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Lee, J.Y.* ; Zhu, C.* ; Boldridge, M.A.* ; Stark, R.L.* ; Bonilla, G.* ; Watari, K.* ; Papa, C. ; Xu, L.* ; Gonzalez, F.* ; Tang, X.* ; Dang, K.T.* ; Son, K.* ; Chetal, K.* ; Ibrahim, P.* ; Sadreyev, R.I.* ; Sheikh, B.N. ; Karin, M.* ; Näär, A.M.*

A multi-functional oral small molecule targeting energy and lipid metabolism to treat obesity and related metabolic disorders.

Sci. Adv. 12:eaed3119 (2026)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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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Publication type Article: Journal article
Document type Scientific Article
Keywords Acetyl-coa Carboxylase; Fatty-acid Synthesis; Reduces Hepatic Steatosis; Life-style Modification; 5-(tetradecyloxy)-2-furoic Acid; Running Endurance; Ppar-delta; Inhibition; Oxidation; Mechanism
ISSN (print) / ISBN 2375-2548
e-ISSN 2375-2548
Journal Science Advances
Quellenangaben Volume: 12, Issue: 34, Pages: , Article Number: eaed3119 Supplement: ,
Publisher American Association for the Advancement of Science (AAAS)
Publishing Place Washington, DC [u.a.]
Reviewing status Peer reviewed
Institute(s) Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG)
Grants NIH/NIDDK
University of Michigan Animal Phenotyping Core
University of California, Berkeley