SUMO-specific protease 2 (SENP2) suppresses browning of white adipose tissue through C/EBPβ modulation

Abstract

SUMO-specific protease 2 (SENP2) is highly expressed in white adipose tissue (WAT) and plays an important role in the early stages of adipogenesis. To investigate the function of SENP2 in adipocytes, we generated adipocyte-specific Senp2 knock-out (Senp2-aKO) mice. Compared to wild-type mice, Senp2-aKO mice had reduced adipose tissue mass and smaller multi-locular adipocytes in inguinal WAT (iWAT). Body temperatures of Senp2-aKO mice were effectively regulated during cold exposure. Additionally, Senp2-aKO mice were resistant to high-fat-diet-induced obesity and insulin resistance and exhibited an increase in energy expenditure rates. Expression of thermogenic genes, including Ucp1, was significantly increased in iWAT (and less efficiently in epidydimal WAT [eWAT]) of Senp2-aKO mice, suggesting that SENP2 depletion accelerates browning of WAT. Further, suppression of HOXC10 was essential for beige adipocyte formation in SENP2-deficient cells of iWAT, and Hoxc10 transcriptional suppression was mediated by C/EBP{beta}, a direct target of SENP2. Sumoylated C/EBP{beta} efficiently inhibited Hoxc10 transcription through recruitment of the transcriptional co-repressor DAXX. Similarly, Senp2 knockdown using siRNAs during adipogenesis promoted thermogenic adipocyte differentiation of precursor cells in both iWAT and eWAT, and C/EBP{beta} was a common mediator. Together these results suggest that SENP2 plays critical role in white adipocyte differentiation by suppressing differentiation toward thermogenic adipocytes through modulation of C/EBP{beta} in both iWAT and eWAT.