Rab4b is a small GTPase involved in the control of the glucose transporter GLUT4 localization in adipocyte.
BACKGROUND
Endosomal small GTPases of the Rab family, among them Rab4a, play an essential role in the control of the glucose transporter GLUT4 trafficking, which is essential for insulin-mediated glucose uptake. We found that adipocytes also expressed Rab4b and we observed a consistent decrease in the expression of Rab4b mRNA in human and mice adipose tissue in obese diabetic states. These results led us to study this poorly characterized Rab member and its potential role in glucose transport.


RESULTS
We used 3T3-L1 adipocytes to study by imaging approaches the localization of Rab4b and to determine the consequence of its down regulation on glucose uptake and endogenous GLUT4 location. We found that Rab4b was localized in endosomal structures in preadipocytes whereas in adipocytes it was localized in GLUT4 and in VAMP2-positive compartments, and also in endosomal compartments containing the transferrin receptor (TfR). When Rab4b expression was decreased with specific siRNAs by two fold, an extent similar to its decrease in obese diabetic subjects, we observed a small increase (25%) in basal deoxyglucose uptake and a more sustained increase (40%) in presence of submaximal and maximal insulin concentrations. This increase occurred without any change in GLUT4 and GLUT1 expression levels and in the insulin signaling pathways. Concomitantly, GLUT4 but not TfR amounts were increased at the plasma membrane of basal and insulin-stimulated adipocytes. GLUT4 seemed to be targeted towards its non-endosomal sequestration compartment.


CONCLUSIONS
Taken our results together, we conclude that Rab4b is a new important player in the control of GLUT4 trafficking in adipocytes and speculate that difference in its expression in obese diabetic states could act as a compensatory effect to minimize the glucose transport defect in their adipocytes.
Kaddai
Vincent
V
INSERM U895, Centre Méditerranéen de Médecine Moléculaire (C3M), Team 7, Cellular and Molecular Physiopathology of Obesity and Diabetes, Nice, France.
Gonzalez
Teresa
T
Keslair
Frédérique
F
Grémeaux
Thierry
T
Bonnafous
Stéphanie
S
Gugenheim
Jean
J
Tran
Albert
A
Gual
Philippe
P
Le Marchand-Brustel
Yannick
Y
Cormont
Mireille
M
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000201:enzymology*; D000328:Adult; D000818:Animals; D001692:Biological Transport / Q000235:genetics / Q000502:physiology; D005260:Female; D005455:Fluorescent Antibody Technique; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D007328:Insulin; D034741:RNA, Small Interfering; C495678:Slc2a1 protein, mouse; D020691:rab GTP-Binding Proteins; D005947:Glucose