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Post-translational control of beige fat biogenesis by PRDM16 stabilization

Author

Listed:
  • Qiang Wang

    (Beth Israel Deaconess Medical Center and Harvard Medical School)

  • Huixia Li

    (Xi’an Jiaotong University Health Science Center)

  • Kazuki Tajima

    (National Hospital Organization, Yokohama Medical Center)

  • Anthony R. P. Verkerke

    (Beth Israel Deaconess Medical Center and Harvard Medical School)

  • Zachary H. Taxin

    (Beth Israel Deaconess Medical Center and Harvard Medical School)

  • Zhishuai Hou

    (Beth Israel Deaconess Medical Center and Harvard Medical School)

  • Joanne B. Cole

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Boston Children’s Hospital
    Harvard Medical School)

  • Fei Li

    (Beth Israel Deaconess Medical Center and Harvard Medical School)

  • Jake Wong

    (Beth Israel Deaconess Medical Center and Harvard Medical School)

  • Ichitaro Abe

    (Beth Israel Deaconess Medical Center and Harvard Medical School)

  • Rachana N. Pradhan

    (Genentech)

  • Tadashi Yamamuro

    (Beth Israel Deaconess Medical Center and Harvard Medical School)

  • Takeshi Yoneshiro

    (The University of Tokyo)

  • Joel N. Hirschhorn

    (Broad Institute of MIT and Harvard
    Boston Children’s Hospital
    Harvard Medical School
    Harvard Medical School)

  • Shingo Kajimura

    (Beth Israel Deaconess Medical Center and Harvard Medical School
    Howard Hughes Medical Institute)

Abstract

Compelling evidence shows that brown and beige adipose tissue are protective against metabolic diseases1,2. PR domain-containing 16 (PRDM16) is a dominant activator of the biogenesis of beige adipocytes by forming a complex with transcriptional and epigenetic factors and is therefore an attractive target for improving metabolic health3–8. However, a lack of knowledge surrounding the regulation of PRDM16 protein expression hampered us from selectively targeting this transcriptional pathway. Here we identify CUL2–APPBP2 as the ubiquitin E3 ligase that determines PRDM16 protein stability by catalysing its polyubiquitination. Inhibition of CUL2–APPBP2 sufficiently extended the half-life of PRDM16 protein and promoted beige adipocyte biogenesis. By contrast, elevated CUL2–APPBP2 expression was found in aged adipose tissues and repressed adipocyte thermogenesis by degrading PRDM16 protein. Importantly, extended PRDM16 protein stability by adipocyte-specific deletion of CUL2–APPBP2 counteracted diet-induced obesity, glucose intolerance, insulin resistance and dyslipidaemia in mice. These results offer a cell-autonomous route to selectively activate the PRDM16 pathway in adipose tissues.

Suggested Citation

  • Qiang Wang & Huixia Li & Kazuki Tajima & Anthony R. P. Verkerke & Zachary H. Taxin & Zhishuai Hou & Joanne B. Cole & Fei Li & Jake Wong & Ichitaro Abe & Rachana N. Pradhan & Tadashi Yamamuro & Takeshi, 2022. "Post-translational control of beige fat biogenesis by PRDM16 stabilization," Nature, Nature, vol. 609(7925), pages 151-158, September.
    • Handle: RePEc:nat:nature:v:609:y:2022:i:7925:d:10.1038_s41586-022-05067-4
    DOI: 10.1038/s41586-022-05067-4
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    Cited by:

    1. Xun Huang & Xinmeng Li & Hongyu Shen & Yiheng Zhao & Zhao Zhou & Yushuang Wang & Jingfei Yao & Kaili Xue & Dongmei Wu & Yifu Qiu, 2023. "Transcriptional repression of beige fat innervation via a YAP/TAZ-S100B axis," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    2. Yong Geun Jeon & Hahn Nahmgoong & Jiyoung Oh & Dabin Lee & Dong Wook Kim & Jane Eunsoo Kim & Ye Young Kim & Yul Ji & Ji Seul Han & Sung Min Kim & Jee Hyung Sohn & Won Taek Lee & Sun Won Kim & Jeu Park, 2024. "Ubiquitin ligase RNF20 coordinates sequential adipose thermogenesis with brown and beige fat-specific substrates," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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