Abstract
Insulin is a potent adipogenic hormone that triggers an induction of a series of transcription factors governing differentiation of pre-adipocytes into mature adipocytes. However, the exact link between the insulin signaling cascade and the intrinsic cascade of adipogenesis remains incompletely understood. Herein we demonstrate that inhibition of prenylation of p21ras and Rho-A arrests insulin-stimulated adipogenesis. Inhibition of farnesylation of p21ras also blocked the ability of insulin to activate mitogen-activated protein (MAP) kinase and cyclic AMP response element-binding (CREB) protein. Expression of two structurally different inducible constitutively active CREB constructs rescued insulin-stimulated adipocyte differentiation from the inhibitory influence of prenylation inhibitors. Constitutively active CREB constructs induced expression of PPARgamma2, 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, triggers the intrinsic cascade of adipogenesis.
Highlights
From the Research Service, Veterans Affairs Medical Center and Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80220
We examined the effect of the prenylation inhibitors on the expression of the transcription proteins participating in the pre-adipocyte differentiation process
FTase inhibitor (FTI) and GGTase I inhibitor-286 (GGTI), blocked the expression of C/EBP and C/EBP␣ (Fig. 2), indicating that farnesylation and geranylgeranylation are necessary for the induction of C/EBP and C/EBP␣ expression
Summary
Vol 276, No 30, Issue of July 27, pp. 28430 –28435, 2001 Printed in U.S.A. ACTIVATION OF CREB RESCUES ADIPOGENESIS FROM THE ARREST CAUSED BY INHIBITION OF PRENYLATION*. Expression of two structurally different inducible constitutively active CREB constructs rescued insulin-stimulated adipocyte differentiation from the inhibitory influence of prenylation inhibitors. Active CREB constructs induced expression of PPAR␥2, 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, triggers the intrinsic cascade of adipogenesis. Availability of prenylated p21ras is required for the activation of MAP kinase [22, 23] The latter has been shown to phosphorylate and activate cyclic AMP response element binding (CREB) protein that is critically important for adipogenesis [24]. We examined whether inhibition of prenylation of p21ras and Rho-A can affect insulin-induced 3T3-L1 adipocyte differentiation
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