FTO inhibits UPRmt-induced apoptosis by activating JAK2/STAT3 pathway and reducing m6A level in adipocytes.
Zhentong ShenPing LiuQian SunYizhou LiRabin AcharyaXinjian LiChao SunPublished in: Apoptosis : an international journal on programmed cell death (2021)
As a nucleic acid demethylase, Fat and obesity associated gene (FTO) plays a vital role in modulating adipose metabolism. However, it is still unknown how FTO affects apoptosis in adipocytes. In this study, we found that overexpression of FTO inhibited the expression of pro-apoptosis factors Caspase-3, Caspase-9 and Bax and mitochondrial unfolded protein response (UPRmt) markers HSP60 and ClpP in vivo and in vitro. Particularly, overexpression of FTO inhibited mitochondria-dependent apoptosis in adipocytes. Further studies revealed that FTO suppressed UPRmt by reducing HSP60 mRNA N6-methyladenosine (m6A) modification. Moreover, FTO inhibited the activation of Caspase-3 via JAK2/STAT3 signaling pathway in adipocytes. Further experiments showed that pro-apoptosis gene Bax was upregulated by UPRmt-activated PKR/eIF2α/ATF5 axis in adipocytes. In summary, this study confirms that FTO reduces adipocytes apoptosis by activiting JAK2/STAT3 signaling pathway and inhibiting UPRmt, revealing a novel mechanism of FTO on adipocytes apoptosis, which provides some new potential therapy for treating obesity and related metabolic syndromes.
Keyphrases
- induced apoptosis
- endoplasmic reticulum stress
- signaling pathway
- oxidative stress
- adipose tissue
- cell death
- cell cycle arrest
- high fat diet induced
- pi k akt
- insulin resistance
- metabolic syndrome
- cell proliferation
- nucleic acid
- epithelial mesenchymal transition
- copy number
- genome wide
- risk assessment
- weight gain
- weight loss
- long non coding rna
- anti inflammatory
- skeletal muscle
- gene expression
- single cell
- amino acid
- physical activity