Blockbuster weight-loss drugs such as semaglutide (Ozempic, Wegovy) and tirzepatide (Mounjaro) help people lose weight largely by reducing appetite and, in turn, limiting how much they eat. But researchers are now exploring whether a small molecule first studied almost 50 years ago could instead get the body to expend more energy.
Researchers at the University of California, Berkeley, report that 5-(tetradecyloxy)-2-furoic acid, or TOFA, reduces body fat in high-weight mice without decreasing food intake. The compound appears to be suppressing fatty acid synthesis while activating pathways involved in burning fat and expending energy. The findings could lead to a treatment that would complement existing appetite-curbing drugs (Sci. Adv. 2026, DOI: 10.1126/sciadv.aed3119).
TOFA was developed in the 1970s as a lipid-lowering compound and was later found to inhibit acetyl coenzyme A carboxylases 1 and 2 (ACC1/2), enzymes involved in fatty acid metabolism. Other ACC inhibitors have since been tested as treatments for metabolic diseases, but they can increase circulating triglycerides, fats in the blood that, at high levels, are associated with cardiovascular conditions.
“I was struck by the fact that it was a unique ACC inhibitor,” says Anders Näär, a metabolic biologist at the University of California, Berkeley, who helped lead the work. Unlike other compounds in the class, TOFA had originally been developed to lower blood lipids.
Since TOFA’s structure resembles a fatty acid, Näär suspected it could interact with peroxisome proliferator-activated receptors (PPARs), a family of proteins that regulate genes involved in fat metabolism and energy use. But first, Näär asked Justin Lee, then a graduate student, to test what the compound would do in mice that had been fed a high-fat diet for several weeks and had gained a significant amount of weight.
The animals lost weight without eating less. “At that point, we really had no idea why,” Lee says.
The team tested different doses and treatment schedules across more than 20 experiments in mouse models of high weight, diabetes, and fatty liver disease, finding improvements in body weight, glucose control, and liver fat. “I was so taken aback by the consistency of the effect of the compound,” he says, including when collaborators tested TOFA independently.
In metabolic cage experiments, mice who had been treated with TOFA expended about 18% more energy than untreated mice under some conditions. The increase in expended energy also persisted when the mice were kept in thermoneutral environments, suggesting that heat generation by brown fat did not fully account for the effect. Näär says the liver, skeletal muscle, heart, or a combination of tissues could be involved.
When analyzing the gene expression of liver tissue in treated mice, the researchers found increased activity in pathways controlled by PPARs. Follow-up experiments showed that TOFA binds directly to and partially activates two members of the family, PPARα and PPARδ.
Näär hypothesizes that the partial activation of PPARα and PPARδ means TOFA activates the receptors without overstimulating downstream metabolic pathways, but more work is needed to be sure.
Scott L. Friedman, a hepatologist at the Icahn School of Medicine at Mount Sinai who was not involved with the study, says TOFA’s combination of targets is unusual. “It turns out to be a two for the price of one, if you will,” he says. He is also encouraged that TOFA doesn’t raise triglycerides, “overcoming the liability” that halted development of previous ACC1/2 inhibitors.
Although increasing energy expenditure can sound like a golden-ticket treatment, the approach has raised safety concerns in the past. The mitochondrial uncoupler 2,4-dinitrophenol was once used as a weight-loss drug but can cause dangerous increases in body temperature. Näär says his team did not observe hyperthermia in TOFA-treated mice.
TOFA could lead to an additive drug to those already prescribed for weight loss. When administered with semaglutide or tirzepatide, the mice lost more weight than those treated with any drug alone, and they had improved glucose control and reduced triglycerides in the blood and liver.
Näär, Lee, and study coauthor Prabha Ibrahim have cofounded ReRx Therapeutics to develop their findings to treat metabolic diseases, including metabolic dysfunction-associated steatohepatitis (MASH) and type 2 diabetes, and for weight loss. They have completed dose-ranging toxicity studies in rats and plan to test their lead compound, called ReRx-001, in rhesus macaques.
The team stresses that the findings are still preclinical and that TOFA may be toxic to or not work in humans. Näär worries that people could try to buy TOFA online and experiment with it. “It’s very early preclinical,” Näär says. “So don’t do that.”
Ana Georgescu covers a wide range of topics in Physical Sciences. She is also a frequent contributor to the Business desk and is probably working on a short video project at any given time.
