Adipose eosinophils, along with other adipose immune cells, regulate the activation of beige adipocytes. Beige adipocytes residing within white adipose tissue perform thermogenesis, and therefore may be able to be harnessed to reduce obesity by burning rather than storing excess fuels. In our research we seek to better understand adipose eosinophils such that their thermogenic therapeutic potential may be unlocked.
Using a genetic mouse model, we uncovered gene regulatory mechanisms in mice that allowed adipose eosinophils to secrete molecules important for beige fat activation and prevention of weight gain. We termed these factors eosinokines.
We next explored whether adipose eosinophils are a specialised subtype of eosinophils and whether that might account for their protective rather than destructive roles. Using a highly optimised RNA extraction protocol, we performed the first bulk RNA-seq of adipose eosinophils from mice. We found that adipose eosinophils are transcriptionally distinct from blood eosinophils, with more than a thousand differentially expressed genes.
Using this data, we sought to identify transcription factors that might drive adipose eosinophils to adopt their specialised identity and identified ATF3 as one candidate. We knocked ATF3 out in a human eosinophilic cell line and saw increased pro-inflammatory gene expression, suggesting that ATF3 may reprogram eosinophils to become homeostatic upon migrating into adipose tissue. We also discovered that eosinophils lacking ATF3 have a lower expression of angiogenic genes, suggesting that ATF3 normally activates angiogenesis in eosinophils. Using a genetic mouse model with elevated numbers of eosinophils and an eosinophil-specific ATF3 knockout mouse model, we showed that ATF3 contributes to promotion of VEGFA expression and angiogenesis to support eosinophil functional specialisation within adipose tissue.
We are now leveraging our understanding of adipose eosinophil biology and our datasets to prioritise candidate eosinokines that drive thermogenesis for the development of new therapeutic targets for obesity.