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.
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Abbreviations
- APPBP1:
-
amyloid beta precursor protein-binding protein 1
- CD36:
-
cluster of differentiation 36
- C/EBP:
-
CCAAT/enhancer-binding protein
- ChIP:
-
chromatin immunoprecipitation
- CT:
-
computed tomography
- DAPI:
-
4′,6-diamidino-2-phenylindole
- FABP4:
-
fatty acid-binding protein 4
- FASN:
-
fatty acid synthase
- H-ADSCs:
-
human adipose tissue-derived mesenchymal stem cells
- HFD:
-
high-fat diet
- LDL:
-
low-density lipoproteins
- MDM2:
-
murine double minute 2
- NCD:
-
normal control diet
- NEDD8:
-
neuronal precursor cell expressed developmentally downregulated 8
- Neddylation:
-
NEDD8-based post-translation modification
- PPARγ:
-
peroxisome proliferator-activated receptor gamma
- PPREs:
-
peroxisome proliferator response elements
- SENP8:
-
sentrin-specific protease 8
- TG:
-
triglycerides
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Acknowledgements
This work was supported by a Korean Health Technology R&D grant (A121106, A120476, HI15C2695), National Research Foundation grants of Korea government (2012R1A5A2A44671346, 2009-0090188). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Author contributions
YSC designed experiments. HSP, UIJ, JYS, DHS and SWK performed experiments and interpreted results. JWP, JYC, LSJ, SYK, JY, HWL and YSC provided critical materials. HSP, JWP, JBK, KSP and YSC interpreted results and analyzed statistics. HSP, UIJ, JWP and YSC wrote the manuscript
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Park, HS., Ju, UI., Park, JW. et al. PPARγ neddylation essential for adipogenesis is a potential target for treating obesity. Cell Death Differ 23, 1296–1311 (2016). https://doi.org/10.1038/cdd.2016.6
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DOI: https://doi.org/10.1038/cdd.2016.6
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