Post-translational control of beige fat biogenesis by PRDM16 stabilization

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 and Shingo Kajimura ()
Additional contact information
Qiang Wang: Beth Israel Deaconess Medical Center and Harvard Medical School
Huixia Li: Xi’an Jiaotong University Health Science Center
Kazuki Tajima: National Hospital Organization, Yokohama Medical Center
Anthony R. P. Verkerke: Beth Israel Deaconess Medical Center and Harvard Medical School
Zachary H. Taxin: Beth Israel Deaconess Medical Center and Harvard Medical School
Zhishuai Hou: Beth Israel Deaconess Medical Center and Harvard Medical School
Joanne B. Cole: Broad Institute of MIT and Harvard
Fei Li: Beth Israel Deaconess Medical Center and Harvard Medical School
Jake Wong: Beth Israel Deaconess Medical Center and Harvard Medical School
Ichitaro Abe: Beth Israel Deaconess Medical Center and Harvard Medical School
Rachana N. Pradhan: Genentech
Tadashi Yamamuro: Beth Israel Deaconess Medical Center and Harvard Medical School
Takeshi Yoneshiro: The University of Tokyo
Joel N. Hirschhorn: Broad Institute of MIT and Harvard
Shingo Kajimura: Beth Israel Deaconess Medical Center and Harvard Medical School

Nature, 2022, vol. 609, issue 7925, 151-158

Abstract: 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.

Date: 2022
References: Add references at CitEc
Citations: View citations in EconPapers (2)

Downloads: (external link)
https://www.nature.com/articles/s41586-022-05067-4 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:609:y:2022:i:7925:d:10.1038_s41586-022-05067-4

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-022-05067-4

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().