Researchers at UC Berkeley report that a compound called TOFA made obese mice burn up to 18% more energy, shed fat while keeping lean muscle, and show better blood sugar and liver markers. The compound also produced stronger results when combined with GLP-1 medications such as Ozempic, Wegovy, Mounjaro, and Zepbound.
What TOFA Does in the Body
TOFA, short for 5-tetradecyloxy-2-furoic acid, is a small molecule that blocks part of the cell’s lipid production machinery while switching on genes that tell cells to burn fat for fuel. In mice fed a high-fat diet, the compound raised whole-body energy expenditure by as much as 18% without increasing physical activity or body temperature. Treated animals lost fat but showed no significant drop in lean muscle mass, and they also had lower blood sugar, lower triglycerides, and reduced signs of fatty liver disease.
Body weight responds to two levers: taking in fewer calories or spending more energy. GLP-1 drugs work almost entirely on the first lever, so the Berkeley team set out to pull the second one.
Why Pull the Energy-Spending Lever
GLP-1 receptor agonists have reshaped the treatment of obesity, type 2 diabetes, and fatty liver disease, producing meaningful weight loss in many patients. The drug class also carries trade-offs that researchers and clinicians are still working to address:
- Gastrointestinal side effects, including nausea, are common.
- Reduced food intake can lead to nutritional shortfalls.
- Weight loss often includes muscle along with fat, which can raise frailty risk, though the exact increase depends on factors like age and diet.
TOFA’s approach, raising how much energy the body uses rather than cutting how much food goes in, is designed to avoid some of those problems, at least in mice.
How TOFA Differs From Other ACC Inhibitors
TOFA belongs to a class of drugs called ACC inhibitors that lower the production of cholesterol and triglycerides. Several ACC inhibitors have reached mid-stage clinical trials for metabolic disease, but none has been approved, in part because many of them raise triglyceride levels, a concern for cardiovascular risk. The Berkeley group found that TOFA does not cause that triglyceride spike, possibly because it also activates two cellular receptors, known as PPAR alpha and PPAR delta, that drive fat uptake and burning.
TOFA triggers a coordinated metabolic response.
One Molecule Beat a Two-Drug Combo
To test whether TOFA’s effects could be matched with separate drugs, the team gave mice one compound meant to suppress lipid production plus another meant to raise energy expenditure. That pairing did not improve overall metabolic health as much as TOFA did on its own, which suggests the specific combination of actions inside a single molecule may matter.
Pairing TOFA With GLP-1 Drugs
The researchers then tested TOFA alongside semaglutide (sold as Ozempic and Wegovy) and tirzepatide (sold as Mounjaro and Zepbound). In obese mice, the combination produced larger improvements in body weight, glucose control, insulin levels, and triglycerides than either treatment alone. The team describes the effect as additive or synergistic, and frames TOFA as a complement to current GLP-1 therapy rather than a replacement.
Where the Research Stands
All of the published work was done in mice. Safety and effectiveness in humans are still unknown and will need clinical trials to evaluate. With support from Berkeley’s life sciences entrepreneurship programs, including Nucleate and Berkeley SkyDeck, the researchers have formed a company called ReRx Therapeutics to push the work toward potential use in patients. The study was funded through discretionary funds from UC Berkeley, with additional assistance from the UCSF Liver Center and the University of Michigan Animal Phenotyping Core.
The findings were published August 21 in Science Advances.
FAQ
What is TOFA and how does it work?
TOFA (5-tetradecyloxy-2-furoic acid) is a small molecule that blocks part of the cell’s lipid production machinery and activates PPAR receptors that switch on fat-burning and energy-use genes. In obese mice, this raised energy expenditure by as much as 18% and reduced fat without significant muscle loss.
Can TOFA be combined with Ozempic, Wegovy, Mounjaro, or Zepbound?
In mouse experiments, TOFA combined with semaglutide (Ozempic, Wegovy) or tirzepatide (Mounjaro, Zepbound) produced larger improvements in body weight, glucose, insulin, and triglycerides than either treatment alone. Whether the same holds in humans is not yet known.
Is TOFA available as a treatment?
No. TOFA has only been tested in animals so far. The research team has launched a company, ReRx Therapeutics, to help move the compound toward clinical trials, but no human safety or effectiveness data have been published.
