GLUCOBAT · In vivo fuel utilization and metabolic regulation by brown adipose tissue

Brown adipose tissue (BAT) has a high capacity to dissipate chemical energy generated from glucose and lipids as heat, a process typically induced by cold exposure, termed thermogenesis. This process has gained significant clinical interest as a strategy against obesity and diabetes because of its potential to expend excess calories as heat. However, our understanding of BAT metabolism on an organismal level is still rudimentary, thus, to advance BAT-targeted therapies, we must first comprehensively define how BAT utilizes its key fuels, such as glucose in vivo. It is widely assumed that the major role of glucose during thermogenesis is to provide energy for the TCA cycle and subsequent uncoupling by the key thermogenic protein in BAT, uncoupling protein 1 (UCP1). However, recent literature reveal that this assumption is oversimplified since glucose has many fates once it enters cells, feeding into additional metabolic pathways beyond the TCA cycle, which are necessary for optimum thermogenesis. In this project, I will use state-of-the-art glucose-tracing technology that utilizes mass spectrometry, combined with classic Cre-Lox and novel CRISPR/Cas9 genome editing strategies to precisely define how thermogenic adipose tissue utilizes glucose in vivo and to delineate the role of solute carrier transporters of the SCL family, including SLC25a1, for glucose utilization and thermogenesis. SLC25a1 delivers the glucose-derived metabolite citrate across the mitochondrial membrane for use in de novo lipid synthesis, a process that are highly regulated in the BAT of cold exposed mice. This project will expand our understanding of how thermogenic adipocytes utilize glucose and will potentially reveal novel therapeutic strategies to enhance thermogenesis. My previous experience with BAT metabolism and mass spectrometry-based isotopic tracing combined with the technological tools of my outgoing host and my host institute ideally poises me to successfully achieve my goals.