Decades-Old Compound Burns Fat in Obese Mice Without Cutting Their Appetite

A Different Kind of Weight-Loss Science

Most weight-loss drugs work largely by reducing appetite and food intake. But an experimental compound appears to work differently: in mice, it helps the body use more of the energy it takes in — and that approach could offer an entirely new way to tackle obesity.

The compound, called TOFA (5-tetradecyloxy-2-furoic acid), was originally developed in the 1970s as a lipid-lowering compound and was later found to inhibit enzymes involved in fatty acid metabolism. It has been used in laboratory research for years, but according to lead researcher Anders Näär, its ability to activate fat-burning programs had apparently been there all along — nobody had looked for it.

What the Study Found

In a study published in Science Advances, researchers found that the compound produced an average weight loss of 18 percent in obese male mice over four weeks, without changing how much the animals ate. Most of the loss came from body fat, while their muscle and other lean tissues were largely preserved.

TOFA works by interfering with the production of lipids such as cholesterol and triglycerides, while simultaneously activating genes that encourage cells to use fat for fuel and produce more energy. In treated mice, energy expenditure increased by up to 18 percent — without the animals becoming more active or developing a higher body temperature. That's a crucial distinction: the mice weren't simply running more or running hotter. Their metabolism was quietly, efficiently doing more work.

The treatment appeared to bring benefits well beyond weight loss. It lowered blood sugar and insulin levels, helped the mice respond better to glucose, and reduced fat in their blood and livers. In other experiments, TOFA also reduced signs of fatty liver disease, including fat buildup, inflammation, and scarring.

Why Muscle Loss Matters

Because GLP-1 drugs reduce appetite and food intake, they may also contribute to nutritional deficiencies and loss of muscle, potentially increasing the risk of frailty and other long-term health issues. That muscle loss is one of the most persistent criticisms of blockbuster drugs like Ozempic and Wegovy — and it's exactly the problem TOFA appears to sidestep.

Näär stresses that TOFA does not appear to protect muscle directly. Because the mice continued eating normally, most of the weight they lost likely came from fat. "In our mice it simply did not produce the loss of lean mass that often accompanies weight loss," he said. Muscle plays a critical role in regulating blood sugar and maintaining metabolism , which makes preserving it a significant health priority — not just an aesthetic one.

A Potential Partner for GLP-1 Drugs

In mice, combining TOFA with GLP-1 drugs led to greater improvements in body weight, glucose control, insulin levels, and triglycerides than either treatment alone. "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.

Other compounds in the same drug class have run into problems during development, including increases in triglycerides that could raise heart-health risks — but the Berkeley researchers found that TOFA may behave differently. In addition to blocking fat production, it activates cellular receptors involved in switching on genes that help cells take up fat and burn it for energy.

The compound has only been tested in mice so far , and the road from a promising animal study to an approved human treatment is long and uncertain. Still, the concept itself is a meaningful shift in thinking: rather than simply telling the body to eat less, what if a drug could teach it to spend more? If TOFA or something like it clears the hurdles of human trials, it could fundamentally change how doctors approach obesity — not as a problem of willpower or appetite, but of metabolic efficiency.