期刊
CELL DEATH AND DIFFERENTIATION
卷 28, 期 5, 页码 1688-1704出版社
SPRINGERNATURE
DOI: 10.1038/s41418-020-00694-8
关键词
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资金
- National Natural Science Foundation of China [81770933, 81772886]
- Double Hundred Plan of Shanghai Jiao Tong University School of Medicine [20191812]
- Program of Innovative Research team of High-level Local Universities in Shanghai
The study identifies Kdm6a as a critical epigenetic switch that modulates macrophage polarization and disrupts energy balance, ultimately driving obesity and metabolic syndrome. Knockout of Kdm6a in myeloid cells reverses HFD-induced M1-M2 imbalance in white adipose tissue and blocks HFD-induced obesity, while also increasing BAT activity, WAT browning, and energy expenditure in mice. These findings suggest that Kdm6a in macrophages plays a key role in regulating energy metabolism and impacting obesity-related processes.
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(F/Y);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(F/Y);Lyz2-Cre mice. Furthermore, Kdm6a regulated the Ire1 alpha 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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