Activation of adipose tissue macrophages (ATMs) contributes to chronic inflammation and insulin resistance in obesity. This study profiled the chromatin accessibility of blood monocytes and ATMs from obese and lean mice using ATAC-seq. Distinct chromatin accessibility was observed between monocytes and ATMs from obese and lean mice. The study identified ETS translocation variant 5 (ETV5) as a critical transcription factor suppressing ATM activation. ETV5 expression was significantly decreased in ATMs from obese mice, leading to macrophage activation and increased IL6 and ER stress. These findings suggest ETV5 as a potential therapeutic target for obesity-related inflammation.