RT Journal Article
SR Electronic
T1 INSULIN GROWTH FACTOR I AND ITS RECEPTOR ARE ANTAGONISTIC MODULATORS OF GLUCOSE HANDLING BY ASTROCYTES
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 023556
DO 10.1101/023556
A1 E. Hernandez-Garzón
A1 A.M. Fernandez
A1 A. Perez-Alvarez
A1 S. Mederos
A1 P. Perez-Domper
A1 P. Bascuñana
A1 R.F. de la Rosa
A1 M. Delgado
A1 M.A. Pozo
A1 A. Miranda-Vizuete
A1 D. Guerrero-Gomez
A1 E. Moreno
A1 P.J. McCormick
A1 A. Santi
A1 L. Genis
A1 A. Trueba
A1 C. Garcia-Caceres
A1 M.H. Tschöp
A1 A. Araque
A1 G. Perea
A1 E.D. Martin
A1 I. Torres Aleman
YR 2015
UL http://biorxiv.org/content/early/2015/07/31/023556.abstract
AB Reducing insulin-like growth factor I receptor (IGF-IR) levels or administration of IGF-I show beneficial effects in the brain. We now provide evidence to help resolve this paradox. The unliganded IGF-IR inhibits glucose uptake by astrocytes while its stimulation with IGF-I, in concert with insulin activation of the insulin receptor, produces the opposite effect. In vivo imaging showed that shRNA interference of brain IGF-IR increased glucose uptake by astrocytes while pharmacological blockade of IGF-IR reduced it. Brain 18FGlucose-PET of IGF-IR shRNA injected mice confirmed an inhibitory role of unliganded IGF-IR on glucose uptake, whereas glucose-dependent recovery of neuronal activity in brain slices was blunted by pharmacological blockade of IGF-IR. Mechanistically, we found that the unliganded IGF-IR retains glucose transporter 1 (GLUT1), the main glucose transporter in astrocytes, inside the cell while IGF-I, in cooperation with insulin, synergistically stimulates MAPK/PKD to promote association of IGF-IR with GLUT 1 via Rac1/GIPC1 and increases GLUT1 availability at the cell membrane. These findings identify IGF-I and its receptor as antagonistic modulators of brain glucose uptake.