TY - JOUR T1 - INSULIN GROWTH FACTOR I AND ITS RECEPTOR ARE ANTAGONISTIC MODULATORS OF GLUCOSE HANDLING BY ASTROCYTES JF - bioRxiv DO - 10.1101/023556 SP - 023556 AU - E. Hernandez-Garzón AU - A.M. Fernandez AU - A. Perez-Alvarez AU - S. Mederos AU - P. Perez-Domper AU - P. Bascuñana AU - R.F. de la Rosa AU - M. Delgado AU - M.A. Pozo AU - A. Miranda-Vizuete AU - D. Guerrero-Gomez AU - E. Moreno AU - P.J. McCormick AU - A. Santi AU - L. Genis AU - A. Trueba AU - C. Garcia-Caceres AU - M.H. Tschöp AU - A. Araque AU - G. Perea AU - E.D. Martin AU - I. Torres Aleman Y1 - 2015/01/01 UR - http://biorxiv.org/content/early/2015/07/31/023556.abstract N2 - 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. ER -