Long isoforms of NRF1 negatively regulate adipogenesis via suppression of PPARγ expression

Peng Xue; Yongyong Hou; Zhuo Zuo; Zhendi Wang; Suping Ren; Jian Dong; Jingqi Fu; Huihui Wang; Melvin E. Andersen; Qiang Zhang; Yuanyuan Xu; Jingbo Pi

doi:10.1016/j.redox.2019.101414

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Long isoforms of NRF1 negatively regulate adipogenesis via suppression of PPARγ expression

Journal article

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Long isoforms of NRF1 negatively regulate adipogenesis via suppression of PPARγ expression

Peng Xue, Yongyong Hou, Zhuo Zuo, Zhendi Wang, Suping Ren, Jian Dong, Jingqi Fu, Huihui Wang, Melvin E. Andersen, Qiang Zhang, …

Redox biology, Vol.30, pp.101414-101414

02/2020

DOI: 10.1016/j.redox.2019.101414

PMCID: PMC6957832

PMID: 31931283

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Abstract

Nuclear factor erythroid 2-related factor 1 (NRF1), a ubiquitously expressed CNC-bZIP transcription factor, plays a critical role in white adipocyte (WAC) biology, whereas the underlying mechanisms remain unknown. The mouse Nrf1 gene is transcribed in a number of alternatively spliced forms, resulting in two long protein isoforms (L-NRF1) containing 741 and 742 amino acids (aa) and multiple short isoforms (S-NRF1). Our previous study found that adipocyte-specific knockout of Nrf1 [Nrf1(f)-KO] in mice disturbs the expression of lipolytic genes in adipocytes, leading to adipocyte hypertrophy followed by inflammation, pyroptosis and insulin resistance. In the present study, we found that the stromal vascular fraction (SVF) cells isolated from white adipose tissues (WAT) of Nrf1(f)-KO mice display augmented adipogenesis showing elevated mRNA and protein expression of adipogenic markers and lipid accumulation. In 3T3-L1 cells, stable knockdown (KD) of all or long isoforms of Nrf1 (termed as A-Nrf1-KD and L-Nrf1-KD, respectively) using lentiviral shRNAs resulted in enhanced and accelerated adipogenic differentiation. Conversely, overexpression of L-NRF1-741, but not any of the S-NRF1, substantially attenuated adipogenesis in 3T3-L1 cells. These findings indicate that L-NRF1 might serve as a critical negative regulator of adipogenesis. Mechanistic investigation revealed that L-NRF1 may negatively regulates the transcription of peroxisome proliferator-activated receptor γ (PPARγ), in particular the master regulator of adipogenesis PPARγ2. Taken all together, the findings in the present study provide further evidence for a novel role of NRF1 beyond its participation in cellular antioxidant response and suggest that L-NRF1 is a negative regulator of PPARγ2 expression and thereby can suppress adipogenesis. [Display omitted] •SVF cells isolated from WAT of Nrf1(f)-KO mice displayed augmented adipogenesis.•Stable silencing of L-Nrf1 in 3T3-L1 cells resulted in enhanced and accelerated adipogenesis.•Overexpression of L-NRF1-741, but not S-NRF1s, attenuated adipogenesis in 3T3-L1 cells.•L-NRF1 suppressed adipogenesis via downregulating PPARγ2 expression.

Adipogenesis

NRF1

PPARγ

White adipocytes

Details

Title: Subtitle: Long isoforms of NRF1 negatively regulate adipogenesis via suppression of PPARγ expression
Creators: Peng Xue - School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China; ScitoVation LLC, Research Triangle Park, NC, USA.
Yongyong Hou - School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China.
Zhuo Zuo - School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China.
Zhendi Wang - School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China.
Suping Ren - School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China.
Jian Dong - Research Triangle Park Foundation
Jingqi Fu - School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China.
Huihui Wang - School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China.
Melvin E. Andersen - Research Triangle Park Foundation
Qiang Zhang - Emory University
Yuanyuan Xu - School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China.
Jingbo Pi - School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China.
Resource Type: Journal article
Publication Details: Redox biology, Vol.30, pp.101414-101414
DOI: 10.1016/j.redox.2019.101414
PMID: 31931283
PMCID: PMC6957832
NLM abbreviation: Redox Biol
ISSN: 2213-2317
eISSN: 2213-2317
Publisher: Elsevier B.V
Grant note: DOI: 10.13039/501100001809, name: National Natural Science Foundation of China, award: 81573106, 81830099, 81402661, 81573187; name: Liaoning Key Research and Development Guidance Plan, award: 2019JH8/10300012; name: Liaoning Revitalization Talents Program, award: XLYC1807225
Language: English
Date published: 02/2020
Academic Unit: Neurology
Record Identifier: 9984302208802771

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