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

Abstract

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 Kdm2a (LysM-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 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 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.

Ablation of KDM2A Inhibits Preadipocyte Proliferation and Promotes Adipogenic Differentiation

“…Previous ATAC-seq analysis showed that KDM2A −/− in macrophages resulted in a significant gain of peaks at the PPARγ locus in three particular sites [ 23 ]. Our data show that the mRNA level ( Figure 5 F) and protein expression ( Figure 7 A,B) of PPARγ, as a crucial differentiation transcriptional regulator, were significantly upregulated after transfection and induction of differentiation for 4 d. Intriguingly, the knockdown of KDM2A impelled the translocation of PPARγ from the cytoplasm to the nucleus by immunofluorescence staining ( Figure 7 A).…”

“…At the molecular level, adipocyte differentiation is a highly ordered process regulated by transcription factors, such as C/EBPα, C/EBPβ and PPARγ [ 32 , 33 ]. Recent studies have shown that in KDM2A knockout in macrophages, the level of H3K36me2 at the PPARγ locus is significantly enhanced, making macrophages inclined to M2 polarization, thus preventing mice from obesity and insulin resistance induced by a high-fat diet [ 23 ]. qPCR analysis also showed that KDM2A knockdown promoted the mRNA level of C/EBPα and PPARγ, as well as the genes related to TG synthesis, including DGAT1, GPAM and AGPAT6.…”

Bioinformatics Analysis of next generation sequencing data for Risk Prediction in Patients with Type 1 diabetes mellitus

“…KDM7A [61], LMNA (lamin A/C) [62], PFKFB3 [63], NEU1 [64], DUSP22 [65], ADORA2B [66], CRTC2 [67], GRN (granulin precursor) [68], CTSD (cathepsin D) [69], IGFBP4 [70], SMYD2 [71], OSM (oncostatin M) [72], INVS (inversin) [73], ANKFY1 [74], SEMA4D [75], PPM1A [76], IFNG (interferon gamma) [77], CTBP1 [78], ATP6 [79], COX2 [80], RPS19 [81], COX1 [82] and TLK1 [83] are potential biomarkers for the detection and prognosis of renal diseases. A previous study reported that LXN (latexin) [84], LMNA (lamin A/C) [85], PFKFB3 [86], NEU1 [87], TBK1 [88], GRN (granulin precursor) [89], CTSD (cathepsin D) [90], ACADS (acyl-CoA dehydrogenase short chain) [91], IRF7 [92], S1PR1 [93], ZAP70 [94], IDH1 [95], IL15 [96], PIK3R1 [97], OSM (oncostatin M) [98], SOCS3 [99], USP21 [100], CEP19 [101], KDM2A [102], TP53 [103], BRD2 [104], ATP6 [105], BRD4 [106], COX2 [107], RPS6 [108], ND2 [109], CYTB (cytochrome b) [110] and COX1 [111] are altered expressed in obesity. Altered expression of BCL3 [112], TRAF2 [113], NEU1 [114], SNAP29 [115], AGPAT2 [116], LPCAT3 [117], ADORA2B [118], CTSD (cathepsin D) [119], ACADS (acyl-CoA dehydrogenase short chain) [120], ACAD9 [121], E4F1 [122], IRF7 [123], TAF1 [124], S1PR1 [125], RASSF1 [126], ELAC2 [127], RNF146 [128], COX15 [129], SMYD2 [130], IDH1 [131], MTO1 [132], IL15 [133], PIK3R1 [13...…”

“…Enrichment analysis of GO and REACTOME pathway was carried out to explore the interaction between DEGs. Pathways include metabolism [ [89], CTSD (cathepsin D) [90], ACADS (acyl-CoA dehydrogenase short chain) [91], IRF7 [92], S1PR1 [93], ZAP70 [94], IDH1 [95], IL15 [96], PIK3R1 [97], OSM (oncostatin M) [98], SOCS3 [99], USP21 [100], CEP19 [101], KDM2A [102], TP53 [103], BRD2 [104], ATP6 [105], BRD4 [106], COX2 [107], RPS6 [108], ND2 [109], CYTB (cytochrome b) [110] and COX1 [111] are altered expressed in obesity. Altered expression of BCL3 [112], TRAF2 [113], NEU1 [114], SNAP29 [115], AGPAT2 [116], LPCAT3 [117], ADORA2B [118], CTSD (cathepsin D) [119], ACADS (acyl-CoA dehydrogenase short chain) [120], ACAD9 [121], E4F1 [122], IRF7 [123], TAF1 [124], S1PR1 [125], RASSF1 [126], ELAC2 [127], RNF146 [128], COX15 [129], SMYD2 [130], IDH1 [131], MTO1 [132], IL15 [133], PIK3R1 [134], ASB1 …”

Epigenetic regulation of inflammation by CxxC domain‐containing proteins*

“…4,62 In the immune system, Kdm2a deficiency in macrophages enhances thermogenesis, leading to superior protection against HFD-induced obesity by enhancing H3K36me2 at the Pparg locus. 63 KDM2A and its partner H3K36 methylase NSD1 collaborate to regulate the NFκB signaling pathway through the demethylation of K218 and K221 of the p65 subunit of NFκB. 64 The increased expression of KDM2A has been reported in psoriasis patients, and KDM2A might play a negative role in the inflammatory reaction of keratinocytes.…”