Abstract | N:
6-methyladenosine ( m6A), the most abundant internal modification on mRNAs in eukaryotes, play roles in adipogenesis. However, the underlying mechanism remains largely unclear. Here, we show that m6A plays a critical role in regulating macroautophagy/autophagy and adipogenesis through targeting Atg5 and Atg7. Mechanistically, knockdown of FTO, a well-known m6A demethylase, decreased the expression of ATG5 and ATG7, leading to attenuation of autophagosome formation, thereby inhibiting autophagy and adipogenesis. We proved that FTO directly targeted Atg5 and Atg7 transcripts and mediated their expression in an m6A-dependent manner. Further study identified that Atg5 and Atg7 were the targets of YTHDF2 (YTH N6-methyladenosine RNA binding protein 2). Upon FTO silencing, Atg5 and Atg7 transcripts with higher m6A levels were captured by YTHDF2, which resulted in mRNA degradation and reduction of protein expression, thus alleviating autophagy and adipogenesis. Furthermore, we generated an adipose-selective fto knockout mouse and find that FTO deficiency decreased white fat mass and impairs ATG5- and ATG7-dependent autophagy in vivo. Together, these findings unveil the functional importance of the m6A methylation machinery in autophagy and adipogenesis regulation, which expands our understanding of such interplay that is essential for development of therapeutic strategies in the prevention and treatment of obesity. ABBREVIATIONS:
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Authors | Xinxia Wang, Ruifan Wu, Youhua Liu, Yuanling Zhao, Zhen Bi, Yongxi Yao, Qing Liu, Hailing Shi, Fengqin Wang, Yizhen Wang |
Journal | Autophagy
(Autophagy)
Vol. 16
Issue 7
Pg. 1221-1235
(07 2020)
ISSN: 1554-8635 [Electronic] United States |
PMID | 31451060
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Atg5 protein, mouse
- Atg7 protein, mouse
- Autophagy-Related Protein 5
- RNA, Messenger
- RNA-Binding Proteins
- YTHDF2 protein, mouse
- N-methyladenosine
- FTO protein, mouse
- Alpha-Ketoglutarate-Dependent Dioxygenase FTO
- Autophagy-Related Protein-1 Homolog
- Ulk1 protein, mouse
- Autophagy-Related Protein 7
- Adenosine
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Topics |
- 3T3-L1 Cells
- Adenosine
(analogs & derivatives, metabolism)
- Adipocytes
(metabolism, ultrastructure)
- Adipogenesis
- Adiposity
- Alpha-Ketoglutarate-Dependent Dioxygenase FTO
(metabolism)
- Animals
- Autophagy
- Autophagy-Related Protein 5
(metabolism)
- Autophagy-Related Protein 7
(metabolism)
- Autophagy-Related Protein-1 Homolog
(metabolism)
- Gene Knockdown Techniques
- Methylation
- Mice
- Mice, Knockout
- Models, Biological
- RNA, Messenger
(genetics, metabolism)
- RNA-Binding Proteins
(metabolism)
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