A multi-functional oral small molecule targeting energy and lipid metabolism as a treatment for diet-induced obesity [Exp 5]

These diseases are mechanistically interconnected through complex pathways involving dysregulated energy and lipid metabolism. As a result, therapeutic strategies that target a single molecule or pathway are unlikely to achieve optimal efficacy without inducing adverse effects.

Here, we identified an orally bioavailable small molecule, 5-tetradecyloxy-2-furoic acid (TOFA), that effectively rebalances energy expenditure and lipid synthesis by both inhibiting acetyl-CoA carboxylases 1 and 2 (ACC1/2) and acting as a novel agonist of Peroxisome Proliferator-Activated Receptors alpha and delta (PPARɑ/δ). TOFA significantly alleviated obesity and associated metabolic dysfunctions in mouse models without side effects common to current treatments, such as muscle wasting.