TY - JOUR T1 - Long-Term Treatment with Novel Glycogen Synthase Kinase-3 Inhibitor Improves Glucose Homeostasis in ob/ob Mice: Molecular Characterization in Liver and Muscle JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 17 LP - 24 DO - 10.1124/jpet.105.090266 VL - 316 IS - 1 AU - Oksana Kaidanovich-Beilin AU - Hagit Eldar-Finkelman Y1 - 2006/01/01 UR - http://jpet.aspetjournals.org/content/316/1/17.abstract N2 - Glycogen synthase kinase-3 (GSK-3) is critically involved in insulin signaling, and its selective inhibition may present a new therapy for treatment of insulin resistance and type 2 diabetes. The current studies were designed to examine the impact of long-term in vivo inhibition of GSK-3 and its effects in the specific tissues. ob/ob mice were treated daily with one dose (400 nmol, i.p.) of a selective GSK-3 peptide inhibitor, L803-mts, for 3 weeks. Treatment with L803-mts reduced blood glucose levels, improved glucose tolerance, and prevented elevation of hyperglycemia with age. However, L803-mts did not affect either body weight or food consumption and was not toxic, as judged by histopathology and blood chemistry analyses. Consistent with these results, L803-mts suppressed mRNA levels of hepatic phosphoenolpyruvate carboxykinase (PEPCK) (50%) and increased hepatic glycogen content by 50%. On the other hand, L803-mts did not affect glucose 6-phosphate (G-6-P) phosphatase (G-6-Pase) mRNA levels or its enzymatic activity in the liver. Investigation for possible mechanisms responsible for PEPCK suppression indicated that phosphorylation of cAMP-responsive element transcription factor (CREB) at Ser133 was reduced remarkably by L803-mts, which was also associated with reduced phosphorylation at Ser129 and no change in total CREB. This suggested that PEPCK was suppressed by GSK-3 inhibition-mediated inactivation of CREB. In skeletal muscle, treatment with L803-mts led both to up-regulation in GLUT4 expression and to a 20% increase in glycogen content. Our studies show that long-term treatment with GSK-3 inhibitor improves glucose homeostasis in ob/ob mice and demonstrates a novel role of GSK-3 in regulating hepatic CREB activity and expression of muscle GLUT4. The American Society for Pharmacology and Experimental Therapeutics ER -