Role of SENP2 on browning of white adipose tissue

Abstract

SUMO-specific proteases (SENPs) play important roles in the control of various cellular events. Recent studies have shown that SENP2 regulates fatty acid metabolism through transcriptional induction of the FAO-related enzymes by desumoylation of PPARδ and PPARγ in skeletal muscle. SENP2 also plays a critical role in the regulation of adipogenesis.<br/> To investigate the role of SENP2 in adipocytes, I generated adipocyte-specific SENP2 knockout mice (SENP2-adipoKO) using adiponectin-cre mice. On the high fat-diet (HFD), SENP2-adipoKO mice had less weight gain, lower fat mass, smaller adipocyte size and improved glucose tolerance compared to control mice. SENP2-adipoKO mice displayed increased oxygen consumption and CO2 production. The mRNA levels of BAT-specific genes were higher in the subcutaneous WAT (SC-WAT) of SENP2-adipoKO mice. SENP2-adipoKO mice also showed increased thermogenic response to cold exposure.<br/> When I differentiated adipocytes from stromal vascular fraction (SVF), brown adipocyte-specific genes were significantly increased in the SENP2-adipoKO SVF-derived adipocytes, while Hoxc10 mRNA level decreased in the SENP2-adipoKO SVF-derived adipocytes. Hoxc10 has been known as a key negative regulator in the process of browning of SC fat. Hoxc10 overexpression using AAV-Hoxc10 in the SVF decreased Ucp1, Cidea and Elovl3 mRNA levels in the SENP2-adipoKO SVF–derived adipocytes. Knockdown of C/EBPβ suppressed the induction of Ucp1 and Cidea expression by SENP2 KO. Moreover, the reduction of Hoxc10 expression by SENP2 KO was restored by C/EBPβ knockdown.<br/> There is a putative C/EBPβ binding site in Hoxc10 promoter. C/EBPβ decreased Hoxc10 promoter activity in the presence of UBC9- and SUMO-expression vectors, Hoxc10 promoter activity was restored when SENP2-expression vector was cotransfected. These results suggest that sumoylated form of C/EBPβ efficiently suppresses Hoxc10 transcription.<br/> In summary, loss of SENP2 leads to accumulation of sumoylated form of C/EBPβ which efficiently represses Hoxc10 transcription and eventually contributes to promote browning of white adipose tissue.