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

Obesity and related metabolic disorders have surged globally, representing a significant public health burden. 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. Moreover, TOFA acted synergistically with incretin analogs such as semaglutide and tirzepatide to improve obesity, dyslipidemia, and insulin resistance. Collectively, our findings suggest that the coordinated multi-targeting of lipid homeostasis and energy metabolism by TOFA is an effective approach to address multiple associated metabolic diseases.