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 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.
Klemm
D J
DJ
Research Service, Veterans Affairs Medical Center and Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80220, USA.
Leitner
J W
JW
Watson
P
P
Nesterova
A
A
Reusch
J E
JE
Goalstone
M L
ML
Draznin
B
B
D017667:Adipocytes / Q000166:cytology* / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004789:Enzyme Activation; D064429:Fatty Acid Synthases / Q000096:biosynthesis; D005347:Fibroblasts / Q000378:metabolism; D051275:Glucose Transporter Type 4; D007328:Insulin / Q000378:metabolism*; D020738:Leptin / Q000096:biosynthesis; D020935:MAP Kinase Signaling System; D051379:Mice; D008954:Models, Biological; D009004:Monosaccharide Transport Proteins / Q000096:biosynthesis; D009124:Muscle Proteins; D010766:Phosphorylation; D017368:Protein Prenylation; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis; D014162:Transfection
D017362:Cyclic AMP Response Element-Binding Protein; D051275:Glucose Transporter Type 4; D007328:Insulin; D020738:Leptin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D011993:Recombinant Fusion Proteins; C495693:Slc2a4 protein, mouse; D014157:Transcription Factors; D064429:Fatty Acid Synthases; D016283:Proto-Oncogene Proteins p21(ras)