2. Academic Validation
  3. PGE2 -EP3 axis promotes brown adipose tissue formation through stabilization of WTAP RNA methyltransferase

PGE2 -EP3 axis promotes brown adipose tissue formation through stabilization of WTAP RNA methyltransferase

  • EMBO J. 2022 Aug 16;41(16):e110439. doi: 10.15252/embj.2021110439.
Xixi Tao  # 1,  Ronglu Du  # 1,  Shumin Guo  # 1,  Xiangling Feng 1,  Tingting Yu 1,  Qian OuYang 2,  Qiaoli Chen 2,  Xutong Fan 1,  Xueqi Wang 1,  Chen Guo 3,  Xiaozhou Li 3,  Fengxia Xue 3,  Shuai Chen 2,  Minghan Tong 4,  Michael Lazarus 5,  Shengkai Zuo 1,  Ying Yu 1,  Yujun Shen 1
Affiliations

Affiliations

  • 1 Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, Center for Cardiovascular Diseases, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
  • 2 State Key Laboratory of Pharmaceutical Biotechnology, MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, Nanjing, China.
  • 3 Department of Gynecology and Obstetrics, Tianjin Key Laboratory of Female Reproductive Health and Eugenics, Tianjin Medical University General Hospital, Tianjin, China.
  • 4 State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
  • 5 International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba City, Japan.
  • # Contributed equally.
PMID: 35781818 DOI: 10.15252/embj.2021110439
Abstract

Brown adipose tissue (BAT) functions as a thermogenic organ and is negatively associated with cardiometabolic diseases. N6 -methyladenosine (m6 A) modulation regulates the fate of stem cells. Here, we show that the prostaglandin E2 (PGE2 )-E-prostanoid receptor 3 (EP3) axis was activated during mouse interscapular BAT development. Disruption of EP3 impaired the browning process during adipocyte differentiation from pre-adipocytes. Brown adipocyte-specific depletion of EP3 compromised interscapular BAT formation and aggravated high-fat diet-induced obesity and Insulin resistance in vivo. Mechanistically, activation of EP3 stabilized the Zfp410 mRNA via WTAP-mediated m6 A modification, while knockdown of Zfp410 abolished the EP3-induced enhancement of brown adipogenesis. EP3 prevented ubiquitin-mediated degradation of WTAP by eliminating PKA-mediated ERK1/2 inhibition during brown adipocyte differentiation. Ablation of WTAP in brown adipocytes abrogated the protective effect of EP3 overexpression in high-fat diet-fed mice. Inhibition of EP3 also retarded human embryonic stem cell differentiation into mature brown adipocytes by reducing the WTAP levels. Thus, a conserved PGE2 -EP3 axis promotes BAT development by stabilizing WTAP/Zfp410 signaling in a PKA/ERK1/2-dependent manner.

Keywords

E-prostanoid 3 receptor; WTAP; brown pre-adipocytes; differentiation; m6A.

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