Post-translational control of beige fat biogenesis by PRDM16 stabilization.

Nature 2022 Sep

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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. © 2022. The Author(s).

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 Yoneshiro, Joel N Hirschhorn, Shingo Kajimura. Post-translational control of beige fat biogenesis by PRDM16 stabilization. Nature. 2022 Sep;609(7925):151-158