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Skeletal Phenotype Analysis of a Conditional Stat3 Deletion Mouse Model
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m6A methylation modulates adipogenesis through JAK2-STAT3-C/EBPβ signaling
Ruifan Wu1, Guanqun Guo1, Zhen Bi1
1College of Animal Sciences, Zhejiang University, Key Laboratory of Animal Nutrition & Feed Sciences, Ministry of Agriculture, Zhejiang Provincial Laboratory of Feed and Animal Nutrition, No. 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, China.
Summary
The m6A demethylase FTO regulates adipogenesis by controlling JAK2 expression. Deleting FTO inhibits fat cell differentiation via the JAK2-STAT3-C/EBPβ pathway, revealing a key role for m6A modification.
Area of Science:
- Molecular Biology
- Epigenetics
- Cell Biology
Background:
- N6-methyladenosine (m6A) is the most prevalent internal mRNA modification in eukaryotes.
- m6A plays a critical role in regulating adipogenesis, the process of fat cell formation.
- The precise molecular mechanisms by which m6A influences adipogenesis are not fully understood.
Purpose of the Study:
- To elucidate the role of the m6A demethylase FTO in adipogenesis.
- To investigate the signaling pathways involved in FTO-mediated regulation of adipogenesis.
- To identify the molecular targets and mechanisms through which FTO affects adipocyte differentiation.
Main Methods:
- Utilized porcine and mouse preadipocyte models to study adipogenesis.
- Employing gene deletion and knockdown techniques to manipulate FTO and YTHDF2 expression.
- Investigated signaling pathways including JAK2-STAT3-C/EBPβ using molecular assays.
- Validated target gene regulation using dual-luciferase assays and mRNA decay analysis.
Main Results:
- Deletion of FTO in preadipocytes significantly inhibited adipogenesis.
- FTO deficiency led to suppressed JAK2 expression and STAT3 phosphorylation.
- This suppression resulted in reduced C/EBPβ transcription, crucial for adipocyte differentiation.
- The m6A reader YTHDF2 was found to target JAK2 mRNA, promoting its decay and inhibiting the JAK2-STAT3-C/EBPβ pathway.
Conclusions:
- FTO-mediated m6A modification is essential for regulating adipogenesis through the JAK2-STAT3-C/EBPβ signaling axis.
- m6A modification of JAK2 mRNA by YTHDF2 accelerates its decay, thereby controlling adipocyte differentiation.
- These findings provide novel insights into the post-transcriptional regulation of adipogenesis by m6A and its associated proteins.
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