Post-translational control of beige fat biogenesis by PRDM16 stabilization

Article

关键词: ADIPOSE-CELL FATE;    HIF-ALPHA;    BROWN;    ACTIVATION;    PROTEIN;    THERMOGENESIS;    COMPLEX;    MITOCHONDRIAL;    RECRUITMENT;    INSIGHTS;   

DOI  :  10.1038/s41586-022-05067-4

来源: SCIE

【 摘 要 】

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.

【 授权许可】

Free