An oral small molecule that increases energy expenditure rather than suppressing appetite produced substantial weight loss while preserving lean mass in mouse models of obesity, suggesting a potentially complementary strategy to GLP-1–based therapies
Researchers from the University of California, Berkeley, identified 5-tetradecyloxy-2-furoic acid (TOFA) as a multifunctional regulator of lipid and energy metabolism. Unlike incretin drugs such as semaglutide and tirzepatide, which primarily reduce energy intake by suppressing appetite, TOFA increased energy expenditure without reducing food consumption
In mice with high-fat diet-induced obesity, oral TOFA produced an average 18% reduction in body weight. The loss was primarily fat mass, with no significant change in lean mass or food intake. Treatment also lowered fasting glucose and insulin, improved glucose tolerance, reduced liver fat, and lowered circulating triglycerides and cholesterol. The findings were published in Science Advances
Metabolic-cage experiments offered clues to how the drug produced these effects. TOFA increased energy expenditure by approximately 18% at room temperature and under thermoneutral conditions. The effect was not explained by greater physical activity, malabsorption, or increased body temperature, and fat oxidation appeared to be the predominant energy source
Mechanistically, TOFA appears to combine two metabolic actions in a single molecule. It inhibits acetyl-CoA carboxylases 1 and 2 (ACC1/2), enzymes involved in fatty-acid synthesis, while partially activating PPARα and PPARδ, nuclear receptors that regulate lipid metabolism and energy expenditure. The latter activity may help distinguish TOFA from conventional ACC inhibitors, which can cause elevated triglycerides
“Our findings demonstrate that TOFA engages both ACC1/2 inhibition and PPARα/δ agonism within a single molecule,” the authors wrote, describing a combination that produced metabolic benefits not achieved by targeting either pathway alone
The researchers also tested TOFA with semaglutide and tirzepatide. Although the individual treatments produced similar weight reductions in obese mice, combining TOFA with either incretin resulted in significantly greater weight loss. Importantly, the additional loss reflected fat rather than lean mass. Combination therapy also produced greater improvements in glucose control, insulin levels, and serum and liver triglycerides
The authors suggest that the distinct mechanisms could make TOFA particularly useful alongside incretin drugs, potentially allowing lower doses while addressing concerns such as lean-mass loss and weight regain. “Combination treatments of TOFA with incretin-based therapeutics could allow lower and less frequent dosing,” they wrote
TOFA also improved features of metabolic dysfunction-associated steatotic liver disease and steatohepatitis in mouse models, reducing hepatic fat accumulation, inflammation, and markers of fibrosis
The findings remain preclinical, but the approach could offer a different way to treat obesity—targeting how the body uses and stores energy rather than relying solely on reducing energy intake
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