Tissue-specific expression and regulation of GSK-3 in human skeletal muscle and adipose tissue

1 Veterans Affairs San Diego Healthcare System; and 2 Department of Medicine, University of California, San Diego, California Submitted 12 April 2006 ; accepted in final form 30 May 2006 Glycogen synthase kinase-3 (GSK-3) is a ubiquitous kinase implicated in both insulin action and adipogenesis. To determine how these multiple roles may relate to insulin resistance, we studied the regulation of GSK-3 protein expression and phosphorylation in skeletal muscle and isolated adipocytes from nonobese healthy control (HC), obese control (OC), and obese type 2 diabetic (OT2D) subjects. At baseline there were no differences in the GSK-3 protein expression in adipocytes. OC subjects underwent a 6-mo caloric restriction resulting in a 7% decrease in body mass index (BMI) and a 21% improvement in insulin-stimulated whole body glucose disposal rate (GDR). GSK-3 and GSK-3 expression decreased in adipocytes ( P < 0.05), whereas GSK-3 protein expression increased in skeletal muscle ( P < 0.05). OT2D subjects were treated with troglitazone or metformin for 3–4 mo. After troglitazone treatment GDR improved ( P < 0.05) despite an increase in BMI ( P < 0.05), whereas metformin had no significant effect on GDR. There was no significant change in GSK-3 expression in adipocytes following troglitazone, whereas both GSK-3 and - were decreased in skeletal muscle ( P < 0.05). Metformin treatment had no significant impact on GSK-3 protein expression in either adipocytes or skeletal muscle. Neither treatment influenced GSK-3 serine phosphorylation in skeletal muscle or adipocytes. These results suggest that there is tissue specificity for the regulation of GSK-3 in humans. In skeletal muscle GSK-3 plays a role in control of metabolism and insulin action, whereas the function in adipose tissue is less clear. glycogen synthase kinase-3; weight loss; thiazolidinedione; type 2 diabetes mellitus; metabolism; insulin action Address for reprint requests and other correspondence: R. R. Henry, VA San Diego Healthcare System, 3350 La Jolla Village Drive (9111G), San Diego, CA 92161 (e-mail: rrhenry{at}vapop.ucsd.edu )