Abstract
Activation of adipose tissue macrophages (ATMs) contributes to chronic inflammation and insulin resistance in obesity. However, the transcriptional regulatory machinery involved in ATM activation during the development of obesity is not fully understood. Here, we profiled the chromatin accessibility of blood monocytes and ATMs from obese and lean mice using assay for transposase-accessible chromatin sequencing (ATAC-seq). We found that monocytes and ATMs from obese and lean mice exhibited distinct chromatin accessibility status. There are distinct regulatory elements that are specifically associated with monocyte or ATM activation in obesity. We also discovered several transcription factors that may regulate monocyte and ATM activation in obese mice, specifically a predicted transcription factor named ETS translocation variant 5 (ETV5). The expression of ETV5 was significantly decreased in ATMs from obese mice and its downregulation was mediated by palmitate stimulation. The decrease in ETV5 expression resulted in macrophage activation. Our results also indicate that ETV5 suppresses endoplasmic reticulum (ER) stress and Il6 expression in macrophages. Our work delineates the changes in chromatin accessibility in monocytes and ATMs during obesity, and identifies ETV5 as a critical transcription factor suppressing ATM activation, suggesting its potential use as a therapeutic target in obesity-related chronic inflammation.
Highlights
Obesity induces a low-grade inflammatory state that contributes to insulin resistance, diabetes, and metabolic syndrome [1, 2]
adipose tissue macrophages (ATMs) activation To explore the transcription factor (TF) involved in the regulation of monocyte and macrophage activation during obesity, we predicted TFs that can bind to accessible sites in the C1, C4, C5, C6, and C7 regions (Fig. 2A)
We identified several TFs that are enriched in different regulatory element clusters, which may participate in monocyte activation (C1), monocyte to macrophage differentiation (C4 and C5), and macrophage activation (C6 and C7) in obesity
Summary
Obesity induces a low-grade inflammatory state that contributes to insulin resistance, diabetes, and metabolic syndrome [1, 2]. Chronic inflammation in adipose tissue is characterized by increased infiltration and activation of innate and adaptive immune cells [3, 4]. Among these immune cells, adipose tissue macrophages (ATMs) are the most abundant cell type, and it has been suggested that they play critical roles in obesityassociated inflammation [5, 6]. Monocytes and macrophages are recruited from the blood and other tissues by hypertrophic adipocytes through the monocyte chemotactic protein-1 (MCP-1)/C-C chemokine receptor type 2 (CCR2) signaling pathway upon the accumulation of extracellular free fatty acids (FFAs) in adipose tissue [9, 10]. In adipose tissue from obese mice, ATMs are the main source of inflammatory mediators, such as IL-6 and tumor necrosis factor-α (TNF-α), which can induce insulin resistance by inhibiting the tyrosine phosphorylation of insulin receptor substrate (IRS) [5, 6, 13]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
