PROJECT SUMMARY / ABSTRACT The ever-increasing incidence of obesity and type 2 diabetes has led to a concurrent increase in metabolic associated liver diseases such as metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). The presence of these diseases increases the risk of progression to liver cirrhosis and hepatocellular carcinoma. However, there are currently no FDA approved drugs for the treatment of MASLD or MASH. Fibroblast growth factor 21 (FGF21) has shown efficacy in reducing liver fat and fibrosis in pre-clinical models, leading to the development of a promising class of long-lived FGF21 analogs as pharmaceutical treatments for MASH. Recently, our lab demonstrated that FGF21 reduces body weight and increases energy expenditure via action in a genetically defined (Vglut2+) neuronal population. Our new preliminary data suggests that FGF21’s effect on hepatic triglyceride levels and fibrosis, but not cholesterol content, is also mediated through Vglut2+ neurons. Our central hypothesis is that FGF21 reverses MASH by signaling to glutamatergic neurons to increase sympathetic nerve activity to the liver to lower hepatic steatosis and fibrosis, and that FGF21 action on hepatocytes reduces hepatic cholesterol levels This proposal seeks to determine the mechanisms by which FGF21 and its analogs reverse MASH by 1) determining the direct central target of FGF21 that mediates the resolution of MASH, 2) determine how central versus hepatic FGF21 signaling alone or in combination functions to reverse hepatic steatosis, and 3) determine the contribution and mechanisms of FGF21-mediated changes in liver-innervating neurons to regulate liver function. Proposed studies employ a suite of genetic mouse models to selective abolish or add-back β-klotho (the obligate co- receptor for FGF21) from specific cell types with a physiologically relevant dietary MASH model to dissect the contributions of Vglut2+ neurons and hepatocytes in the effects of FGF21. Together, these studies will determine how FGF21 reverses MASH and may reveal novel pathways that could be selectively targeted for future therapeutic strategies.