Regulation of Akt signaling by O-GlcNAc in euglycemia

• Published in: American journal of physiology: endocrinology and metabolism Vol. 295; no. 4; pp. E974 - E980
• Main Authors: Soesanto, Yudi A, Luo, Bai, Jones, Deborah, Taylor, Rodrick, Gabrielsen, J. Scott, Parker, Glendon, McClain, Donald A
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.10.2008
• Subjects: Adenoviridae - genetics; Animals; Blood Glucose - physiology; Cell Line; Genetic Vectors - physiology; Liver - metabolism; Mice; Mice, Inbred C57BL; N-Acetylglucosaminyltransferases - physiology; Oncogene Protein v-akt - physiology; Phosphatidylinositol 3-Kinases - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction - physiology; Wheat Germ Agglutinins
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.90366.2008

Division of Endocrinology, University of Utah School of Medicine, Salt Lake City, Utah Submitted 15 April 2008 ; accepted in final form 26 August 2008 The hexosamine biosynthesis pathway (HBP) regulates the posttranslational modification of nuclear and cytoplasmic protein by O -linked N -acetylglucosamine ( O -GlcNAc). Numerous studies have demonstrated that, in hyperglycemic conditions, excessive glucose flux through this pathway contributes to the development of insulin resistance. The role of the HBP in euglycemia, however, remains largely unknown. Here we investigated the effect of O -GlcNAc on hepatic Akt signaling at physiological concentrations of glucose. In HepG2 cells cultured in 5 mM glucose, removal of O -GlcNAc by adenoviral-mediated overexpression of O -GlcNAcase increased Akt activity and phosphorylation. We also observed that Akt was recognized by succinylated wheat germ agglutinin (sWGA), which specifically binds O -GlcNAc. Overexpression of O -GlcNAcase in HepG2 cells reduced the levels of Akt in sWGA precipitates. The increased Akt activity was accompanied by increased phosphorylation of Akt substrates and reduced mRNA for glucose-6-phosphatase and phospho enol pyruvate carboxykinase (PEPCK). The increased Akt activity was not a result of activation of its upstream activator phosphoinositide 3-kinase (PI 3-kinase). Further demonstrating Akt regulation by O -GlcNAc, we found that overexpression of O -GlcNAcase in the livers of euglycemic mice also significantly increased Akt activity, resulting in increased phosphorylation of downstream targets and decreased mRNA for glucose-6-phosphatase. Together, these data suggest that O -GlcNAc regulates Akt signaling in hepatic models under euglycemic conditions. hexosamine; hepatic; gluconeogenic enzymes Address for reprint requests and other correspondence: D. A. McClain, Div. of Endocrinology, Univ. of Utah, 30 N. 2030 E, Salt Lake City, UT 84132 (e-mail: donald.mcclain{at}hsc.utah.edu )