Kdm2a deficiency in macrophages enhances thermogenesis to protect mice against HFD-induced obesity by enhancing H3K36me2 at the Pparg locus

<jats:title>Abstract</jats:title><jats:p>Kdm2a catalyzes H3K36me2 demethylation to play an intriguing epigenetic regulatory role in cell proliferation, differentiation, and apoptosis. Herein we found that myeloid-specific knockout of <jats:italic>Kdm2a</jats:italic> (<jats:italic>LysM-</jats:italic>Cre-<jats:italic>Kdm2a</jats:italic><jats:sup>f/f</jats:sup>, <jats:italic>Kdm2a</jats:italic><jats:sup><jats:italic>−/−</jats:italic></jats:sup>) promoted macrophage M2 program by reprograming metabolic homeostasis through enhancing fatty acid uptake and lipolysis. <jats:italic>Kdm2a</jats:italic><jats:sup><jats:italic>−/−</jats:italic></jats:sup> increased H3K36me2 levels at the <jats:italic>Pparg</jats:italic> locus along with augmented chromatin accessibility and Stat6 recruitment, which rendered macrophages with preferential M2 polarization. Therefore, the <jats:italic>Kdm2a</jats:italic><jats:sup><jats:italic>−/−</jats:italic></jats:sup> 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 and repressed chronic inflammation following HFD challenge. Particularly, <jats:italic>Kdm2a</jats:italic><jats:sup><jats:italic>−/−</jats:italic></jats:sup> macrophages provided a microenvironment in favor of thermogenesis. Upon HFD or cold challenge, the <jats:italic>Kdm2a</jats:italic><jats:sup><jats:italic>−/−</jats:italic></jats:sup> mice manifested higher capacity for inducing adipose browning and beiging to promote energy expenditure. Collectively, our findings demonstrate the importance of Kdm2a-mediated H3K36 demethylation in orchestrating macrophage polarization, providing novel insight that targeting Kdm2a in macrophages could be a viable therapeutic approach against obesity and insulin resistance.</jats:p>