BAF60a Deficiency in Macrophage Promotes Diet-Induced Obesity and Metabolic Inflammation

Abstract

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.

A chromatin remodeling checkpoint of diet-induced macrophage activation in adipose tissue

“…Obesity-associated metabolic dysfunction of the adipose tissue is a significant factor in the pathogenesis of insulin resistance and Type 2 diabetes (T2D). ATMs are dynamically implicated in modulating metabolic homeostasis and the immune milieu in the adipose tissue [ [9] , [10] , [11] , [12] , [13] ].…”

“…The interplay between the environment and the immune cells is connected with metabolic homeostasis under pathophysiologic conditions. T2D is considered an immune-related inflammatory disease, in which the ATMs are key players orchestrating metabolic chronic meta-inflammation and contributing to the pathogenesis of metabolic disease [ [11] , [12] , [13] ]. M1 polarization (classical activation characterized by the production of pro-inflammatory cytokines and chemokines such as IL-6, IL-12 and TNF-α which may impair insulin action in adipocytes) and M2 polarization (alternative activation characterized by the secretion of anti-inflammatory cytokines protecting adipocytes from inflammation and damage) of ATM present an equilibrium in physiologic conditions.…”

“…In contrast, during obesity, macrophages that are recruited in the adipose tissue acquire a pro-inflammatory phenotype. Interestingly, there is a distinct metabolically activated phenotype of ATMs, which is different from the M1/M2 activation [ [11] , [12] , [13] ]. However, the molecular regulators that integrate the environmental signals to control ATM activation and adipose inflammation during obesity and T2D remain unclear.…”

“…The BAF60 family members, including BAF60a, BAF60b and BAF60c, can recruit the SWI/SNF complex to target genes to remodel nucleosomes structure and transcription [ 12 ]. Recently, a research article published in Diabetes titled “BAF60a Deficiency in Macrophage Promotes Diet-Induced Obesity and Metabolic Inflammation” by Kong et al has identified BAF60a as a pivotal chromatin remodeling checkpoint factor to regulate macrophage pro-inflammatory activation in white adipose tissue upon high fat diet (HFD) feeding [ 13 ]. Moreover, the authors also unveiled that BAF60a/Atf3 axis is the key regulator in obesity-associated ATM activation, adipose tissue inflammation and metabolic dysfunction.…”

“…In this new study [ 13 ], the authors first observed that expression of BAF60a, but not BAF60b and BAF60c, is significantly reduced in stromal vascular fraction (SVF) of white adipose tissue (WAT) in diabetic mice compared to those from control mice. Further studies have shown that the lower expression of BAF60a in SVFs is mainly due to the downregulation of BAF60a expression in macrophages in response to palmitic acid and TNF-α, or lipopolysaccharide (LPS) treatments, suggesting that the decreased BAF60a expression in macrophages, downstream of lipid-toxicity, inflammatory signaling, and metabolic endotoxemia, may be involved in the pro-inflammatory activation of ATM in adipose tissue during obesity and type 2 diabetes pathogenesis.…”