Arylsulfatase K Regulates Macrophage Activation And Its Implication In The Pathogenesis Of Obesity

Background and Aims: Arylsulfatase K(ARSK),a newly discovered lysosomal enzyme,has the activity of glucuronid-2-sulfatase for desulfation of glycosaminoglycans,like heparan sulfate(HS),chondroitin sulfate(CS)and dermatan sulfate(DS).Recent studies revealed that reduction of HS sulfation contributed to enhanced activation of proinflammatory macrophages,thus aggravating high fat diet induced obesity.However,it remains to be investigated whether ARSK,the enzyme for catalyzing HS desulfation,is involved in the regulation of macrophage functions,and whether targeting macrophage ARSK can be a novel therapeutic avenue for the treatment of obesity.Therefore,this study was designed to reveal the effect of ARSK on macrophage function and its implication in the pathogenesis of obesity.Methods: First,to verify whether there is a relationship between ARSK and macrophage activation,the ARSK m RNA expression is detected in adipose tissue macrophages(ATMs)from obese patients and healthy donors.Next,in order to determine whether ARSK functions as a brake or accelerator of macrophage activation,human ATMs were transfected with ARSK or Scramble si RNA,followed by detecting and comparing the expression of proinflammatory cytokines,such as IL-1β,IL-6 and TNF-α.Also,macrophage Arsk specific knockout mice(KO mice)were constructed to figure out the association of ARSK and macrophage activation.To explore the function of macrophage ARSK in adipose tissue browning,KO mice and their control littermates(WT mice)were cold-exposed for 7 days,a condition previously shown to induce browning of WAT in vivo,and then their body temperature was detected every day and some markers related to browning,like UCP-1 and PGC-1α,were analyzed.In addition,after irradiation,ob/ob mice received bone marrow cells from WT mice or KO mice via tail vein injection were employed as the obese animal model to dissect the impact of macrophage deficient in ARSK on obesity.Results: Compared to healthy controls,obese patients exhibited much higher ARSK m RNA expression in adipose tissue macrophages(ATMs).Inhibiting ARSK attenuated proinflammatory macrophage activation and reduced the production of the proinflammatory mediators like IL-1β,IL-6 and TNF-α in human macrophages.When exposure to cold stimulation,KO mice had higher body temperature than control littermates owing to enhanced browning in white adipose tissue.Besides,Macrophage lack of ARSK exerted a protective effect on ob/ob mice,evidenced by the lower body weight,alleviated inflammation levels as well as improved insulin sensitivity in the ob/ob mice received bone marrow cells from KO mice compared to those from WT mice.Conclusion: The deletion of macrophage ARSK weakened macrophage activation,enhanced browning of adipose tissue,and protected ob/ob mice against obesity.