1382-P: Fasting Reveals Tissue-Specific Dysregulation of De Novo Lipogenesis in Diabetic Mice

Introduction and Objective: Diabetes is characterized by systemic metabolic dysfunction driven in part by impaired nutrient utilization, resulting in defective switching between glucose and lipid utilization. While the liver is a canonical site of lipogenesis, the kidney is highly dependent on fatty acid oxidation, making it particularly sensitive to disruptions in systemic lipid metabolism. The objective of this study was to determine whether fasting-induced metabolic responses are tissue-specific and whether fasting appropriately suppresses de novo lipogenesis in the liver and kidney of diabetic mice. Methods: Male B6.BKS(D)-Lepr db/J (db/db, diabetic) and non-diabetic db/+ controls mice were fasted for 2, 4, or 8 hours or remained fed until euthanasia at the end of the dark cycle. Changes in hepatic and renal lipid metabolic regulation were assessed using molecular and metabolic markers. Fractional palmitate synthesis, a marker of DNL, was assessed by administering deuterated water (²H2O) to mice and quantifying deuterium incorporation into palmitate by LC/MS. Results: Despite minimal systemic effects on parameters like body weight and blood glucose, fasting differentially regulated lipid metabolism in liver and kidney. Fasting decreased malonyl-CoA levels in the liver and kidney of db/+ mice, while in db/db mice, levels remained elevated. In contrast to db/+ mice, fasting paradoxically increased fractional palmitate synthesis in both the liver and kidney of db/db mice. This was accompanied by increased hepatic expression of key lipogenic genes (Acc1, Acc2, and Fasn), whereas renal lipogenic gene expression remained largely unchanged relative to fed db/+ mice. In the kidney, fasting reduced SREBP1c protein abundance while increasing p-ACC/t-ACC ratio, indicating persistent post-translational inhibition of ACC despite altered upstream lipogenic signaling. Conclusion: These findings demonstrate tissue-specific defects in metabolic flexibility under fasting conditions, which may contribute to cardiometabolic and renal disease progression. Disclosure A. Dixon: None. S. Chakraborty: None. P. Kayampilly: None. S. Pennathur: None.