A 1970s compound could help burn fat without any muscle loss

The compound is 5-tetradecyloxy-2-furoic acid, or TOFA, first identified in the 1970s. It belongs to a class called ACC inhibitors, which suppress the body's production of lipids such as cholesterol and triglycerides. Several ACC inhibitors have reached mid-stage clinical testing and none has been approved for metabolic disease, largely because many of them push triglycerides up, which carries cardiovascular risk.

TOFA appears to work on two fronts at once. Alongside inhibiting ACC, it activates PPARα and PPARδ, cellular receptors that switch on genes for taking up fat and burning it for fuel. In mice, that combination raised energy expenditure by as much as 18% with no increase in physical activity and no rise in body temperature. It also did not produce the triglyceride increase seen with other ACC inhibitors, which the researchers attribute to the dual mechanism.

Obese mice given TOFA lost fat with no significant loss of lean muscle mass. Insulin sensitivity and glucose control improved, triglycerides fell, and markers of fatty liver disease improved.

"Body weight responds to two levers: taking in fewer calories, or spending more energy," said Anders Näär, professor of metabolic biology and nutrition at Berkeley and senior author. "GLP-1s work almost entirely on the first, so we went after the second."

The team tested whether two separate compounds could reproduce the effect, giving mice one agent to block lipid production and another to raise energy expenditure. The pairing did not improve overall metabolic health as much as TOFA alone, which suggests the combination of actions within a single molecule matters.

"It is not simply blocking lipid synthesis," said first author Justin Y. Lee, who conducted the work as a PhD student at Berkeley. "It is also activating energy expenditure pathways that may help the body handle excess lipid and glucose more effectively."

The researchers also paired TOFA with semaglutide and with tirzepatide. In mice, each combination produced larger improvements in body weight, glucose control, insulin levels and triglycerides than either treatment alone. Näär described TOFA as working additively or synergistically with the appetite-suppressing drugs, and framed it as complementary rather than a replacement.

TOFA has been studied only in animals. Its safety and efficacy in humans are untested, and mouse metabolic results have a long history of not transferring cleanly. Nothing here changes clinical practice.

It is worth watching for one reason. Muscle preservation is the open question in modern weight care: patients on GLP-1 therapy lose fat, but lean mass usually goes with it, and that matters most for older patients and anyone at risk of frailty. A mechanism that spends energy instead of suppressing appetite is aimed squarely at that problem.

The researchers have founded a company, ReRx Therapeutics, to carry the work toward patients. Näär, Lee, and co-author Prabha Ibrahim are co-founders or officers and equity holders in ReRx, which has optioned the related UC Berkeley intellectual property.