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

Cell Death Differ. 2021 Jun;28(6):1880-1899. doi: 10.1038/s41418-020-00714-7.

Longmin Chen ^# ¹, Jing Zhang ^# ¹, Yuan Zou ¹, Faxi Wang ¹, Jingyi Li ¹, Fei Sun ¹, Xi Luo ¹, Meng Zhang ¹ ², Yanchao Guo ¹ ², Qilin Yu ¹, Ping Yang ¹, Qing Zhou ¹, Zhishui Chen ¹ ³, Huilan Zhang ¹, Quan Gong ⁴, Jiajun Zhao ⁵, Decio L Eizirik ⁶, Zhiguang Zhou ⁷, Fei Xiong ⁸, Shu Zhang ⁹, Cong-Yi Wang ¹⁰

Affiliations

1 The Center for Biomedical Research, Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
2 Department of Nephrology,Tongji Hospital, Tongji College of Medicine, Huazhong University of Science and Technology, Wuhan, China.
3 Key Laboratory of Organ Transplantation, Ministry of Education, 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, China.
8 The Center for Biomedical Research, Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. feixiong@tjh.tjmu.edu.cn.
9 The Center for Biomedical Research, Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. szhang@tjh.tjmu.edu.cn.
10 The Center for Biomedical Research, Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. wangcy@tjh.tjmu.edu.cn.
# Contributed equally.

PMID: 33462408 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-Kdm2a^f/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.

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