Dissecting the role of aryl hydrocarbon receptor in thermogenic adipose tissue (360G-Wellcome-211080_Z_18_Z)

The obesity crisis has reached epidemic proportions and represents one of the most significant global public health challenges. The recent discovery of energy dissipating brown adipose tissue (BAT) in adult humans has raised the possibility of targeting BAT for the treatment of obesity. Indeed, studies in humans and mice have demonstrated an inverse relationship of BAT activity with obesity and metabolic syndrome. I propose to explore the potential of natural dietary compounds that are sensed by the aryl hydrocarbon receptor (AHR) as novel inducers of BAT activity. I will identify the physiological role of AHR in thermogenesis and utilize conditional gene-targeting approaches to define cell-autonomous functions of AHR in specific cell-types within BAT. Importantly, I will determine whether dietary AHR ligands, such as phytochemicals and microbiota metabolites, can induce the thermogenic activity of BAT, promote energy expenditure and improve metabolic disease in the context of obesity. To elucidate the mechanisms by which AHR modulates thermogenic programs, I will identify its direct transcriptional targets in specific cell-types using ChIP-seq and RNA-seq. Together, these studies will provide important insights into the regulation of thermogenesis by specific dietary factors and may facilitate the use of natural AHR ligands for the treatment of obesity.