The Role Of SENP2 In Lipid Metabolism In Adipose Tissue

Adipose tissue is critical to maintaining lipid metabolic homeostasis and its abnormality?obesity or lipodystrophy?is associated with severe metabolic diseases.We previously showed an essential role of SUMO-specific protease 2?SENP2?in development.Adipocyte develops from mesoderm,in which SENP2 is highly expressed.We thus hypothesize that SENP2 play a critical role in adipose development and function.To test it,we generated adipocyte-specific SENP2 knockout mice by crossing Senp2^flox/flox and Adiponectin-cre mice.We found the progressive lipodystrophy in adipose tissues and fat accumulation in liver and muscle tissues in adipocyte-specific deletion of SENP2 mice.We also found hyperlipidemia and hypercholesterolemia in these mice.Moreover,adipocyte-specific deletion of SENP2mice exhibited more severe insulin resistance and hepatic steatosis but less obesity during high-fat diet.We further showed that histone methyltransferase SETDB1 is a SUMOylated protein.SENP2 can deconjugate the sumoylated SETDB1.SUMOylation can promote SETDB1-mediated histone 3 lysine 9 trimethylation on Pparg and Cebpa promoter loci by increasing the occupancy in these loci.SENP2 ablation in adipocytes resulted in the accumulation of SUMOylated SETDB1,which would suppressed the transcription of Pparg and Cebpa and its lipid metabolism-related target genes through SETDB1-mediated histone 3 lysine 9 trimethylation.Consequently,SENP2 ablation caused lipid storage deficiency in adipocytes.Our results reveal a vital role of adipose SENP2 in lipodystrophy.