THE ACTIVATION OF GLYCOGEN-SYNTHASE BY INSULIN SWITCHES FROM KINASE INHIBITION TO PHOSPHATASE ACTIVATION DURING ADIPOGENESIS IN 3T3-L1 CELLS

The effects of insulin and platelet-derived growth factor (PDGF) on gl ycogen synthase activation were compared in 3T3-L1 fibroblasts and adi pocytes, In the fibroblasts, PDGF elicited a stronger phosphorylation of mitogen-activated protein kinase (MAPK) and AKT than did insulin. B oth agents caused a comparable stimulation of receptor autophosphoryla tion, MAPK, and phosphatidylinositol 3-kinase (PI3-K) activation in th e adipocytes, However, adipogenesis resulted in the uncoupling of PI3- K activation by PDGF from subsequent AKT phosphorylation, The relative contributions of glycogen synthase kinase-3 (GSK-3) inactivation and protein phosphatase-1 (PP1) activation in the regulation of glycogen s ynthase in both cell types were evaluated. Insulin and PDGF caused a s mall increase in glycogen synthase a activity in the fibroblasts, Addi tionally, both agents caused a similar inhibition of GSK-3, while havi ng no effect on PP1 activity. Following differentiation, insulin treat ment resulted in a 5-fold stimulation of glycogen synthase, whereas PD GF was without effect. Both agents caused a comparable inhibition of G SK-3 activity in the adipocytes, whereas only insulin activated PP1. F inally, wortmannin completely blocked the stimulation of PP1 by insuli n in 3T3-L1 adipocytes, indicating that PI3-K inhibition can impinge o n PP1 activation. Cumulatively these results suggest that the weak act ivation of glycogen synthase in 3T3-L1 fibroblasts is mediated by GSK- 3 inactivation, whereas in the more metabolically active adipocytes, t he insulin-specific activation of glycogen synthase is mediated by PP1 activation.