A compound that biochemists first cataloged in the 1970s sat largely ignored in the scientific literature for decades. Researchers at UC Berkeley are now studying it as a possible obesity treatment, and the mechanism it uses is almost the opposite of what the drugs dominating headlines today actually do.
Drugs like Ozempic, Wegovy, Mounjaro, and Zepbound help people lose substantial amounts of weight and improve blood sugar control. These medications work by affecting signals involved in appetite and digestion, helping people feel full sooner and eat less. Researchers are now exploring a different strategy: helping the body use more energy rather than mainly reducing how much food a person eats.
A research team led by Anders Näär, a professor of metabolic biology and nutrition at the University of California, Berkeley, studied a compound called 5-tetradecyloxy-2-furoic acid, or TOFA, to pursue that second lever. What TOFA did in mice – published in Science Advances – is drawing attention from metabolic researchers.
What TOFA Does – and Why It’s Different From Current Obesity Treatment Approaches
TOFA belongs to a class of compounds that block enzymes called acetyl-CoA carboxylases, or ACCs. These enzymes help the body make fats such as fatty acids and triglycerides. Blocking them reduces fat production, which has made ACC inhibitors candidates for treating metabolic diseases.
Earlier ACC inhibitors ran into a consistent problem: they caused triglycerides in the blood to rise, an unwanted effect because high triglyceride levels can contribute to cardiovascular risk. No ACC inhibitor has received approval for treating metabolic disease.
TOFA appears to sidestep that problem through an additional mechanism. Näär’s team found that TOFA also activates PPAR-alpha and PPAR-delta – cellular receptors that control genes helping cells take in fats and burn them for energy. These receptors function like switches that upgrade the body’s fat-burning machinery at the cellular level and are involved in fatty acid oxidation and lipid metabolism.
The result of activating both pathways simultaneously – reducing fat production while increasing fat combustion – created a coordinated change in metabolism. In mice, energy expenditure increased by as much as 18% with no change in physical activity or body temperature. Unlike earlier ACC inhibitors, TOFA did not raise triglycerides.
The Muscle Loss Problem GLP-1 Drugs Haven’t Solved
Weight loss sounds straightforwardly good, but what the body actually sheds during that process matters. The Endocrine Society has reported that a meaningful portion of weight lost on semaglutide can come from lean mass, including muscle. Maintaining muscle is important because it supports strength, movement, balance, and healthy aging, and plays a role in blood sugar control after meals.
In the animal data, obese mice treated with TOFA lost fat while showing no significant reduction in lean muscle mass. Näär’s team observed selective fat loss, not simply weight loss. TOFA increased energy expenditure without reducing food consumption, and the weight lost came primarily from fat mass with no significant change in lean mass. Whether this translates to humans remains entirely unproven.
Beyond Weight: Metabolic Benefits in the Animal Data
The study, published in Science Advances, shows TOFA blocked the production of lipids like cholesterol and triglycerides while simultaneously activating genes that help cells burn fat and generate energy. In mice, it improved insulin sensitivity and glucose control, lowered triglycerides, and improved features of fatty liver disease.
Fatty liver disease – more precisely called metabolic dysfunction-associated steatotic liver disease (MASLD) – is closely tied to obesity and type 2 diabetes. Liver damage in obesity is often silent until it reaches an advanced stage, making improvements in this area clinically relevant.
Näär’s lab also tested a key hypothesis about why TOFA worked so broadly. Separate groups of mice received two different compounds – one to suppress fat production, another to boost energy use – rather than TOFA alone. That split approach did not replicate the same metabolic improvements. The coordinated, simultaneous action of inhibiting fat synthesis while activating fat combustion appears to drive the result.
Justin Y. Lee, the study’s first author – who completed this research as a doctoral student at Berkeley and is now a postdoctoral researcher at UCSF – described TOFA as engaging something broader than simple ACC inhibition, in contrast to single-mechanism approaches.
The Combination Question: TOFA Alongside GLP-1 Drugs
In animal experiments, TOFA produced stronger results when combined with GLP-1 drugs such as semaglutide (Ozempic and Wegovy) and tirzepatide (Mounjaro and Zepbound). Combined treatments produced greater improvements across multiple markers, including weight, blood glucose, insulin response, and triglycerides. GLP-1 drugs reduce caloric intake; TOFA increases energy expenditure – in principle, targeting both levers at once.
Näär has described his team’s view of TOFA as a complement to GLP-1 therapy rather than a replacement. Patients on existing GLP-1 medications who plateau or do not respond fully could benefit from a treatment working through a completely different mechanism.
A Decades-Old Compound, a Long Road Ahead
TOFA has been known since the 1970s as an ACC inhibitor but was never developed for obesity or metabolic disease. Its new potential emerged when Näär’s lab investigated the full range of things it actually does in living cells.
The Berkeley team cautions that TOFA has only been studied in animals, and its safety and efficacy in humans has not been tested. With support from Berkeley’s life sciences entrepreneurship ecosystem, including Nucleate and Berkeley SkyDeck, Näär, Lee, and colleague Prabha Ibrahim have co-founded ReRx Therapeutics, a company developing oral small-molecule therapeutics for severe metabolic diseases, to carry this work toward patients.
Before TOFA or a related compound could become a medicine, it would need extensive laboratory testing followed by carefully controlled clinical trials. That process can take years, and many promising experimental drugs never reach patients. The history of drug development in metabolic disease contains many compounds that were effective in rodents and ultimately failed in human trials. Earlier ACC inhibitors reached clinical testing and stalled – that history provides important context for the current findings.
What This Means for You
The TOFA research doesn’t produce anything available to take today. GLP-1 drugs work on appetite, and they work well, but they don’t address how the body spends energy and can reduce muscle alongside fat. A treatment that increases energy expenditure without requiring more exercise or raising body temperature would be meaningfully distinct from what’s currently available. The Berkeley findings are preliminary and confined to animal models, and whether this kind of shift is achievable safely in people – at the right dose, with durable effects – will require years of clinical work.
The conversation about obesity medicine is moving beyond appetite suppression alone. Researchers are looking for treatments that preserve muscle, improve insulin sensitivity, address fatty liver disease, and do more than lower the number on the scale. TOFA is one early candidate in that direction.
Disclaimer: This information is not intended to be a substitute for professional medical advice, diagnosis, or treatment and is for information only. Always seek the advice of your physician or another qualified health provider with any questions about your medical condition and/or current medication. Do not disregard professional medical advice or delay seeking advice or treatment because of something you have read here.
AI Disclaimer: This article was created with the assistance of AI tools and reviewed by a human editor.
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