Understanding the transcriptional landscape in immunity and metabolism

Recent decades have heralded a greater appreciation of the intricate crosstalk that exists between immunity and metabolism, significantly expanding therapeutic horizons. A fundamental layer of regulation in immunometabolism is at the transcriptional level, where gene expression is controlled in response to cues from the environment. This thesis sought to further develop our understanding of the transcriptional landscape in immunity and metabolism, combining in vitro and in vivo techniques to study how the inflammatory response and adipose tissue homeostasis are regulated. Using a transgenic mouse model lacking the transcriptional repressor Krüppel-like factor 3 (KLF3), we demonstrated that KLF3 suppresses the inflammatory response following endotoxin challenge. Mice lacking KLF3 exhibited systemic inflammation, characterised by elevated white blood cells, increased circulating inflammatory factors and an abundance of pro inflammatory monocytes. Using ex vivo macrophages grown in culture, we showed that KLF3 bound to and repressed important genes involved in the inflammatory response. We propose this as the mechanism by which KLF3 controls the suppression of inflammation in monocytes and macrophages. Additionally, we demonstrated that Klf3-/- mice exhibit a distinct predisposition towards ‘browning’ of their adipose tissue, where white fat cells assume the features of brown fat, namely heat generation by thermogenesis and increased energy expenditure, producing ‘beige’ fat. Having shown that beige-selective genes are highly up regulated in the adipose tissue of Klf3 /- mice, we then demonstrated that eosinophils are highly abundant in Klf3-/- fat and express factors that are known to elicit browning. We tested our hypothesis that eosinophils drive the beige fat phenotype by transplanting bone marrow from Klf3-/- mice into wild type mice. These experiments showed that transferral of Klf3-/- haematopoietic cells alone protected wild type mice from diet-induced obesity through higher expression of important beige fat markers and elevated eosinophil infiltration. From these findings we propose that KLF3 is responsible for regulating eosinophil derived factors that facilitate the activation of beige fat. Together, these results have delineated a role for KLF3 in the control of inflammation and adipose tissue homeostasis, improving our overall understanding of how these processes are regulated at the transcriptional level