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Publication
A multi-functional oral small molecule targeting energy and lipid metabolism to
treat obesity and related metabolic disorders.
Authors Lee JY, Zhu C, Boldridge MA, Stark RL, Bonilla G, Watari K, Papa C, Xu L,
Gonzalez F, Tang X, Dang KT, Son K, Chetal K, Ibrahim P, Sadreyev RI, Sheikh BN,
Karin M, Näär AM
Submitted By Submitted Externally on 8/26/2026
Status Published
Journal Science advances
Year 2026
Date Published 8/21/2026
Volume : Pages 12 : eaed3119
PubMed Reference 42627907
Abstract 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 (PPARa/d), 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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