Adipose tissue eosinophils regulate the activation of thermogenic beige adipocytes, which could be harnessed to reduce obesity. Despite being destructive in diseases such as asthma, eosinophils have a protective role in the adipose tissue. Here we asked critical questions to enable translation to anti-obesity therapies: which genetic regulators switch eosinophils from being destructive to protective? And, how do adipose eosinophils play this protective role in metabolic health?
We previously performed the first bulk RNA-seq of adipose-resident eosinophils. We found that adipose eosinophils are transcriptionally distinct from circulating eosinophils and identified Activator Protein 1 (AP-1) proteins as key transcriptional regulators of the adipose eosinophil transcriptomic profile.
Next, we took a functional genomics approach, using CRISPR/Cas9 genome editing to individually knock-out the identified transcription factors in human eosinophilic EoL-1 cells. RNA-seq and Chromatin Immunoprecipitation (ChIP) analyses revealed AP-1 member protein Activating Transcription Factor 3 (ATF3) as a key regulator of adipose eosinophil gene expression.
We found that IL-5 transgenic mice, with elevated numbers of adipose eosinophils, had higher vascular endothelial growth factor A (VEGFA) levels and enhanced adipose tissue vascularisation. VEGFA is critical for adipose tissue angiogenesis, a process essential for maintaining tissue health and promoting the conversion of adipose tissue to thermogenic beige fat. We showed that VEGFA expression is regulated by ATF3 in adipose tissue eosinophils. Deletion of ATF3 in eosinophils in cell culture models and in mice led to reduced VEGFA expression, increased pro-inflammatory gene expression, and impaired adipose tissue vascularisation and thermogenesis.
These findings establish ATF3 as a key regulator of adipose eosinophil function that we propose drives the switch from destructive to protective adipose eosinophil phenotypes. This study also reveals a previously unrecognised mechanism by which eosinophils can support metabolic health through driving angiogenesis. This work therefore provides new insights into potential therapeutic targets for obesity.