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FTO inhibits UPRmt-induced apoptosis by activating JAK2/STAT3 pathway and reducing m6A level in adipocytes

Zhentong Shen1,2, Ping Liu1,2, Qian Sun1,2

  • 1College of Animal Science and Technology, Northwest A&F University, NO.22 Xinong Road, Yangling, 712100, Shaanxi, China.

Apoptosis : an International Journal on Programmed Cell Death
|July 2, 2021
PubMed

Insights

The Fat and obesity associated gene (FTO) inhibits adipocyte apoptosis by activating the JAK2/STAT3 pathway and suppressing mitochondrial unfolded protein response (UPRmt). This reveals a new mechanism for treating obesity and metabolic disorders.

Area of Science:

  • Cell Biology
  • Metabolic Regulation
  • Molecular Mechanisms

Background:

  • The Fat and obesity associated gene (FTO) is a nucleic acid demethylase crucial for adipose metabolism.
  • The precise role of FTO in adipocyte apoptosis remains largely uncharacterized.

Purpose of the Study:

  • To investigate the effect of FTO on apoptosis in adipocytes.
  • To elucidate the molecular mechanisms underlying FTO's influence on adipocyte apoptosis.

Main Methods:

  • Overexpression of FTO in adipocytes (in vivo and in vitro).
  • Analysis of apoptosis-related factors (Caspase-3, Caspase-9, Bax) and UPRmt markers (HSP60, ClpP).
  • Investigation of FTO's impact on HSP60 mRNA m6A modification and JAK2/STAT3 signaling pathway activation.

Main Results:

  • FTO overexpression inhibited pro-apoptosis factors and UPRmt markers, specifically reducing mitochondria-dependent apoptosis.
  • FTO suppressed UPRmt by decreasing HSP60 mRNA m6A modification.
  • FTO inhibited Caspase-3 activation via the JAK2/STAT3 pathway.
  • The UPRmt-activated PKR/eIF2α/ATF5 axis upregulated the pro-apoptosis gene Bax.

Conclusions:

  • FTO reduces adipocyte apoptosis through JAK2/STAT3 activation and UPRmt inhibition.
  • This study reveals a novel mechanism for FTO in adipocyte apoptosis.
  • Findings offer potential therapeutic strategies for obesity and related metabolic syndromes.
Keywords:
AdipocytesApoptosisFTOUPRmtm6A

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