Experimental Fat-Burning Compound Promotes Fat Loss Without Muscle Loss

However, GLP-1 drugs can also cause side effects, including nausea and other gastrointestinal problems. Because they reduce appetite and calorie consumption, they may contribute to nutritional deficiencies and muscle loss in some patients, potentially increasing the long-term risk of frailty and other health complications.

Researchers at the University of California, Berkeley, are investigating a different approach to treating obesity and diabetes. Instead of primarily reducing calorie intake, their strategy aims to increase the amount of energy the body uses by boosting metabolic activity.

A new approach to weight loss and metabolic health

In a study published August 21 in Science Advances, researchers reported that a molecular compound called 5-tetradecyloxy-2-furanic acid, or TOFA, may improve metabolism in several ways. The compound interferes with the production of lipids, including cholesterol and triglycerides, while activating genes that encourage cells to burn fat for energy.

In experiments involving mice, TOFA improved insulin sensitivity and blood sugar control, reduced triglyceride levels, and eased signs of fatty liver disease. Obese mice treated with TOFA lost body fat without experiencing a significant reduction in lean muscle mass.

“Body weight responds to two basic levers: eating fewer calories or expending more energy,” said Anders Naar, a professor of metabolic biology and nutrition at the University of California, Berkeley, and lead author of the study. “GLP-1 medications work very effectively through the first mechanism, so we wanted to investigate the second.”

Revisiting a compound discovered decades ago

TOFA was first identified in the 1970s and belongs to a class of compounds known as acetyl-CoA carboxylase, or ACC, inhibitors. These compounds reduce the body’s ability to produce lipids.

Several ACC inhibitors are being evaluated in mid-stage clinical trials, but none have been approved to treat metabolic diseases. A major challenge is that some ACC inhibitors can raise triglyceride levels, potentially increasing cardiovascular risk.

The Berkeley research team found that TOFA behaves differently. In addition to inhibiting ACC and reducing lipid production, TOFA activates the cellular receptors PPARα and PPARδ. These receptors switch on genes involved in fat uptake and the conversion of fat into energy.

In mice, TOFA increased energy expenditure by as much as 18% without making the animals more physically active or raising their body temperature. Researchers also found that the compound did not produce the triglyceride increase associated with some other ACC inhibitors. The researchers believe this may result from TOFA’s combined effects on fat production and energy metabolism.

“TOFA appears to trigger a coordinated metabolic response,” said study author Justin Y. Lee, a postdoctoral fellow at the University of California, San Francisco, who conducted the research while pursuing his Ph.D. at Berkeley. “It does more than block lipid synthesis; it also activates energy-consuming pathways and may help the body process excess lipids and glucose more efficiently.”

TOFA outperformed a two-drug strategy in mice

The researchers also tested whether TOFA’s effects could be reproduced using two separate compounds: one designed to suppress fat production and another intended to increase energy expenditure.

The two-compound combination did not improve overall metabolic health as effectively as TOFA alone. This finding suggests that the compound’s coordinated effects on lipid production and energy use may be important to its potential benefits.

The team next examined whether TOFA could complement existing GLP-1 medications. These included semaglutide, sold under the brand names Ozempic and Wegovy, and tirzepatide, sold as Mounjaro and Zepbound.

In mice, combining TOFA with GLP-1 drugs produced greater improvements in body weight, blood sugar control, insulin levels, and triglycerides than either treatment alone.

“In our combination experiments, TOFA acted additively or synergistically with GLP-1 appetite suppressants,” Naar said. “This suggests that the two approaches may be complementary rather than substitutes.”

Human studies are still needed

Despite these promising findings, TOFA has only been tested in animal studies. Its safety, effectiveness, appropriate dosage, and potential side effects in humans remain unknown and must be evaluated in future clinical research.

With support from Berkeley’s life sciences entrepreneurship ecosystem, including Nucleate and Berkeley SkyDeck, the researchers founded ReRx Therapeutics to help advance the compound toward potential clinical applications.

The study was funded by discretionary funds from the University of California, Berkeley, with additional support from the University of California, San Francisco Liver Center, and the University of Michigan Animal Phenotyping Core.

Additional authors included Chi Zhu, Melissa A. Boldridge, Rachelle L. Stark, Lei Xu, Federico Gonzalez, Xin Tang, Kaitlyn T. Dang, and Kook Son of the University of California, Berkeley; Gracia Bonilla, Kashish Chetar, and Ruslan I. Sadlev of Massachusetts General Hospital; Kosuke Watari and Michael Karin of the University of California, San Diego; Christina Papa and Bilal N. Sheikh of the Munich Helmholtz Center; and Prabha Ibrahim of ReRx Therapeutics.