Inhibition of glycogen-synthase kinase 3 stimulates glycogen synthase and glucose transport by distinct mechanisms in 3T3-L1 adipocytes

The role of glycogen-synthase kinase 3 (GSK3) in insulin-stimulated glucose transport and glycogen synthase activation was investigated in 3T3-L1 adip ocytes, GSK3 protein was clearly present in adipocytes and was found to be more abundant than in muscle and liver cell lines. The selective GSK3 inhib itor, LiCl, stimulated glucose transport and glycogen synthase activity (20 and 65%, respectively, of the maximal (1 mu M) insulin response) and poten tiated the responses to a submaximal concentration (1 nM) of insulin. LiCl- and insulin-stimulated glucose transport were abolished by the phosphatidy linositol 3-kinase (PIS-kinase) inhibitor, wortmannin; however, LiCl stimul ation of glycogen synthase was not. In contrast to the rapid stimulation of glucose transport by insulin, transport stimulated by LiCl increased gradu ally over 3-5 h reaching 40% of the maximal insulin-stimulated level. Both LiCl- and insulin-stimulated glycogen synthase activity were maximal at 25 min. However, insulin-stimulated glycogen synthase activity returned to bas al after 2 h, coincident with reactivation of GSK3, After a 2-h exposure to insulin, glycogen synthase was refractory to restimulation with insulin, i ndicating selective desensitization of this pathway. However, LiCl could pa rtially stimulate glycogen synthase in desensitized cells. Furthermore, coi ncubation with LiCl during the 2 h exposure to insulin completely blocked d esensitization of glycogen synthase activity. In summary, inhibition of GSK 3 by LiCl: 1) stimulated glycogen synthase activity directly and independen tly of PI3-kinase, 2) stimulated glucose transport at a point upstream of P I3-kinase, 3) stimulated glycogen synthase activity in desensitized cells, and 4) prevented desensitization of glycogen synthase due to chronic insuli n treatment. These data are consistent with GSK3 playing a central role in the regulation of glycogen synthase activity and a contributing factor in t he regulation of glucose transport in 3T3-L1 adipocytes.