Vutiglabridin ameliorates obesity by directly reducing fat mass through AMPK/lipophagy activation in adipocytes

Current anti-obesity therapies that suppress appetite often cause undesirable reductions in lean mass by indirectly depleting systemic energy store. In this study, we developed a novel anti-obesity drug, Vutiglabridin (VUTI), designed to selectively reduce fat mass while preserving lean mass. We evaluated its efficacy in high-fat diet-induced obese (DIO) mice and investigated its underlying mechanism in in vitro adipocyte models. VUTI dose-dependently and selectively decreased fat mass, resulting in normalization of body weight within 3 weeks while preserving lean mass. Pharmacokinetic and mechanistic analyses revealed that VUTI targets white adipose tissue (WAT), where it enhances lipid degradation through AMPK-mediated lipophagy in both mouse and human adipocytes. The lipid degradation-enhancing effect of VUTI was shown to be dependent on paraoxonase 2 (PON2). Multi-omics analyses, including proteomic and transcriptomic profiling of epididymal WAT in DIO-mice, further confirmed this mechanism. Collectively, these findings demonstrate that VUTI represents a promising therapeutic strategy for obesity by inducing fat-selective reduction via AMPK-mediated lipophagy.