UC Berkeley researchers found that TOFA, tested in obese mice, increases energy expenditure by up to 18% and reduces fat mass without the muscle loss associated with GLP-1 drugs like Ozempic and Wegovy — and works even better when combined with them.
GLP-1 receptor agonists — sold as Ozempic, Wegovy, Mounjaro and Zepbound — have transformed obesity and diabetes treatment over the past several years, primarily by suppressing appetite and reducing calorie intake. That mechanism carries a known trade-off: by reducing food intake, these drugs can also cause loss of lean muscle mass alongside fat, a side effect linked to frailty and other complications, particularly in older patients.
Researchers at UC Berkeley, led by professor of metabolic biology and nutrition Anders Näär, have identified a molecular compound — 5-tetradecyloxy-2-furoic acid, or TOFA — that works through a fundamentally different lever: increasing the amount of energy the body burns, rather than reducing the amount it takes in. In obese mice, TOFA increased energy expenditure by up to 18% with no change in physical activity levels or body temperature, reduced body fat with no significant loss of lean muscle mass, and improved insulin sensitivity, glucose control, triglyceride levels and markers of fatty liver disease. Published in Science Advances, the study also found that TOFA produced stronger metabolic improvements when combined with GLP-1 drugs than either treatment alone.
How it works
TOFA is known to inhibit an enzyme involved in producing lipids such as cholesterol and triglycerides, a class of compound called an ACC inhibitor. But the Berkeley team found that TOFA does more than block lipid production: it also activates two cellular receptors, PPARα and PPARδ, which switch on genes that let cells take up circulating fat and burn it for energy. “TOFA appears to engage a coordinated metabolic response,” said study first author Justin Y. Lee, a postdoctoral researcher at UCSF who conducted the work as a Berkeley PhD student. “It is not simply blocking lipid synthesis. It is also activating energy expenditure pathways that may help the body handle excess lipid and glucose more effectively.” This dual mechanism appears to explain another notable feature of the results: unlike some other ACC inhibitors, which can dangerously raise triglyceride levels as a side effect, TOFA did not produce this rise — a safety concern that has previously limited development of this drug class.
Why it matters
Muscle plays an underappreciated but important role in regulating blood sugar and overall metabolic health, and the muscle-loss side effect associated with appetite-suppressing weight-loss drugs is an active area of clinical concern as GLP-1 medications reach ever-larger patient populations. A compound that increases fat burning through a genuinely different biological pathway — one that could, on this early evidence, complement rather than compete with existing GLP-1 therapy — represents a potentially significant addition to the obesity and diabetes treatment toolkit, particularly for patients for whom preserving lean mass is a clinical priority. The caveats are standard for this stage of drug development: these are mouse results only, TOFA has not yet been tested in humans, and safety, dosing and efficacy in people remain to be established through further preclinical work and eventual clinical trials. Obesity and type 2 diabetes are major and rising public health burdens in India, as in the study’s country of origin, making any credible new mechanistic lead in this area relevant well beyond the immediate research context — though, as with any early-stage compound, a substantial and uncertain distance separates today’s mouse data from an approved therapy.
Rithvisha Kiran
Key facts
- TOFA (5-tetradecyloxy-2-furoic acid) increased energy expenditure by up to 18% in obese mice, without increased activity or body temperature
- Reduced body fat with no significant lean-muscle loss; improved insulin sensitivity, glucose control, triglycerides and fatty liver markers
- Works via dual mechanism: blocks lipid-synthesis enzyme ACC while activating PPARα/PPARδ receptors that drive fat-burning gene expression
- Produced stronger effects in combination with GLP-1 drugs (Ozempic/Wegovy-class) than either treatment alone
- Published in Science Advances; led by Anders Näär’s laboratory, UC Berkeley, with UCSF; mouse-model findings only, not yet tested in humans
