Glycogen Synthase Kinase 3α-Specific Regulation of Murine Hepatic Glycogen Metabolism

SUMMARY Glycogen synthase kinase 3 comprises two isoforms (GSK-3a and GSK-3b) that are implicated in type II diabetes, neurodegeneration, and cancer. GSK-3 activity is elevated in human and rodent models of diabetes, and various GSK-3 inhibitors improve glucose tolerance and insulin sensitivity in rodent models of obesity and diabetes. Here, we report the generation of mice lacking GSK-3a. Unlike GSK-3b mutants, which die before birth, GSK-3aknockout (GSK-3a KO) animals are viable but display enhanced glucose and insulin sensitivity accompanied by reduced fat mass. Fasted and glucose-stimulated hepatic glycogen content was enhanced in GSK-3a KO mice, whereas muscle glycogen was unaltered. Insulin-stimulated protein kinase B (PKB/Akt) and GSK-3b phosphorylation was higher in GSK3a KO livers compared to wild-type littermates, and IRS-1 expression was markedly increased. We conclude that GSK-3 isoforms exhibit tissue-specific physiological functions and that GSK-3a KO mice are insulin sensitive, reinforcing the potential of GSK-3 as a therapeutic target for type II diabetes.