A molecule first discovered in the 1970s is getting a second look from UC Berkeley scientists who say it helped obese mice burn fat and shed weight without cutting their food intake or losing muscle. The compound, known as TOFA, worked by revving up the body's own energy-burning machinery rather than suppressing appetite the way blockbuster drugs like Ozempic and Wegovy do.
Researchers targeted the body's metabolic rate directly, aiming to trigger genes that help cells burn fat and produce energy, according to FOX 9 Minneapolis-St. Paul. Senior author Anders Näär explained the thinking behind the approach, saying that “GLP-1s work almost entirely on reducing calorie intake,” which is why his team instead targeted energy expenditure. Näär also framed the core biological tension driving the research: body weight, he said, responds to two levers — taking in fewer calories, or spending more energy.
The findings, published in Science Advances in August 2026, showed that treated mice's cells burned up to 18% more energy without any rise in body temperature or additional physical activity, per the same account. TOFA — chemically known as 5-tetradecyloxy-2-furoic acid — works by preventing the body from producing lipids such as cholesterol and triglycerides, and obese mice given the compound lost fat as a result.
A Dual Mechanism That Sidesteps an Old Drug Class's Failure
According to ScienceDaily, TOFA partially activates or interacts with both the PPAR-alpha and PPAR-delta cellular receptors, which switch on fat-burning genes, while also inhibiting acetyl-CoA carboxylase enzymes known as ACC1 and ACC2. That two-pronged action distinguishes it from other ACC inhibitors. TOFA is part of a class of ACC inhibitors. Several ACC inhibitors reached mid-stage clinical testing, but none was approved, in part because many could raise blood triglyceride levels. As Drug Discovery News reports, TOFA did not raise triglycerides in mice, possibly because of its combined effects, although the findings do not establish cardiovascular safety.
The mouse data also pointed to a durability advantage over existing weight-loss drugs. Mice treated with oral TOFA maintained their weight loss significantly longer after treatment stopped than mice treated with semaglutide, which experienced rapid weight rebound once appetite suppression ended, according to Inc. Magazine. Weight regain after stopping GLP-1 medications remains a widespread challenge in clinical obesity management, which is part of why that finding drew attention.
Pairing TOFA With Existing GLP-1 Drugs
Researchers also tested TOFA alongside GLP-1 drugs rather than positioning it as a replacement for them. In combination experiments on obese mice, pairing TOFA with semaglutide or tirzepatide produced greater weight loss along with greater reductions in glucose than either GLP-1 drug alone, per MDSpire News. The combined treatment worked additively or synergistically, and mice given both TOFA and a GLP-1 drug showed better results in body weight, glucose control, insulin, and triglycerides than those on either treatment alone.
That complementary framing matters because GLP-1 medications carry known drawbacks, including nausea and other gastrointestinal side effects, nutritional deficiencies, and muscle loss, FOX 9 Minneapolis-St. Paul notes. Obese mice given TOFA, by contrast, did not experience significant muscle mass loss — a distinction researchers see as a key selling point. Human data underscores why that matters: body composition results from the 68-week STEP-1 clinical trial of semaglutide found that reduced lean mass accounted for up to 40% of overall weight lost by patients, according to Drugs.com, a loss that has raised concerns about frailty, particularly in older adults. According to a PubMed-indexed review available through the National Institutes of Health, lean mass constituted 25%-39% of total weight lost with incretin agonists, including 35.2% for semaglutide and 25.4% for tirzepatide.
From Berkeley Lab to Startup, With Years of Testing Ahead
The study's results were formally announced in a statement issued by the University of California, Berkeley, whose researchers examined the effects of TOFA in mice for the work published in Science Advances. Näär and his co-researchers have since founded ReRx Therapeutics, a UC Berkeley spin-off backed by local incubators Nucleate and Berkeley SkyDeck, to push TOFA toward eventual human clinical trials, according to UC Berkeley. The project drew on support from university discretionary funds plus research collaboration from the UCSF Liver Center and the University of Michigan, the university says.
Still, the study involved mice only, and researchers have yet to determine whether TOFA is safe or effective in humans. Human testing is still needed, according to ScienceAlert — and preclinical success does not guarantee that the mouse results will hold up in people. A ClinicalTrials.gov search for TOFA, 5-tetradecyloxy-2-furoic acid, obesity and ReRx Therapeutics returned no matching documents, underscoring that the compound's development remains preclinical based on the available registry search.
Part of a Broader Search for Alternatives to Appetite Suppression
The interest in energy-burning alternatives comes as GLP-1 drugs have become deeply embedded in American health habits. TOFA represents an approach that does not rely solely on appetite suppression.
TOFA is not the only approach researchers are exploring to help patients maintain weight loss without relying solely on appetite suppression. Interim 2026 data from a trial on duodenal mucosal resurfacing, an endoscopic procedure, showed patients kept more than 80% of their prior GLP-1 weight loss six months after stopping medication, Hoodline has reported previously. For now, TOFA remains a preclinical compound tested in mice, and the provided evidence does not establish a timeline for determining whether the same fat-burning effect will translate to human patients.
