The Role Of SENP1 In Adipose Tissue Macrophages During Obese Pathogenesis

Adipose tissue can be divided developmentally and functionally into two main categories:white adipose tissue stores triglycerides that serves as mammals’longterm nutrient storage depot.Brown adipocyte in both mice and humans is to convert chemical energy into heat via uncoupling protein 1（UCP1）,which is a key site of heat production.Like brown adipocytes,beige adipocytes（also known as brown like or brite adipocytes）express high level of UCP1,dissipating energy as heat.The development of beige adipocytes in WAT（so called’browning’）may reduce adverse effects of WAT,which can help to improve metabolic health.However,mechanisms involed in white adipose tissue browning have remained obscure.SUMOylation is a kind of ubiquitin-like modification.It acts as an important regulatory mechanism in multiple physiological and pathological processes by changing the location and activity of target molecules or interacting with other proteins.SUMO modification is a dynamic process,which is catalyzed by SUMO-specific ligases and removed by SUMO-specific proteases（SENPs）.Previous work in our lab has identified SENP1 as a critical regulator in macrophage activation.Emerging studies indicate that adipose tissue macrophages（ATMs）play critical roles in adipose tissue inflammation and insulin resistance induced by obesity.Hence,we postulated that SENP1 might be associated with obesity-induced insulin resistance by regulating the activity of macrophages.To test this hypothesis,we intercrossed floxed SENP1(Senp1^f/f)mice with the Lysozyme2-Cre（Lyz2-Cre）line to generate macrophage-specific SENP1-knockout(Senp1^f/f;Lyz2-Cre)mice.Compared with control mice,Senp1^f/f;Lyz2-Cre mice were prominently resistant to HFD-induced obesity and insulin resistance.By analysing inflammation of adipose tissue during either NCD or early stage of HFD,we discovered that the beneficial metabolic effects caused by macrophage-SENP1 ablation were not due to the pro-inflammatory effect of macrophage SENP1 in adipose tissues.We assessed energy homeostasis in Senp1^f/f;Lyz2-Cre and Senp1^f/f mice after feeding HFD for 4 weeks.Our studies demonstrated that the absence of SENP1 in macrophages caused browning of sc WAT,leading mice caloric expenditure increased.Here we found that SENP1 was involved in negative regulation of norepinephrine（NE）production in ATMs and thereby limited beige adipogenesis in sc WAT.The upregulated SENP1 in obesity acts as a specific de-SUMOylation protease for NR4A1,which directly suppressed the transcription of TH expression.In contrast,macrophage-specific knockout of SENP1 increased SUMO1 conjugation to NR4A1and elevated TH expression during HFD feeding.Collectively,our studies indicate that SENP1 is an important negative regulator of TH expression.Macrophage SENP1 ablation can increase TH expression and NE production,which promotes the beige adipogenesis of sc WAT and preventes obesity-related metabolic dysregulation.