Post-translational control of beige fat biogenesis by PRDM16 stabilization.
Qiang WangHuixia LiKazuki TajimaAnthony R P VerkerkeZachary H TaxinZhishuai HouJoanne B ColeFei LiJake WongIchitaro AbeRachana N PradhanTadashi YamamuroTakeshi YoneshiroJoel N HirschhornShingo KajimuraPublished in: Nature (2022)
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.
Keyphrases
- adipose tissue
- insulin resistance
- high fat diet induced
- high fat diet
- gene expression
- protein protein
- metabolic syndrome
- binding protein
- polycystic ovary syndrome
- healthcare
- type diabetes
- skeletal muscle
- amino acid
- small molecule
- magnetic resonance
- poor prognosis
- public health
- single cell
- transcription factor
- long non coding rna
- stem cells
- body mass index
- climate change
- contrast enhanced
- bone marrow
- oxidative stress
- mesenchymal stem cells
- human health
- glycemic control