A multi-functional oral small molecule targeting energy and lipid metabolism to treat obesity and related metabolic disorders
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.
Authors
- Chi Zhu (ORCID: https://orcid.org/0000-0001-9529-7000)
- Ruslan I. Sadreyev (ORCID: https://orcid.org/0000-0002-4240-5466)
- Lei Xu (ORCID: https://orcid.org/0000-0002-1862-786X)
- Christina Papa
- Kashish Chetal (ORCID: https://orcid.org/0000-0001-9314-5759)
- Justin Y. Lee (ORCID: https://orcid.org/0000-0002-7147-5359)
- Kosuke Watari (ORCID: https://orcid.org/0000-0003-0260-2323)
- Anders M. Näär (ORCID: https://orcid.org/0000-0002-7569-0291)
- Kook Son (ORCID: https://orcid.org/0009-0000-3892-9710)
- Michael Karin (ORCID: https://orcid.org/0000-0002-2758-6473)
- Bilal N. Sheikh (ORCID: https://orcid.org/0000-0002-1970-6236)
- Xin Tang (ORCID: https://orcid.org/0009-0006-2640-2309)
- Kaitlyn T. Dang (ORCID: https://orcid.org/0009-0003-8897-2735)
- Rachelle L. Stark (ORCID: https://orcid.org/0009-0003-6612-4372)
- Melissa A. Boldridge (ORCID: https://orcid.org/0009-0001-1603-5510)
- Gracia Bonilla
- Federico Gonzalez (ORCID: https://orcid.org/0009-0005-5734-2882)
- Prabha Ibrahim
Institutions
- Helmholtz Centre for Environmental Research (DE)
- University of California San Diego (US)
- Massachusetts General Hospital (US)
- Aminex Therapeutics (United States) (US)
- University of California, Berkeley (US)
Publication Details
- Journal
- Science Advances
- Published
- 2026-08-21
- DOI
- https://doi.org/10.1126/sciadv.aed3119
- Primary Topic
- Diet and metabolism studies
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Novo Nordisk
- Liver Center, University of California, San Francisco