小柯机器人

美国哈佛医学院Shingo Kajimura研究小组发现，PRDM16稳定性介导米色脂肪生物生成的翻译后调控。2022年8月17日，《自然》杂志在线发表了这项成果。

研究人员发现，CUL2-APPBP2是泛素E3连接酶，通过催化PRDM16（PR domain-containing 16）蛋白的多泛素化来决定其稳定性。抑制CUL2-APPBP2能充分延长PRDM16蛋白的半衰期，促进米色脂肪细胞的生物生成。相反，在老年脂肪组织中发现CUL2-APPBP2的表达升高，并通过降解PRDM16蛋白抑制脂肪细胞的产热。重要的是，脂肪细胞特异性敲除CUL2-APPBP2延长了PRDM16蛋白的稳定性，抵消了饮食引起的肥胖、葡萄糖不耐受、胰岛素抵抗和小鼠血脂异常。这些结果提供了一个在脂肪组织中选择性地激活PRDM16通路的细胞自主途径。

令人信服的证据表明，棕色和米色脂肪组织对代谢性疾病有保护作用。PRDM16通过与转录和表观遗传因子形成复合物，是米色脂肪细胞生物生成的主导激活因子，因此是改善代谢健康的一个有吸引力的靶点。然而，由于缺乏围绕PRDM16蛋白表达调控的知识，阻碍了人们选择性地靶向这一转录途径。

附：英文原文

Title: Post-translational control of beige fat biogenesis by PRDM16 stabilization

Author: Wang, Qiang, Li, Huixia, Tajima, Kazuki, Verkerke, Anthony R. P., Taxin, Zachary H., Hou, Zhishuai, Cole, Joanne B., Li, Fei, Wong, Jake, Abe, Ichitaro, Pradhan, Rachana N., Yamamuro, Tadashi, Yoneshiro, Takeshi, Hirschhorn, Joel N., Kajimura, Shingo

Issue&Volume: 2022-08-17

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 health3,4,5,6,7,8. 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.

DOI: 10.1038/s41586-022-05067-4

Source: https://www.nature.com/articles/s41586-022-05067-4

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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