2. Academic Validation
  3. Blockage of PPARγ T166 phosphorylation enhances the inducibility of beige adipocytes and improves metabolic dysfunctions

Blockage of PPARγ T166 phosphorylation enhances the inducibility of beige adipocytes and improves metabolic dysfunctions

  • Cell Death Differ. 2022 Nov 3. doi: 10.1038/s41418-022-01077-x.
Nanfei Yang 1 2,  Yuxin Wang 1,  Qiang Tian 1,  Qiuping Wang 1,  Yan Lu 1,  Luchen Sun 1,  Sijie Wang 1,  Yuncheng Bei 1,  Jianguo Ji 3,  Hu Zhou 4,  Wei Yang 5,  Pengju Yao 3,  Wenyuan Zhu 3,  Lingyun Sun 6,  Zhifeng Huang 7,  Xiaokun Li 8,  Pingping Shen 9 10
Affiliations

Affiliations

  • 1 State Key Laboratory of Pharmaceutical Biotechnology, Department of Rheumatology and Immunology, The Affiliated Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, School of Life Sciences, Nanjing University, Nanjing, 210023, China.
  • 2 School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
  • 3 State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, 100871, China.
  • 4 Department of Analytical Chemistry and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
  • 5 Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA.
  • 6 Department of Rheumatology and Immunology, the Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, China.
  • 7 Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health) & School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
  • 8 Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health) & School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. xiaokunli@wmu.edu.cn.
  • 9 State Key Laboratory of Pharmaceutical Biotechnology, Department of Rheumatology and Immunology, The Affiliated Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, School of Life Sciences, Nanjing University, Nanjing, 210023, China. ppshen@nju.edu.cn.
  • 10 Shenzhen Research Institute of Nanjing University, Shenzhen, 518000, China. ppshen@nju.edu.cn.
PMID: 36329235 DOI: 10.1038/s41418-022-01077-x
Abstract

Beige adipocytes in mammalian white adipose tissue (WAT) can reinforce fat catabolism and energy expenditure. Promoting beige adipocyte biogenesis is a tantalizing tactic for combating obesity and its associated metabolic disorders. Here, we report that a previously unidentified phosphorylation pattern (Thr166) in the DNA-binding domain of PPARγ regulates the inducibility of beige adipocytes. This unique posttranslational modification (PTM) pattern influences allosteric communication between PPARγ and DNA or coactivators, which impedes the PPARγ-mediated transactivation of beige cell-related gene expression in WAT. The genetic mutation mimicking T166 phosphorylation (p-T166) hinders the inducibility of beige adipocytes. In contrast, genetic or chemical intervention in this PTM pattern favors beige cell formation. Moreover, inhibition of p-T166 attenuates metabolic dysfunction in obese mice. Our results uncover a mechanism involved in beige cell fate determination. Moreover, our discoveries provide a promising strategy for guiding the development of novel PPARγ agonists for the treatment of obesity and related metabolic disorders.

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