Macrophage products impact metabolism,as illustrated by obesity-associated pathologies.Metabolic adaptation is also a key component of macrophage polarization and plasticity,instrumental to their function in inflammation,homeostasis,and immunity.Kdm2 a catalyzes H3K36me2 demethylation to play an intriguing epigenetic regulatory role in cell proliferation,differentiation and apoptosis.However,its role in macrophage and the pathoetiology of obesity remains undetermined.Herein we found that myeloid-specific knockout of Kdm2a(Lys M-Cre-Kdm2af/f,Kdm2a-/-)promoted macrophage M2 program by reprograming metabolic homeostasis through enhancing fatty acid uptake and lipolysis.Kdm2a-/-increased H3K36me2 levels at the Pparg locus along with augmented chromatin accessibility and Stat6 recruitment,which rendered macrophages with preferential M2 polarization.Therefore,the Kdm2a-/-mice were highly protected from high-fat diet(HFD)-induced obesity,insulin resistance and hepatic steatosis,and featured by the reduced accumulation of adipose tissue macrophages(ATMs)and repressed chronic inflammation following HFD challenge.Particularly,Kdm2a-/-macrophages provided a microenvironment in favor of thermogenesis.Upon HFD or cold challenge,the Kdm2a-/-mice manifested higher capacity for inducing adipose browning and beiging to promote energy expenditure.Collectively,our findings demonstrated the importance of Kdm2a-mediated H3K36 demethylation in orchestrating macrophage polarization,providing novel insight that targeting Kdm2 a in macrophages could be a viable therapeutic approach against obesity and insulin resistance. |