SUN-491 The Role of Fasting and Glucocorticoid Induced Gene F-box Protein 31 (Fbxo31) in the Regulation of Glucose Homeostasis

Abstract Disclosure: Y. Lee: None. N. Yiv: None. During fasting, the liver plays a crucial role in maintaining glucose homeostasis by stimulating hepatic gluconeogenesis in mammals. Here, we identified Fbxo31 as a fasting-induced gene in the liver that plays a critical role in stimulating gluconeogenesis. Hepatic Fbxo31 knockdown in chow diet fed male C57BL6/J mice results in improved glucose tolerance and reduced gluconeogenesis with affecting insulin sensitivity. Fbxo31 knockdown did not affect the expression of gluconeogenic enzymes such as phosphoenolpyruvate carboxykinase and glucose-6-phosphatase catalytic subunit 1. Instead, Fbxo31 knockdown hepatocytes exhibit decreased mitochondrial activity and ATP production, resulting in impaired energy availability, which limits gluconeogenic capacity. Interestingly, the expression of genes encoded by the mitochondrial genome was significantly lower in Fbxo31 depleted hepatocytes. These results suggest that reducing Fbxo31 expression in hepatocytes decreased mitochondrial biogenesis. Among fasting signals, we found that glucocorticoids but not cAMP increase the expression of Fbxo31 gene in mouse primary hepatocytes and AML12 cells. Two glucocorticoid response elements (GREs) were identified from mouse Fbxo31 gene using artificial reporter genes. One of these GREs (called as pGRE1) is located between -1863 to -1877 from the transcriptional start site whereas another is located between +15618 to +15604 (called as pGRE2). When these two GREs were deleted in the genome of mouse AML12 cells, the ability of glucocorticoids to activate Fbxo31 expression was reduced significantly. Overall, our data indicates that during fasting, glucocorticoids increase the transcription of Fbxo31 gene, which is required to maintain mitochondrial activity and ATP production for the maximal gluconeogenesis. Presentation: Sunday, July 13, 2025