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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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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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 |
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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 |
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