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BAF60a deficiency in macrophage promotes diet-induced obesity and metabolic inflammation

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posted on 13.07.2022, 13:16 authored by Qin Kong, Jiahuan Zou, Ziyin Zhang, Ran Pan, Zhe Yu Zhang, Shuang Han, Yanyong Xu, Yue Gao, Zhuo-Xian Meng

  

Adipose tissue macrophage (ATM) has been shown to play a key role in the pathogenesis of obesity-associated adipose tissue inflammation and metabolic diseases. However, the upstream factors that integrate the environmental signals to control ATM activation and adipose inflammation in obesity remain elusive. Here, we identify BAF60a, a subunit of the SWI/SNF chromatin remodeling complexes, as the central checkpoint regulator of obesity-induced ATM activation, adipose tissue inflammation and systemic metabolic impairment. BAF60a expression was robustly downregulated in the adipose tissue stromal vascular fractions (SVFs) in type 2 diabetic mice. Myeloid-specific BAF60a ablation (BaMKO) promotes ATM pro-inflammatory activation, exacerbating diet-induced obesity, insulin resistance and metabolic dysfunction. Conversely, myeloid-specific overexpression of BAF60a in mice attenuates macrophage pro-inflammatory activation. Mechanistically, transcriptome and chromatin landscape analyses demonstrate that BAF60a inactivation triggers the expression of pro-inflammatory gene program through chromatin remodeling. Moreover, motif analysis of ATAC-Seq and CUT&Tag-Seq data identifies the transcription factor Atf3 that physically interacts with BAF60a to suppress the pro-inflammatory gene expression, thereby controlling ATM activation and metabolic inflammation in obesity. Consistently, myeloid-specific Atf3 deficiency also promotes the pro-inflammatory activation of macrophage. Together, this work uncovers BAF60a/Atf3 axis as the key regulator in obesity-associated ATM activation, adipose tissue inflammation and metabolic diseases.

Funding

This work was supported by grants from the National Key Research and Development Program of China (2018YFA0800403 and 2021YFC2701903 to Z.X.M.), the Training Program of the Major Research Plan of the National Natural Science Foundation of China (91857110 to Z.X.M.), the National Natural Science Fund for Excellent Young Scholars of China (81722012 to Z.X.M.), the National Natural Science Foundation of China (81670740 to Z.X.M. and 82100904 to S.H.), the Zhejiang Provincial Natural Science Foundation of China (LZ21H070001 to Z.X.M. and LQ21C110001 to S.H.), the Innovative Institute of Basic Medical Sciences of Zhejiang University to Z.X.M., the Construction Fund of Medical Key Disciplines of Hangzhou (No. OO20200055 to Y.G.), the Hangzhou Science and Technology Bureau (20150733Q13 and ZD20200129 to Y.G.), the Fundamental Research Funds for the Central Universities to Z.X.M., and the support from K.C. Wong Education Foundation to Z.X.M.

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