounds known as ACC inhibitors. These compounds reduce the body's production of lipids.
Several ACC inhibitors have advanced into mid-stage clinical trials, but none has been approved to treat metabolic disease. One important obstacle is that many of these compounds can increase triglyceride levels, which may raise cardiovascular risk.
The UC Berkeley team found that TOFA behaves differently. In addition to acting as an ACC inhibitor, it activates PPARα and PPARδ, cellular receptors that switch on genes involved in taking up fat and burning it for energy.
In mice, this effect increased energy use by as much as 18% without causing the animals to become more physically active or increasing their body temperature. The researchers also found that TOFA did not produce the rise in triglycerides seen with some other ACC inhibitors, possibly because of its combined effects on lipid production and energy metabolism.
"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."
One Compound Outperformed a Two-Drug Approach
The researchers also tested whether they could reproduce TOFA's effects with two separate compounds. They gave mice one compound designed to suppress lipid production and another intended to increase energy expenditure.
That combination did not improve overall metabolic health as effectively as TOFA by itself, suggesting that TOFA's particular combination of actions may be important to its effects.
The team then examined whether TOFA could be paired with existing GLP-1 medications. These included semaglutide, sold under the brand names Ozempic or Wegovy, and tirzepatide, sold as Mounjaro and Zepbound.
In mice, combining TOFA with these GLP-1 drugs produced larger improvements in body weight, glucose control, insulin levels, and triglycerides than either treatment produced on its own.
"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.
Human Testing Is Still Needed
Despite the promising results, the researchers emphasize that TOFA has so far been studied only in animals. Its safety and effectiveness in humans remain unknown and will need to be evaluated in future studies.
With support from Berkeley's life sciences entrepreneurship ecosystem, including Nucleate and Berkeley SkyDeck, the researchers have created a company called ReRx Therapeutics to help move the research toward potential use in patients.
The research was funded through discretionary funds from UC Berkeley, with additional assistance from the UCSF Liver Center and the University of Michigan Animal Phenotyping Core.
Additional authors include Chi Zhu, Melissa A. Boldridge, Rachelle L. Stark, Lei Xu, Federico Gonzalez, Xin Tang, Kaitlyn T. Dang and Kook Son of Berkeley; Gracia Bonilla, Kashish Chetal and Ruslan I. Sadreyev of Massachusetts General Hospital; Kosuke Watari and Michael Karin of the University of California, San Diego; Christina Papa and Bilal N. Sheikh of the Helmholtz Center Munich; Prabha Ibrahim of ReRx Therapeutics.
Story Source:
Materials provided by University of California - Berkeley. Note: Content may be edited for style and length.
Journal Reference:
- 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, Anders M. Näär. A multi-functional oral small molecule targeting energy and lipid metabolism to treat obesity and related metabolic disorders. Science Advances, 2026; 12 (34) DOI: 10.1126/sciadv.aed3119
Cite This Page:
Facts Only
* A compound named 5-tetradecyloxy-2-furoic acid (TOFA) was studied for burning fat without muscle loss in mice.
* Mice treated with TOFA increased energy use by as much as 18%.
* The treatment reduced body fat without significant reduction in lean muscle mass in obese mice.
* TOFA improved insulin sensitivity and glucose control in mice.
* TOFA reduced triglyceride levels and improved signs of fatty liver disease in mice.
* TOFA was tested in combination with GLP-1 drugs (Ozempic, Wegovy, Mounjaro, Zepbound) in mice, resulting in larger improvements in body weight, glucose control, insulin levels, and triglycerides.
* TOFA acts by interfering with lipid production and activating PPARα and PPARδ genes, which promote fat utilization for energy.
* The researchers tested a combination of a compound suppressing lipid production and one increasing energy expenditure; this combination was less effective than TOFA alone.
* Human testing has not yet been performed.
Executive Summary
Full Take
The narrative presents a compelling tension between two established strategies for managing obesity: caloric restriction versus increased energy expenditure. The observation that combining an energy-expending mechanism (TOFA) with appetite-suppressing drugs (GLP-1s) yields superior results suggests that metabolic health is governed by coordinated systemic responses, not isolated interventions. This shifts the focus from simple appetite control to optimizing the body's internal energy regulation pathways.
The historical context of TOFA being discovered in the 1970s and its subsequent repositioning—from an ACC inhibitor with potential cardiovascular risks to a modulator of lipid metabolism and energy expenditure—highlights how scientific understanding evolves. The limitation that TOFA’s effect was stronger in combination with GLP-1 drugs suggests a pattern where maximizing effects requires acknowledging and integrating existing therapeutic mechanisms, rather than seeking single-target solutions.
The persistence of the need for human testing underscores a critical gap: translating complex in vivo synergy into safe clinical practice. The system appears designed to frame new research as incremental progress (building on GLP-1 success) while demanding rigorous, long-term validation before full implementation. The missing piece is understanding the long-term effects of activating energy expenditure pathways in a human context, and whether this approach can safely mitigate the known risks associated with appetite suppression therapies without causing muscle catabolism.
Bridge Questions: What are the specific long-term safety profiles for TOFA and GLP-1 combinations when applied to human populations? How does the activation of PPARα/δ pathways interact with other hormonal axes that govern energy balance? What metrics beyond weight loss and blood markers need to be prioritized in future clinical trials to assess true improvements in metabolic resilience versus mere symptom management?
Sentinel — Human
The text reads like a high-quality summary of complex scientific research, effectively bridging preliminary findings with broader therapeutic implications for readers.