Protein O-GlcNAcylation Is Essential for the Maintenance of Renal Energy Homeostasis and Function via Lipolysis during Fasting and Diabetes

Significance Statement Lipolysis is of particular importance for energy homeostasis in proximal tubular epithelial cells (PTECs), and it is dysregulated during the pathogenesis of diabetic kidney disease. In knockout mice lacking O-GlcNAc transferase specifically in PTECs, the authors demonstrated that protein O-GlcNAcylation, an intracellular nutrient sensing system, is essential for renal lipolysis and ATP production during prolonged fasting. They also found evidence that this novel regulatory mechanism of renal lipolysis involves farnesoid X receptor–dependent upregulation of carboxylesterase-1 and that deficiency of renal protein O-GlcNAcylation exacerbates tubulopathy in diabetic kidney disease. These findings suggest that manipulation of the renal lipolytic mechanism to overcome the effects of prolonged fasting might represent a novel therapeutic approach for diabetic kidney disease. Background Energy metabolism in proximal tubular epithelial cells (PTECs) is unique, because ATP production largely depends on lipolysis in both the fed and fasting states. Furthermore, disruption of renal lipolysis is involved in the pathogenesis of diabetic tubulopathy. Emerging evidence suggests that protein O-GlcNAcylation, an intracellular nutrient-sensing system, may regulate a number of metabolic pathways according to changes in nutritional status. Although O-GlcNAcylation in PTECs has been demonstrated experimentally, its precise role in lipolysis in PTECs is unclear. Methods To investigate the mechanism of renal lipolysis in PTECs—specifically, the role played by protein O-GlcNAcylation—we generated mice with PTECs deficient in O-GlcNAc transferase (Ogt). We analyzed their renal phenotypes during ad libitum feeding, after prolonged fasting, and after mice were fed a high-fat diet for 16 weeks to induce obesity and diabetes. Results Although PTEC-specific Ogt-deficient mice lacked a marked renal phenotype during ad libitum feeding, after fasting 48 hours, they developed Fanconi syndrome–like abnormalities, PTEC apoptosis, and lower rates of renal lipolysis and ATP production. Proteomic analysis suggested that farnesoid X receptor–dependent upregulation of carboxylesterase-1 is involved in O-GlcNAcylation’s regulation of lipolysis in fasted PTECs. PTEC-specific Ogt-deficient mice with diabetes induced by a high-fat diet developed severe tubular cell damage and enhanced lipotoxicity. Conclusions Protein O-GlcNAcylation is essential for renal lipolysis during prolonged fasting and offers PTECs significant protection against lipotoxicity in diabetes.