Effect of Fasting on De Novo Lipogenesis on the Liver and Kidney of Diabetic Mice

Background: De novo lipogenesis (DNL) is a tightly regulated process that converts excess nutrients into fatty acids. Although DNL is well studied in the liver, the kidney also contributes significantly to this process under physiological conditions. In diabetes, dysregulated DNL promotes systemic and tissue-specific lipid accumulation driven by nutrient excess and/or insulin resistance, contributing to end-organ damage. While fasting typically suppresses lipogenesis, its effects on hepatic and renal DNL in diabetes remain unclear. Methods: To explore the acute effects of fasting on DNL, we examined transcriptional and post-transcriptional changes after 2- and 6-hour fasting periods in db/db mice, a well-established model of type 2 diabetes that exhibits features of both diabetic kidney disease (DKD) and metabolic associated steatotic liver disease (MASLD). Non-diabetic db/+ controls and db/db mice were maintained in either a fed state or fasted for 2 or 6 hours. We analyzed key lipogenic markers, including sterol regulatory element-binding protein 1 (SREBP1), fatty acid synthase (FASN), and acetyl-CoA carboxylase (ACC), at both the mRNA and protein levels in the liver and kidney. ACC activity was assessed by measuring phosphorylated ACC (p-ACC), the inactive form of ACC, and malonyl-CoA, the metabolic product of active ACC. Results: In the fed state, p-ACC levels were lower in the kidney and higher in the liver of db/db mice compared to controls. Fasting decreased p-ACC in db/+ mice but not db/db mice. This was associated with elevated malonyl-CoA levels in db/db mice that were unaffected by fasting in either tissue. In the liver, FASN mRNA and protein levels were elevated in db/db mice under fed conditions, remained high after 2 hours of fasting, and decreased only after 6 hours of fasting. In contrast, in the kidney, FASN mRNA showed no differences, but protein levels were lower in db/db mice, consistent with reduced SREBP1. Additionally, ATP citrate lyase (ACLY), which converts citrate to acetyl-CoA and oxaloacetate, was elevated in both the liver and kidney of db/db mice but decreased after fasting. Conclusion: These findings suggest that fasting differentially alters lipogenesis in the liver and kidney of diabetic mice, with potential implications for the progression of DKD and MASLD. Funding: NIDDK Support, Private Foundation Support