PROPOSAL SUMMARY (ABSTRACT) Research Background and Impact: Non-alcoholic fatty liver disease (NAFLD) is the leading cause of liver disease worldwide and leads to early mortality. Because adolescent NAFLD largely presents as asymptomatic, research should focus on adolescents at particularly high-risk for disease, which includes those with extreme obesity and/or polycystic ovary syndrome (PCOS). The only approved treatment for NAFLD is lifestyle intervention, yet feasibility and long-term maintenance is extremely challenging in youth. Surgical and pharmacological obesity interventions have been explored for treatment of NAFLD in adults, with emerging data suggesting vertical sleeve gastrectomy (VSG) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) improve NAFLD. Data from both adults and pre-clinical rodent models suggest that aberrant hepatic mitochondria and hepatic energy flux are critically involved in the pathogenesis of NAFLD, but whether these underlying mechanisms are responsive to therapy remains unknown. Further, these surgical and pharmacological treatments have not been studied in youth. Therefore, the goal of this proposal is to use a translational research approach to evaluate hepatic fat, metabolism, and mitochondrial function before and after surgical (VSG) and pharmacological (GLP1-RA) interventions in youth (and mice for VSG) at high risk for NAFLD due to obesity and/or PCOS. We will assess hepatic fat via liver MRI, use oral glycerol isotope tracers and serum and hepatic isotopomer analysis via NMR to quantify and describe dynamics of hepatic metabolism, and measure mitochondria function via high resolution respirometry of fresh liver tissue and non-invasive 31Phos-MRS for intrahepatic phosphate concentrations. These studies will provide excellent mechanistic insight into emerging therapeutic options and will improve the immediate and long-term health of at-risk youth. Candidate and Training: My long-term career goal is to be an independent, academic scientist with a translational research program focused on understanding the molecular signaling events underlying the pathophysiology of metabolic disease, with a focus on NAFLD. I have extensive experience in pre-clinical mouse models but to become an independent translational investigator, I need training in clinical trial research. These proposed studies will expand my research capabilities to include clinical trial implementation, stable isotope tracers, and 31Phos MRS. I will also expand my pre-clinical and bench science research techniques to include mouse survival surgery and lipidomics. The opportunities provided by my institution (University of Colorado Anschutz Medical Campus) and by my mentorship team (Drs. Melanie Cree-Green, Darleen Sandoval, Jane Reusch, Craig Malloy, Bryan Bergman, Laura Pyle) will provide excellent training in integrative hepatic metabolism.