Science advancesAug 21, 2026

A small oral drug that affects energy and fat metabolism to treat obesity and related conditions

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗

Updated Aug 22, 2026

Abstract

5-tetradecyloxy-2-furoic acid (TOFA) significantly alleviates obesity and related metabolic disorders without affecting food intake or muscle mass.

TOFA promotes energy expenditure and rebalances lipid synthesis.
It alleviates abnormal glucose homeostasis and fatty liver-related diseases.
TOFA inhibits lipogenic enzymes, specifically acetyl-CoA carboxylases 1 and 2.
It activates key regulators of energy expenditure and lipid metabolism, the Peroxisome Proliferator-Activated Receptors alpha and delta.
TOFA shows a synergistic effect with incretin analogs like semaglutide and tirzepatide in improving metabolic conditions.

Simplified

Obesity and related metabolic disorders have surged globally, and are mechanistically interconnected through dysregulated energy and lipid metabolism pathways. Current incretin-based obesity treatments act to decrease food intake, but are associated with gastrointestinal side effects and muscle wasting. Here, we identified an orally bioavailable multi-functional small molecule, 5-tetradecyloxy-2-furoic acid (TOFA), that promotes energy expenditure and rebalances lipid synthesis, thereby significantly alleviating obesity, abnormal glucose homeostasis and fatty liver-related diseases without affecting food intake or muscle mass. Mechanistically, TOFA inhibits the lipogenic enzymes acetyl-CoA carboxylases 1 and 2 (ACC1/2) and activates the Peroxisome Proliferator-Activated Receptors alpha and delta (PPARα/δ), key regulators of energy expenditure and lipid metabolism gene expression programs. TOFA acted more than additively with incretin analogs such as semaglutide and tirzepatide to improve obesity, dyslipidemia, and insulin resistance. Our findings suggest that the coordinated multi-targeting of energy metabolism and lipid homeostasis by TOFA is an effective approach to address multiple associated metabolic diseases.

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A small oral drug that affects energy and fat metabolism to treat obesity and related conditions

Abstract

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