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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)
Verlagsversion Forschungsdaten 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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter 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
Zeitschrift Science Advances
Quellenangaben Band: 12, Heft: 34, Seiten: , Artikelnummer: eaed3119 Supplement: ,
Verlag American Association for the Advancement of Science (AAAS)
Verlagsort Washington, DC [u.a.]
Begutachtungsstatus Peer reviewed
Institut(e) Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG)
Förderungen NIH/NIDDK
University of Michigan Animal Phenotyping Core
University of California, Berkeley