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

Longmin Chen,Jiajun Zhao,Meng Zhang,Jingyi Li,Décio L Eizirik ,Jing Zhang,Fei Xiong,Fei Sun,Xi Luo,Ping Yang,Fa-Xi Wang ,Quan Gong,Qing Zhou,Huilan Zhang,Yanchao Guo,Zhiguang Zhou,Zhishui Chen,Shu Zhang,Yuan Zou,Qilin Yu,Congyi Wang

doi:10.1038/s41418-020-00714-7

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.

Highlights

Obesity arises from a complex interaction between genetic and environmental factors
A decreased Il6 expression in the KO bone marrow-derived macrophages (BMDMs) was noted in a NF-κB and MAPK pathwayindependent manner, which might be explained by the finding that Kdm2b, a paralog of Kdm2a, was required in macrophage for the induction of IL-6 by facilitating chromatin accessibility at the Il6 promoter [35]
The elevated fatty acid uptake and their subsequent lipolysis fueled fatty acid oxidation (FAO) and contributed to the enhanced oxidative phosphorylation (OXPHOS), which was further confirmed by the seahorse extracellular flux analysis, in which the KO BMDMs displayed higher basal oxygen consumption rate (OCR) along with a markedly increased spare respiratory capacity (SRC) in response to either vehicle or IL-4

Summary

Introduction

Obesity arises from a complex interaction between genetic and environmental factors. genetic predisposition undoubtedly confers the risk of obesity, environmental exposures play a crucial role in the initiation and NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Tongji Hospital, Wuhan, China 4 Clinical Molecular Immunology Center, Department of Immunology, School of Medicine, Yangtze University, Jingzhou, China 5 Department of Endocrinology and Metabolism, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China 6 ULB Center for Diabetes Research, Université Libre de Bruxelles, 808 Route de Lennik, B-1070 Brussels, Belgium 7 Diabetes Center, The Second Xiangya Hospital, Institute of Metabolism and Endocrinology, Central South University, Changsha, ChinaKdm2a deficiency in macrophages enhances thermogenesis to protect mice against HFD-induced obesity by. . .progression of this disorder. Obesity arises from a complex interaction between genetic and environmental factors. Epigenetic factors (e.g., DNA methylation and histone modification) serve as “fingerprints” to record gene-environment interactions or accumulated environmental exposures during the course of daily life processes [1]. Epigenetic factors have attracted growing interests as the mechanistic link between genetic variants and environmental factors in determining the risks of obesity [2]. Histone modifications, such as acetylation, phosphorylation, ubiquitination, sumoylation, and methylation, regulate gene expressions by modulating chromatin structure [3]. Kdm2a is a Jumonji C (JmjC) domain-containing histone KDM that catalyzes the demethylation of H3K36me, which is associated with actively transcribed genes [4,5,6,7,8].

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