Cargando…

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

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 homeostasi...

Descripción completa

Detalles Bibliográficos
Autores principales: Chen, Longmin, Zhang, Jing, Zou, Yuan, Wang, Faxi, Li, Jingyi, Sun, Fei, Luo, Xi, Zhang, Meng, Guo, Yanchao, Yu, Qilin, Yang, Ping, Zhou, Qing, Chen, Zhishui, Zhang, Huilan, Gong, Quan, Zhao, Jiajun, Eizirik, Decio L., Zhou, Zhiguang, Xiong, Fei, Zhang, Shu, Wang, Cong-Yi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185071/
https://www.ncbi.nlm.nih.gov/pubmed/33462408
http://dx.doi.org/10.1038/s41418-020-00714-7
_version_ 1783704709319622656
author Chen, Longmin
Zhang, Jing
Zou, Yuan
Wang, Faxi
Li, Jingyi
Sun, Fei
Luo, Xi
Zhang, Meng
Guo, Yanchao
Yu, Qilin
Yang, Ping
Zhou, Qing
Chen, Zhishui
Zhang, Huilan
Gong, Quan
Zhao, Jiajun
Eizirik, Decio L.
Zhou, Zhiguang
Xiong, Fei
Zhang, Shu
Wang, Cong-Yi
author_facet Chen, Longmin
Zhang, Jing
Zou, Yuan
Wang, Faxi
Li, Jingyi
Sun, Fei
Luo, Xi
Zhang, Meng
Guo, Yanchao
Yu, Qilin
Yang, Ping
Zhou, Qing
Chen, Zhishui
Zhang, Huilan
Gong, Quan
Zhao, Jiajun
Eizirik, Decio L.
Zhou, Zhiguang
Xiong, Fei
Zhang, Shu
Wang, Cong-Yi
author_sort Chen, Longmin
collection PubMed
description 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.
format Online
Article
Text
id pubmed-8185071
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-81850712021-06-11 Kdm2a deficiency in macrophages enhances thermogenesis to protect mice against HFD-induced obesity by enhancing H3K36me2 at the Pparg locus Chen, Longmin Zhang, Jing Zou, Yuan Wang, Faxi Li, Jingyi Sun, Fei Luo, Xi Zhang, Meng Guo, Yanchao Yu, Qilin Yang, Ping Zhou, Qing Chen, Zhishui Zhang, Huilan Gong, Quan Zhao, Jiajun Eizirik, Decio L. Zhou, Zhiguang Xiong, Fei Zhang, Shu Wang, Cong-Yi Cell Death Differ Article 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. Nature Publishing Group UK 2021-01-18 2021-06 /pmc/articles/PMC8185071/ /pubmed/33462408 http://dx.doi.org/10.1038/s41418-020-00714-7 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Chen, Longmin
Zhang, Jing
Zou, Yuan
Wang, Faxi
Li, Jingyi
Sun, Fei
Luo, Xi
Zhang, Meng
Guo, Yanchao
Yu, Qilin
Yang, Ping
Zhou, Qing
Chen, Zhishui
Zhang, Huilan
Gong, Quan
Zhao, Jiajun
Eizirik, Decio L.
Zhou, Zhiguang
Xiong, Fei
Zhang, Shu
Wang, Cong-Yi
Kdm2a deficiency in macrophages enhances thermogenesis to protect mice against HFD-induced obesity by enhancing H3K36me2 at the Pparg locus
title Kdm2a deficiency in macrophages enhances thermogenesis to protect mice against HFD-induced obesity by enhancing H3K36me2 at the Pparg locus
title_full Kdm2a deficiency in macrophages enhances thermogenesis to protect mice against HFD-induced obesity by enhancing H3K36me2 at the Pparg locus
title_fullStr Kdm2a deficiency in macrophages enhances thermogenesis to protect mice against HFD-induced obesity by enhancing H3K36me2 at the Pparg locus
title_full_unstemmed Kdm2a deficiency in macrophages enhances thermogenesis to protect mice against HFD-induced obesity by enhancing H3K36me2 at the Pparg locus
title_short Kdm2a deficiency in macrophages enhances thermogenesis to protect mice against HFD-induced obesity by enhancing H3K36me2 at the Pparg locus
title_sort kdm2a deficiency in macrophages enhances thermogenesis to protect mice against hfd-induced obesity by enhancing h3k36me2 at the pparg locus
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185071/
https://www.ncbi.nlm.nih.gov/pubmed/33462408
http://dx.doi.org/10.1038/s41418-020-00714-7
work_keys_str_mv AT chenlongmin kdm2adeficiencyinmacrophagesenhancesthermogenesistoprotectmiceagainsthfdinducedobesitybyenhancingh3k36me2atthepparglocus
AT zhangjing kdm2adeficiencyinmacrophagesenhancesthermogenesistoprotectmiceagainsthfdinducedobesitybyenhancingh3k36me2atthepparglocus
AT zouyuan kdm2adeficiencyinmacrophagesenhancesthermogenesistoprotectmiceagainsthfdinducedobesitybyenhancingh3k36me2atthepparglocus
AT wangfaxi kdm2adeficiencyinmacrophagesenhancesthermogenesistoprotectmiceagainsthfdinducedobesitybyenhancingh3k36me2atthepparglocus
AT lijingyi kdm2adeficiencyinmacrophagesenhancesthermogenesistoprotectmiceagainsthfdinducedobesitybyenhancingh3k36me2atthepparglocus
AT sunfei kdm2adeficiencyinmacrophagesenhancesthermogenesistoprotectmiceagainsthfdinducedobesitybyenhancingh3k36me2atthepparglocus
AT luoxi kdm2adeficiencyinmacrophagesenhancesthermogenesistoprotectmiceagainsthfdinducedobesitybyenhancingh3k36me2atthepparglocus
AT zhangmeng kdm2adeficiencyinmacrophagesenhancesthermogenesistoprotectmiceagainsthfdinducedobesitybyenhancingh3k36me2atthepparglocus
AT guoyanchao kdm2adeficiencyinmacrophagesenhancesthermogenesistoprotectmiceagainsthfdinducedobesitybyenhancingh3k36me2atthepparglocus
AT yuqilin kdm2adeficiencyinmacrophagesenhancesthermogenesistoprotectmiceagainsthfdinducedobesitybyenhancingh3k36me2atthepparglocus
AT yangping kdm2adeficiencyinmacrophagesenhancesthermogenesistoprotectmiceagainsthfdinducedobesitybyenhancingh3k36me2atthepparglocus
AT zhouqing kdm2adeficiencyinmacrophagesenhancesthermogenesistoprotectmiceagainsthfdinducedobesitybyenhancingh3k36me2atthepparglocus
AT chenzhishui kdm2adeficiencyinmacrophagesenhancesthermogenesistoprotectmiceagainsthfdinducedobesitybyenhancingh3k36me2atthepparglocus
AT zhanghuilan kdm2adeficiencyinmacrophagesenhancesthermogenesistoprotectmiceagainsthfdinducedobesitybyenhancingh3k36me2atthepparglocus
AT gongquan kdm2adeficiencyinmacrophagesenhancesthermogenesistoprotectmiceagainsthfdinducedobesitybyenhancingh3k36me2atthepparglocus
AT zhaojiajun kdm2adeficiencyinmacrophagesenhancesthermogenesistoprotectmiceagainsthfdinducedobesitybyenhancingh3k36me2atthepparglocus
AT eizirikdeciol kdm2adeficiencyinmacrophagesenhancesthermogenesistoprotectmiceagainsthfdinducedobesitybyenhancingh3k36me2atthepparglocus
AT zhouzhiguang kdm2adeficiencyinmacrophagesenhancesthermogenesistoprotectmiceagainsthfdinducedobesitybyenhancingh3k36me2atthepparglocus
AT xiongfei kdm2adeficiencyinmacrophagesenhancesthermogenesistoprotectmiceagainsthfdinducedobesitybyenhancingh3k36me2atthepparglocus
AT zhangshu kdm2adeficiencyinmacrophagesenhancesthermogenesistoprotectmiceagainsthfdinducedobesitybyenhancingh3k36me2atthepparglocus
AT wangcongyi kdm2adeficiencyinmacrophagesenhancesthermogenesistoprotectmiceagainsthfdinducedobesitybyenhancingh3k36me2atthepparglocus