2. Academic Validation
  3. Adipocyte IRE1α promotes PGC1α mRNA decay and restrains adaptive thermogenesis

Adipocyte IRE1α promotes PGC1α mRNA decay and restrains adaptive thermogenesis

  • Nat Metab. 2022 Sep;4(9):1166-1184. doi: 10.1038/s42255-022-00631-8.
Yong Chen  # 1,  Zhuyin Wu  # 1,  Shijia Huang 1,  Xiaoxia Wang 2,  Sijia He 1,  Lin Liu 3,  Yurong Hu 1,  Li Chen 1,  Peng Chen 1,  Songzi Liu 1,  Shengqi He 1,  Bo Shan 4,  Ling Zheng 1,  Sheng-Zhong Duan 5 6,  Zhiyin Song 1,  Lei Jiang 7 8,  Qiong A Wang 7 8,  Zhenji Gan 3,  Bao-Liang Song 1,  Jianmiao Liu 9,  Liangyou Rui 10,  Mengle Shao 11,  Yong Liu 12
Affiliations

Affiliations

  • 1 Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences; TaiKang Center for Life and Medical Sciences; The Institute for Advanced Studies; Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, China.
  • 2 Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
  • 3 State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Department of Spine Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Jiangsu Key Laboratory of Molecular Medicine, Chemistry and Biomedicine Innovation Center (ChemBIC), Model Animal Research Center, Nanjing University Medical School, Nanjing University, Nanjing, China.
  • 4 Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
  • 5 Laboratory of Oral Microbiota and Systemic Diseases, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 6 National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, China.
  • 7 Comprehensive Cancer Center, Beckman Research Institute, City of Hope Medical Center, Duarte, CA, USA.
  • 8 Department of Molecular & Cellular Endocrinology, Diabetes & Metabolism Research Institute, City of Hope Medical Center, Duarte, CA, USA.
  • 9 Cellular Signaling Laboratory, Key Laboratory of Molecular Biophysics of Ministry of Education, Huazhong University of Science and Technology, Wuhan, China.
  • 10 Department of Molecular and Integrative Physiology, the University of Michigan Medical School, Ann Arbor, MI, USA.
  • 11 The Center for Microbes, Development and Health, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
  • 12 Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences; TaiKang Center for Life and Medical Sciences; The Institute for Advanced Studies; Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, China. [email protected].
  • # Contributed equally.
PMID: 36123394 DOI: 10.1038/s42255-022-00631-8
Abstract

Adipose tissue undergoes thermogenic remodeling in response to thermal stress and metabolic cues, playing a crucial role in regulating energy expenditure and metabolic homeostasis. Endoplasmic reticulum (ER) stress is associated with adipose dysfunction in obesity and Metabolic Disease. It remains unclear, however, if ER stress-signaling in adipocytes mechanistically mediates dysregulation of thermogenic fat. Here we show that inositol-requiring Enzyme 1α (IRE1α), a key ER stress sensor and signal transducer, acts in both white and beige adipocytes to impede beige fat activation. Ablation of adipocyte IRE1α promotes browning/beiging of subcutaneous white adipose tissue following cold exposure or β3-adrenergic stimulation. Loss of IRE1α alleviates diet-induced obesity and augments the anti-obesity effect of pharmacologic β3-adrenergic stimulation. Notably, IRE1α suppresses stimulated lipolysis and degrades Ppargc1a messenger RNA through its RNase activity to downregulate the thermogenic gene program. Hence, blocking IRE1α bears therapeutic potential in unlocking adipocytes' thermogenic capacity to combat obesity and metabolic disorders.

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