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Kdm6a 抑制巨噬细胞的交替激活，损害肥胖症中的能量消耗。

Kdm6a suppresses the alternative activation of macrophages and impairs energy expenditure in obesity.

机构信息

Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.

National Clinical Research Center for Oral Disease, Shanghai, 200011, China.

出版信息

Cell Death Differ. 2021 May;28(5):1688-1704. doi: 10.1038/s41418-020-00694-8. Epub 2020 Dec 10.

DOI:10.1038/s41418-020-00694-8
PMID:33303977
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8167088/
Abstract

Histone lysine demethylase 6a (Kdm6a) mediates the removal of repressive trimethylation from histone H3 lysine 27 (H3K27me3) to activate target gene expression. Obesity is associated with metabolic inflammation, and adipose tissue macrophages (ATMs) are key players orchestrating metabolic inflammation. However, it is still unclear whether the Kdm6a pathway in ATMs regulates energy homeostasis. Here, we identified Kdm6a as a critical epigenetic switch that modulates macrophage polarisation and further disrupts energy balance. Myeloid-specific Kdm6a knockout in Kdm6a;Lyz2-Cre mice significantly reversed the high-fat diet (HFD)-induced M1-M2 imbalance in white adipose tissue (WAT) and blocked HFD-induced obesity. The brown adipose tissue (BAT) activity, WAT browning and energy expenditure were significantly increased in Kdm6a;Lyz2-Cre mice. Furthermore, Kdm6a regulated the Ire1α expression in a demethylase activity-dependent manner and augmented the M2 polarisation of macrophages. Macrophage with higher Kdm6a significantly promotes adipogenesis in white adipocyte and inhibits thermogenesis in beige adipocytes. These results suggest that the Kdm6a in macrophages drives obesity and metabolic syndrome by impairing BAT activity and WAT differentiation.

摘要

组蛋白赖氨酸去甲基化酶 6a（Kdm6a）介导了抑制性三甲基化从组蛋白 H3 赖氨酸 27（H3K27me3）的去除，以激活靶基因表达。肥胖与代谢性炎症有关，脂肪组织巨噬细胞（ATMs）是协调代谢性炎症的关键执行者。然而，Kdm6a 途径在 ATMs 中是否调节能量平衡仍不清楚。在这里，我们确定 Kdm6a 是一种关键的表观遗传开关，调节巨噬细胞极化，并进一步破坏能量平衡。在 Kdm6a;Lyz2-Cre 小鼠中，髓系特异性 Kdm6a 敲除显著逆转了高脂肪饮食（HFD）诱导的白色脂肪组织（WAT）中 M1-M2 失衡，并阻止了 HFD 诱导的肥胖。棕色脂肪组织（BAT）活性、WAT 褐变和能量消耗在 Kdm6a;Lyz2-Cre 小鼠中显著增加。此外，Kdm6a 以依赖去甲基化酶活性的方式调节 Ire1α 的表达，并增强巨噬细胞的 M2 极化。具有更高 Kdm6a 的巨噬细胞显著促进白色脂肪细胞中的脂肪生成，并抑制米色脂肪细胞中的产热。这些结果表明，巨噬细胞中的 Kdm6a 通过损害 BAT 活性和 WAT 分化来驱动肥胖和代谢综合征。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/17d9/8167088/20f158cf2833/41418_2020_694_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/17d9/8167088/5bddd74c9903/41418_2020_694_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/17d9/8167088/73605ac1ab82/41418_2020_694_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/17d9/8167088/602acd69c73e/41418_2020_694_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/17d9/8167088/ef557c0bd09d/41418_2020_694_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/17d9/8167088/5a3134cd085a/41418_2020_694_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/17d9/8167088/6ab9bf343f2b/41418_2020_694_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/17d9/8167088/78c6f35e606a/41418_2020_694_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/17d9/8167088/20f158cf2833/41418_2020_694_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/17d9/8167088/5bddd74c9903/41418_2020_694_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/17d9/8167088/73605ac1ab82/41418_2020_694_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/17d9/8167088/602acd69c73e/41418_2020_694_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/17d9/8167088/ef557c0bd09d/41418_2020_694_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/17d9/8167088/5a3134cd085a/41418_2020_694_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/17d9/8167088/6ab9bf343f2b/41418_2020_694_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/17d9/8167088/78c6f35e606a/41418_2020_694_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/17d9/8167088/20f158cf2833/41418_2020_694_Fig8_HTML.jpg

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