| First Author | Wang Q | Year | 2022 |
| Journal | Nature | Volume | 609 |
| Issue | 7925 | Pages | 151-158 |
| PubMed ID | 35978186 | Mgi Jnum | J:333058 |
| Mgi Id | MGI:7398305 | Doi | 10.1038/s41586-022-05067-4 |
| Citation | Wang Q, et al. (2022) Post-translational control of beige fat biogenesis by PRDM16 stabilization. Nature 609(7925):151-158 |
| abstractText | Compelling evidence shows that brown and beige adipose tissue are protective against metabolic diseases(1,2). 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 health(3-8). 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. |
