| Title: | Post-translational control of beige fat biogenesis by PRDM16 stabilization |
| Journal: | Nature |
| Published: | 17 Aug 2022 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/35978186/ |
| DOI: | https://doi.org/10.1038/s41586-022-05067-4 |
| URL: | https://www.nature.com/articles/s41586-022-05067-4.pdf |
| Citations: | 45 (40 in last 2 years) as of 8 Aug 2024 |
Publication 10441
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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.</p>
15 Authors
- 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 Yoneshiro
- Joel N. Hirschhorn
- Shingo Kajimura
1 Application
| Application ID | Title |
|---|---|
| 11898 | Genetic studies of anthropometric traits and methods for analysis of multiple phenotypes |
Enabling scientific discoveries that improve human health