Defining the Role of the Thermogenic Adipocyte in Mediating the Pharmacologic Actions of Fgf21

Obesity is a substantial burden on the US population and rates of obesity are increasing at pandemic scale. Overweight individuals, even at sub-obese levels, enhance the risk of developing complications including type ii diabetes, cardio vascular disease and non-alcoholic fatty liver. Despite this, there remain few effective therapies for the treatment of weight gain and obesity. Fibroblast growth factor 21 (FGF21) is a hormone with pleotropic metabolic actions contributing to discrete, adaptive metabolic pathways. FGF21 has emerged as a potential metabolic therapy as systemic treatment leads to increased glucose tolerance, improved lipid profiles and weight loss. We described FGF21 as the first endocrine agent that induced browning when administered exogenously and demonstrated that FGF21 acts directly to activate brown adipocytes and brown white adipose depots, in vitro. Browning is a process whereby mitochondrial rich, multilocular 'beige' adipocytes appear in white adipose tissue and is associated with improved glucose tolerance and systemic insulin sensitivity. The studies outlined in this grant aim to progress this research by identifying the role of FGF21 signaling in either thermogenic or white adipocytes in vivo. In doing so we will validate and describe two mouse models which negate FGF21 signaling in either thermogenic adipocytes or all adipocytes and will be invaluable for future research on this topic. We believe that thermogenic adipocytes are critical to the glucose lowering and weight loss effects of FGF21 and that discovering the mechanisms that regulate this process will identify novel pathways for therapeutic intervention of metabolic diseases. Relevance: Diabetes and obesity are major problems confronting the US. FGF21 is a factor that improves glucose and weight in obese animals making it an extremely promising agent for treatment of these complications. We hope that interrogation of the biological action of FGF21 will help develop new treatments and strategies for diabetes and obesity management.