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

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Abstract

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.

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Abbreviations

FTO:

Fat and obesity associated gene

UPRmt :

Mitochondrial unfolded protein response

UPRer :

Endoplasmic reticulum unfolded protein response

m6A:

N6-methyladenosine

ER:

Endoplasmic reticulum

CL:

Cycloleucine

Bet:

Betaine

DR:

Death receptor

Cyt C:

Cytochrome C

NR:

Nicotinamide riboside

SRAMP:

Sequence-based RNA adenosine methylation site predictor

ACh:

Acetylcholine

UTR:

Untranslated coding regions

Hsp60:

Heat shock response 60

ClpP:

Caseinolytic protease

Bcl-2:

B-cell lymphoma-2

Bax:

BCL2-associated X

PKR:

Double-stranded RNA-dependent protein kinase

HSL:

Hormone-sensitive lipase

ATGL:

Adipose triacylglyceride lipase

ap2:

Adipocyte protein 2

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Acknowledgements

We would like to express our heartfelt thanks to those who have provided financial and technical support for this experiment. Heartfelt thanks to Mr. Bh Rong, Miss Hh Gu, and Mr. K Yang for their technical help and guidance; besides, sincere thanks to Miss YZ Chen for helping us revise manuscripts and providing language guidance.

Funding

This study was financially supported by the Fundamental Research Funds for the Central Universities (245201971), the Joint Funds of the National Natural Science Foundation of China (U1804106), the Natural Science Foundation of China (81860762), the Qinghai Fundamental Scientific and Technological Research Plan (2018-ZJ-721), the Scientific Research Guiding Plan Topic of Qinghai Hygiene Department (2018-wjzdx-131), the Key Sci-tech innovation team of Shaanxi province (2017KCT-24).

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  1. Chao Sun

    Present address: Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, NO.22 Xinong Road, Yangling, 712100, Shaanxi, China

Authors and Affiliations

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

    Zhentong Shen, Ping Liu, Qian Sun, Yizhou Li, Rabin Acharya, Xinjian Li & Chao Sun

  2. College of Animal Science and Veterinary Medicine, Henan Agricultural University, Zhengzhou, 450000, Henan, China

    Zhentong Shen, Ping Liu, Qian Sun, Yizhou Li, Rabin Acharya, Xinjian Li & Chao Sun

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  1. Zhentong Shen
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The authors declared that there is no any competing financial interests. Author’s Contributions: ZS design, perform experiments, analysis, and writing manuscript; PL: writing manuscript; QS: analysis; YL: design; RA: correcting manuscript; XL: fund support; CS: design. All authors read and approved the final manuscript.

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Correspondence to Chao Sun.

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Shen, Z., Liu, P., Sun, Q. et al. FTO inhibits UPRmt-induced apoptosis by activating JAK2/STAT3 pathway and reducing m6A level in adipocytes. Apoptosis 26, 474–487 (2021). https://doi.org/10.1007/s10495-021-01683-z

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