JPOST Repositoryapplication/xmlhttps://storage.jpostdb.org/JPST004140/files/210829_WAT_SET2_Global_F3.rawhttps://storage.jpostdb.org/JPST004140/files/210829_WAT_SET1_Global_F7.rawhttps://storage.jpostdb.org/JPST004140/files/210829_WAT_SET2_Global_F5.rawhttps://storage.jpostdb.org/JPST004140/files/210829_WAT_SET1_Global_F5.rawhttps://storage.jpostdb.org/JPST004140/files/210829_WAT_SET1_Global_F3.rawhttps://storage.jpostdb.org/JPST004140/files/210829_WAT_SET2_Global_F1.rawhttps://storage.jpostdb.org/JPST004140/files/210829_WAT_SET2_Global_F7.rawhttps://storage.jpostdb.org/JPST004140/files/210829_WAT_SET1_Global_F9.rawhttps://storage.jpostdb.org/JPST004140/files/210829_WAT_SET1_Global_F2.rawhttps://storage.jpostdb.org/JPST004140/files/210829_WAT_SET1_Global_F11.rawhttps://storage.jpostdb.org/JPST004140/files/210829_WAT_SET2_Global_F4.rawhttps://storage.jpostdb.org/JPST004140/files/210829_WAT_SET2_Global_F2.rawhttps://storage.jpostdb.org/JPST004140/files/210829_WAT_SET1_Global_F8.rawhttps://storage.jpostdb.org/JPST004140/files/210829_WAT_SET2_Global_F6.rawhttps://storage.jpostdb.org/JPST004140/files/210829_WAT_SET2_Global_F8.rawhttps://storage.jpostdb.org/JPST004140/files/210829_WAT_SET1_Global_F4.rawhttps://storage.jpostdb.org/JPST004140/files/210829_WAT_SET1_Global_F10.rawhttps://storage.jpostdb.org/JPST004140/files/210829_WAT_SET1_Global_F12.rawhttps://storage.jpostdb.org/JPST004140/files/210829_WAT_SET1_Global_F1.rawhttps://storage.jpostdb.org/JPST004140/files/210829_WAT_SET1_Global_F6.rawprimaryOK200ProteomicsSang-Ku YooMus Musculus (mouse)https://repository.jpostdb.org/entry/JPST004140Jeju univesityjPOSTCurrent 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.Vutiglabridin ameliorates obesity by directly reducing fat mass through AMPK/lipophagy activation in adipocytes.Lee Hyeong Min HM, Lee Jae Ho JH, Kim Sang Hyo SH, Marakkalage Kamindu Gayashan KG, Hur Jihyeon J, Park Hyung Soon HS, Kim Kwang Pyo KP, Shin Gu-Choul GC, Yoo Sang-Ku SKfalseVutiglabridin ameliorates obesity by directly reducing fat mass through AMPK/lipophagy activation in adipocytesCurrent 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.Thu Apr 30 00:00:00 BST 2026PXD0699011009041237461