Journal Article

PPARγ neddylation essential for adipogenesis is a potential target for treating obesity

Chun, Y-S, Song, J Y, Lee, K-H, Kim, S W, Yu, J, Kim, S Y, Kim, J B, Park, K S, Shin, D H, Jeong, L S, Cho, J Y, Park, J-W, Lee, H W, Park, H-S, Ju, U-I

2016

Overview

The preadipocyte-to-adipocyte differentiation (adipogenesis) is a key process in fat mass increase and thus it is regarded as a compelling target for preventing or treating obesity. Of adipogenic hormone receptors, peroxisome proliferator-activated receptor gamma (PPAR γ ) has crucial roles in adipogenesis and lipid accumulation within adipocytes. Here we demonstrate that the NEDD8 (neuronal precursor cell expressed, developmentally downregulated 8)-based post-translation modification (neddylation) of PPAR γ is essential for adipogenesis. During adipogenesis, NEDD8 is robustly induced in preadipocytes and conjugates with PPAR γ , leading to PPAR γ stabilization. When the neddylation process was blocked by NEDD8-targeting siRNAs (or viral vectors) or an inhibitor MLN4924, adipocyte differentiation and fat tissue development were substantially impaired. We also demonstrate that MLN4924 effectively prevents the high-fat diet-induced obesity and glucose intolerance in mice. This study provides a better understanding of how the PPAR γ signaling pathway starts and lasts during adipogenesis and a potential anti-obesity strategy that targets the neddylation of PPAR γ .

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/100 / 14/35 / 3T3-L1 Cells / 42/35 / 45/15 / 631/337 / 692/699/317 / 82/51 / 82/81 / 82/83 / 96/109 / Abdominal Fat - diagnostic imaging / Abdominal Fat - pathology / Adipocytes - cytology / Adipocytes - drug effects / Adipocytes - metabolism / Adipogenesis - drug effects / Animals / Apoptosis / Biochemistry / Biomedical and Life Sciences / CCAAT-Enhancer-Binding Protein-beta - genetics / CCAAT-Enhancer-Binding Protein-beta - metabolism / CCAAT-Enhancer-Binding Protein-delta - genetics / CCAAT-Enhancer-Binding Protein-delta - metabolism / CCAAT-Enhancer-Binding Proteins - genetics / CCAAT-Enhancer-Binding Proteins - metabolism / Cell Biology / Cell Cycle Analysis / Cell Cycle Checkpoints - drug effects / Cell Differentiation - drug effects / Cyclopentanes - pharmacology / Cyclopentanes - therapeutic use / Glucose Intolerance / HEK293 Cells / Humans / Life Sciences / Male / Mice / Mice, Inbred C57BL / NEDD8 Protein - antagonists & inhibitors / NEDD8 Protein - genetics / NEDD8 Protein - metabolism / Obesity - metabolism / Obesity - pathology / Obesity - prevention & control / Original Paper / PPAR gamma - antagonists & inhibitors / PPAR gamma - metabolism / Protein Binding / Proto-Oncogene Proteins c-mdm2 - antagonists & inhibitors / Proto-Oncogene Proteins c-mdm2 - genetics / Proto-Oncogene Proteins c-mdm2 - metabolism / Pyrimidines - pharmacology / Pyrimidines - therapeutic use / Stem Cells / Ubiquitins - antagonists & inhibitors / Ubiquitins - genetics / Ubiquitins - metabolism