A mouse study published in Science Advances reports that an experimental compound called TOFA increased energy expenditure and reduced body fat in obese mice without a significant loss of lean muscle mass. The work was carried out entirely in animals, and the researchers say TOFA's safety and effectiveness in humans remain unknown.

TOFA is 5-tetradecyloxy-2-furoic acid, first discovered in the 1970s and part of a class known as ACC inhibitors, which reduce the body's production of lipids such as cholesterol and triglycerides. The study was led by researchers at UC Berkeley and published on August 21.

The other lever

The Berkeley team says its approach differs from GLP-1 medications sold as Ozempic, Wegovy, Mounjaro and Zepbound, which work largely by reducing appetite and food intake. Rather than lowering calories in, the group went after calories out.

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

Key results

In mice, TOFA increased energy use by as much as 18% without the animals becoming more physically active or raising their body temperature, according to the paper. Treated obese mice lost fat while showing no significant reduction in lean muscle mass, which is the result that makes this worth attention given how much of the current weight-loss conversation is about preserving muscle.

The researchers also reported improved insulin sensitivity and glucose control, lower triglyceride levels and improvements in signs of fatty liver disease. TOFA did not produce the rise in triglycerides seen with some other ACC inhibitors, possibly, they say, because of its combined effects on lipid production and energy metabolism.

Two switches, one molecule

Alongside acting as an ACC inhibitor, TOFA activates PPAR-alpha and PPAR-delta, cellular receptors that switch on genes involved in taking up fat and burning it for fuel. When the team tried to reproduce the effect with two separate compounds, one suppressing lipid production and one raising energy expenditure, the combination did not improve overall metabolic health as effectively as TOFA alone.

Pairing TOFA with semaglutide and tirzepatide in mice produced larger improvements in body weight, glucose control, insulin levels and triglycerides than either treatment alone. Naar said the group views TOFA as complementary to GLP-1 drugs rather than a replacement.

Limitations

TOFA has so far been studied only in animals, and the researchers emphasize that its safety and effectiveness in people will need to be evaluated in future studies. Several ACC inhibitors have reached mid-stage clinical trials, but none has been approved to treat metabolic disease.

The research was funded through discretionary UC Berkeley funds, with assistance from the UCSF Liver Center and the University of Michigan Animal Phenotyping Core. The researchers have formed a company, ReRx Therapeutics, to move the work toward possible use in patients, which is worth knowing when reading how confidently the strategy is framed.

The open question

The authors say the results point to raising metabolic activity rather than suppressing appetite, and that TOFA appears to engage what first author Justin Y. Lee called a coordinated metabolic response. Whether any of that holds in humans is still unanswered.