For the last five years, GLP-1 drugs have changed how doctors treat obesity, diabetes, and fatty liver disease. Most people know them by brand names like Ozempic, Wegovy, Mounjaro, and Zepbound. These drugs work well. They help people lose weight and control blood sugar.
But they are not perfect. Many users get nausea and other stomach problems. The drugs also reduce appetite, so people eat less. Over time, these effects can cause poor nutrition and muscle loss, which can lead to frailty later in life.
Now, scientists at UC Berkeley may have discovered a new way to move forward. Instead of cutting how much people eat, their approach boosts how much energy the body burns. The findings appeared today in Science Advances.
What Is TOFA?
The compound is called 5-tetradecyloxy-2-furoic acid, or TOFA for short. It does two things at once. First, it blocks the body from making certain fats, like cholesterol and triglycerides. Second, it turns on genes that help cells burn fat for fuel.
The researchers tested TOFA in mice. The results were promising. The mice had better insulin sensitivity and better blood sugar control. Their triglyceride levels dropped. Signs of fatty liver disease also improved. Even better, the mice lost fat without losing muscle.
“Body weight responds to two levers: taking in fewer calories or spending more energy,” said Anders Näär, a UC Berkeley professor of metabolic biology and nutrition. He led the study. “GLP-1s work almost entirely on the first, so we went after the second.”
An Old Compound With a New Trick
TOFA is not new. Scientists found it back in the 1970s. It belongs to a group of drugs called ACC inhibitors, which stop the body from producing fat. Several similar drugs have been tested in clinical trials before. None made it to market. The reason: many of them raise triglyceride levels, which can hurt heart health.
TOFA appears to be different. The Berkeley team found that it also switches on two cell receptors, called PPARα and PPARδ. These receptors trigger genes that help cells absorb fat and burn it for energy. In the mouse studies, this process increased energy burning by up to 18 per cent. The mice were not more active. Their body temperature did not rise. The extra calorie burning came from somewhere else in their biology.
This dual action may explain why TOFA avoided the triglyceride problem seen in older ACC inhibitors.
“TOFA appears to engage a coordinated metabolic response,” said Justin Y. Lee, the study’s first author. He is now a postdoctoral researcher at UCSF and did this work 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.”
When the team tried using two separate drugs, one to block fat production and another to boost energy burning, the combination did not work as well as TOFA alone.
Could It Work With GLP-1 Drugs?
The researchers also tested TOFA alongside semaglutide (Ozempic, Wegovy) and tirzepatide (Mounjaro, Zepbound). In mice, the combination outperformed either treatment on its own. Weight loss improved. So did blood sugar, 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.
What Comes Next
So far, TOFA has only been tested in animals. Its safety and effectiveness in humans is still unknown. To move the research forward, the team started a new company called ReRx Therapeutics. They received support from Berkeley’s startup network, including Nucleate and Berkeley SkyDeck.
Funding for the study came from UC Berkeley, with help from the UCSF Liver Center and the University of Michigan Animal Phenotyping Core. Researchers from Massachusetts General Hospital, UC San Diego, and the Helmholtz Center Munich also contributed to the work.
