title: PPARγ neddylation essential for adipogenesis is a potential target for treating obesity.
abstract: 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 (PPARγ) 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 PPARγ is essential for adipogenesis. During adipogenesis, NEDD8 is robustly induced in preadipocytes and conjugates with PPARγ, leading to PPARγ 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 PPARγ signaling pathway starts and lasts during adipogenesis and a potential anti-obesity strategy that targets the neddylation of PPARγ.
authors.affiliation: Department of Biomedical Science, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: H-S
authors.initials: HS
authors.lastname: Park
authors.affiliation: Department of Biomedical Science, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: U-I
authors.initials: UI
authors.lastname: Ju
authors.affiliation: Department of Biomedical Science, Seoul National University College of Medicine, Seoul, Korea.|Ischemic/hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Korea.|Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: J-W
authors.initials: JW
authors.lastname: Park
authors.affiliation: Department of Biomedical Science, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: J Y
authors.initials: JY
authors.lastname: Song
authors.affiliation: Ischemic/hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: D H
authors.initials: DH
authors.lastname: Shin
authors.affiliation: Ischemic/hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: K-H
authors.initials: KH
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Institute of Molecular Biology and Genetics, Seoul National University, Seoul, Korea.
authors.forename: L S
authors.initials: LS
authors.lastname: Jeong
authors.affiliation: College of Pharmacy, Institute of Molecular Biology and Genetics, Seoul National University, Seoul, Korea.
authors.forename: J
authors.initials: J
authors.lastname: Yu
authors.affiliation: College of Pharmacy, Institute of Molecular Biology and Genetics, Seoul National University, Seoul, Korea.
authors.forename: H W
authors.initials: HW
authors.lastname: Lee
authors.affiliation: Department of Radiology, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: J Y
authors.initials: JY
authors.lastname: Cho
authors.affiliation: Department of Radiology, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: S Y
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: S W
authors.initials: SW
authors.lastname: Kim
authors.affiliation: School of Biological Sciences, Institute of Molecular Biology and Genetics, Seoul National University, Seoul, Korea.
authors.forename: J B
authors.initials: JB
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: K S
authors.initials: KS
authors.lastname: Park
authors.affiliation: Department of Biomedical Science, Seoul National University College of Medicine, Seoul, Korea.|Ischemic/hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Korea.|Department of Physiology, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Y-S
authors.initials: YS
authors.lastname: Chun
mesh_terms: D041721:3T3-L1 Cells; D050153:Abdominal Fat / Q000000981:diagnostic imaging / Q000473:pathology; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects; D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000235:genetics / Q000378:metabolism; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D003517:Cyclopentanes / Q000494:pharmacology / Q000627:therapeutic use; D018149:Glucose Intolerance; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000075687:NEDD8 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011485:Protein Binding; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D014452:Ubiquitins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D022762:CCAAT-Enhancer-Binding Proteins; C530718:CEBPA protein, mouse; C545013:Cebpb protein, mouse; C497253:Cebpd protein, mouse; D003517:Cyclopentanes; D000075687:NEDD8 Protein; D047495:PPAR gamma; D011743:Pyrimidines; C491805:Ube1c protein, mouse; D014452:Ubiquitins; D051743:CCAAT-Enhancer-Binding Protein-delta; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; C539933:pevonedistat