Altered expression of O-GlcNAc-modified proteins in a mouse model whose glycemic status is controlled by a low carbohydrate ketogenic diet

Abnormal modification of proteins by O-linked N-acetylglucosamine (O-GlcNAc) is known to be associated with the pathology induced by hyperglycemia. However, the dynamic mechanism of O-GlcNAc modification under hyperglycemic conditions in vivo has not been fully characterized. To understand the mechanism, we established an animal model in which the glycemic status is controlled by the diet. A mutant mouse (ob/ob) which exhibits diet-induced hyperglycemia when fed a regular chow (chow) was used to establish this model; the mice were fed a very low carbohydrate ketogenic diet (KD) to improve hyperglycemia. Using this model, we evaluated the levels of O-GlcNAc-modified proteins in tissues under a hyperglycemic or its improved condition. ELISA and Western blot analyses revealed that altered expression of certain proteins modified by O-GlcNAc were found in the mice tissues, although global O-GlcNAc levels in the tissues remained unaltered by improvement of hyperglycemia. We also found the Akt protein kinase was modified by O-GlcNAc in the liver of ob/ob mice, and the modification levels were decreased by improvement of hyperglycemia. Furthermore, aberrant phosphorylation of Akt was found in the liver of ob/ob mice under hyperglycemic condition. In conclusion, our established mouse model is useful for evaluating the dynamics of O-GlcNAc-modified proteins in tissues associated with glycemic status. This study revealed that the expression level of certain proteins modified by O-GlcNAc is altered when KD improves the hyperglycemia. These proteins could be prospective indexes for nutritional therapy for hyperglycemia-associated diseases, such as diabetes mellitus.