Researchers at UC Berkeley have identified an experimental compound, 5-tetradecyloxy-2-furoic acid (TOFA), that increases metabolic energy expenditure to help burn fat while preserving lean muscle mass. Published in Science Advances on August 21, the study demonstrates that TOFA pairs synergistically with GLP-1 medications like Ozempic and Wegovy to improve metabolic health in animal models.
Over the past several years, popular therapies such as Ozempic, Wegovy, Mounjaro, and Zepbound have transformed how clinicians approach obesity, diabetes, and fatty liver disease. These medications act primarily as appetite suppressants, helping patients reduce caloric intake and manage blood sugar. Yet, rapid weight loss driven solely by reduced food intake often carries unwelcome trade-offs, including gastrointestinal side effects, potential nutritional deficiencies, and a loss of lean muscle tissue that can increase long-term frailty risks.
A research team at UC Berkeley decided to investigate the opposite side of the energy balance equation. Instead of forcing the body to consume fewer calories, their work aims to ramp up how many calories the body burns.
How TOFA Combines Lipid Blocking with Energy Expenditure
Described in a study published online in Science Advances, the molecule known as 5-tetradecyloxy-2-furoic acid (TOFA) attacks metabolic dysfunction through a dual mechanism. Originally discovered in the 1970s as a member of the ACC inhibitor class of compounds, TOFA blocks the cellular production of lipids like cholesterol and triglycerides. However, historical ACC inhibitors stalled in mid-stage clinical trials because they inadvertently raised triglyceride levels, driving up cardiovascular risks.
The research team found that TOFA operates differently. Beyond its role as an ACC inhibitor, it also activates cellular receptors known as PPARα and PPARδ, which switch on genes responsible for pulling in fat and burning it for fuel. In experimental mice, this pathway increased cellular energy expenditure by as much as 18 percent without raising body temperature or changing physical activity levels.
“Body weight responds to two levers: taking in fewer calories, or spending more energy,” said Anders Näär, a professor of metabolic biology and nutrition at UC Berkeley and senior author of the study. “GLP-1s work almost entirely on the first, so we went after the second.”
Anders Näär, professor of metabolic biology and nutrition at UC Berkeley
Because of this coordinated metabolic response, TOFA did not trigger the hazardous triglyceride spikes associated with earlier lipid-blocking compounds. In laboratory tests involving obese mice, the treatment improved insulin sensitivity and glucose control, lowered triglycerides, and reduced signs of fatty liver disease while prompting fat loss without any significant drop in lean muscle mass.
Complementary Performance Alongside Existing GLP-1 Medications
The investigators also tested whether TOFA could match its unique effects if administered as a combination of two separate drugs—one designed to suppress lipid production and another to boost energy expenditure. That split-drug approach failed to improve overall metabolic health as effectively as TOFA alone, indicating that the molecule’s simultaneous actions are critical to its success.
Researchers then evaluated how TOFA performed when paired directly with established GLP-1 therapies, including semaglutide (sold as Ozempic or Wegovy) and tirzepatide (sold as Mounjaro and Zepbound). In animal testing, pairing TOFA with these appetite-suppressing drugs yielded larger improvements in body weight, glucose control, insulin levels, and triglycerides than any individual treatment achieved on its own.
“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.”
Anders Näär, senior author of the study
Moving from Animal Studies Toward Clinical Evaluation
While the preclinical results demonstrate notable improvements in metabolic markers, experts caution that TOFA has been tested exclusively in animals so far. Its safety profile and actual efficacy in human patients remain unproven and require rigorous evaluation in upcoming clinical trials.
To help bridge the gap between academic discovery and patient care, the researchers have established a startup company named ReRx Therapeutics. The venture is backed by Berkeley’s life sciences entrepreneurship ecosystem, which includes support from organizations such as Nucleate and Berkeley SkyDeck. Institutional support for the research came from discretionary funds provided by UC Berkeley, alongside technical assistance from the UCSF Liver Center and the University of Michigan Animal Phenotyping Core.
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