Kdm6a suppresses the alternative activation of macrophages and impairs energy expenditure in obesity.
Kdm6a suppresses the alternative activation of macrophages and impairs energy expenditure in obesity.
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Kdm6a 抑制巨噬细胞的替代激活并损害肥胖症的能量消耗
DOI：
10.1038/s41418-020-00694-8
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发表时间：
2021-05
影响因子：
12.4
通讯作者：
Wang X
中科院分区：
文献类型：
--
作者：
Chen J;Xu X;Li Y;Li F;Zhang J;Xu Q;Chen W;Wei Y;Wang X
组蛋白赖氨酸脱甲基酶6a（Kdm 6a）介导从组蛋白H3赖氨酸27（H3 K27 me 3）去除抑制性三甲基化以激活靶基因表达。肥胖与代谢性炎症相关，脂肪组织巨噬细胞（ATM）是协调代谢性炎症的关键参与者。然而，目前还不清楚ATM中的Kdm 6a通路是否调节能量稳态。在这里，我们将Kdm 6a确定为调节巨噬细胞极化并进一步破坏能量平衡的关键表观遗传开关。骨髓特异性Kdm 6a敲除的Kdm 6a F/Y; Lyz 2-Cremice显著逆转了高脂饮食（HFD）诱导的白色脂肪组织（WAT）中M1-M2失衡，并阻断了HFD诱导的肥胖。Kdm 6aF/Y; Lyz 2-Cremice的棕色脂肪组织（BAT）活性、WAT布朗宁和能量消耗显著增加。此外，Kdm 6a以脱甲基酶活性依赖的方式调节Ire 1 α的表达，并增强巨噬细胞的M2极化。具有较高Kdm 6a的巨噬细胞显著促进白色脂肪细胞的脂肪生成，并抑制米色脂肪细胞的产热。这些结果表明，巨噬细胞中的Kdm 6a通过损害BAT活性和WAT分化来驱动肥胖和代谢综合征。
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 inKdm6aF/Y;Lyz2-Cremice 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 inKdm6aF/Y;Lyz2-Cremice. 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.
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影响因子：
64.8
作者：
Nguyen, Khoa D.;Qiu, Yifu;Cui, Xiaojin;Goh, Y. P. Sharon;Mwangi, Julia;David, Tovo;Mukundan, Lata;Brombacher, Frank;Locksley, Richard M.;Chawla, Ajay
通讯作者：
Chawla, Ajay
影响因子：
12.3
作者：
Väremo L;Henriksen TI;Scheele C;Broholm C;Pedersen M;Uhlén M;Pedersen BK;Nielsen J
通讯作者：
Nielsen J
影响因子：
15.9
作者：
Majumder, Syamantak;Thieme, Karina;Advani, Andrew
通讯作者：
Advani, Andrew
影响因子：
64.8
作者：
Agger, Karl;Cloos, Paul A. C.;Helin, Kristian
通讯作者：
Helin, Kristian
影响因子：
4.9
作者：
Li, Ran;Zhao, Kunchi;Yin, Fei
通讯作者：
Yin, Fei