Insulin-induced adipocyte differentiation - Activation of CREB rescues adipogenesis from the arrest caused by inhibition of prenylation

Insulin is a potent adipogenic hormone that triggers an induction of a seri es of transcription factors governing differentiation of pre-adipocytes int o mature adipocytes. However, the exact link between the insulin signaling cascade and the intrinsic cascade of adipogenesis remains incompletely unde rstood. Herein we demonstrate that inhibition of prenylation of p21(ras) an d Rho-A arrests insulin-stimulated adipogenesis. Inhibition of farnesylatio n of p21(ras) also blocked the ability of insulin to activate mitogen-activ ated protein (MAP) kinase and cyclic AMP response element-binding (CREB) pr otein. Expression of two structurally different inducible constitutively ac tive CREB constructs rescued insulin-stimulated adipocyte differentiation f rom the inhibitory influence of prenylation inhibitors. Constitutively acti ve CREB constructs induced expression of PPAR gamma2, fatty acid synthase, GLUT-4, and leptin both in control and prenylation inhibitors-treated cells . It appears that insulin stimulated prenylation of the Ras family GTPases assures normal phosphorylation and activation of CREB that, in turn, trigge rs the intrinsic cascade of adipogenesis.