Obesity can affect quality of life and is also associated with the development of metabolic dysfunction and increased risk of comorbidities such as cardiovascular disease, type 2 diabetes mellitus and cancer. Despite decades of research, the prevalence of obesity continues to rise throughout the world, making the need for novel therapeutic agents of critical importance. The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor and environmental sensor which regulates a variety of homeostatic mechanisms, such as inflammation and metabolism. AHR ligands are highly lipophilic and tend to accumulate in adipose tissue. As a result, AHR ligands have attracted attention as potential therapeutic agents for the treatment of obesity and metabolic disorder. In this project we show that naturally-occurring AHR ligands may offer some protection from obesity and show therapeutic potential in the aid of weight-loss and recovery of metabolic health in obese mice. This study also shows that these effects are unlikely to be mediated through AHR activity in mature adipocytes and suggests adipose stem and precursor cells (ASPCs) and certain immune cells
as the potential targets of AHR ligands in visceral adipose tissue (VAT). We show that ASPCs make up more than half of the AHR-responsive cells in VAT and that AHR pathway activation in these cells invitro induces the expression and release of factors involved in inflammation, tissue remodelling and angiogenesis. We also show that AHR deletion in ASPCs offers some protection from the development of obesity-associated metabolic syndrome. Finally, we show that most AHR-responsive immune cells in mouse VAT are types of cells associated with the maintenance of adipose tissue homeostasis through the dampening of pro-inflammatory signalling. Overall, we suggest that naturally-occurring AHR ligands may have some therapeutic potential in the treatment of obesity and metabolic syndrome and suggest they may be acting through AHR...