Abstract
BackgroundEndosomal 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.Methodology/Principal FindingsWe 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.Conclusion/SignificanceTaken 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.
Highlights
Glucose transporter 4 (GLUT4) plays an important role in glucose homeostasis
Modifications of some Rabs of the endocytic recycling pathway in diabetes Because defects in GLUT4 trafficking could participate in insulin-resistance [3,4], we determined whether the expression of Rabs involved in endocytic recycling was modified in adipose tissues from obese diabetic mice and humans
Because the total GLUT4 amount was unchanged in lysates, the results suggest that in normal condition nearly half of intracellular GLUT4 were outside the transferrin receptor (TfR) containing endosomes and, more importantly, that GLUT4 appears to be mainly excluded from endosomes when Rab4b is down regulated
Summary
Glucose transporter 4 (GLUT4) plays an important role in glucose homeostasis. It is mainly expressed in cells that exhibit insulin-regulated glucose uptake, i.e adipocytes, skeletal muscle cells and cardiomyocytes. The intracellular trafficking of GLUT4 is a major determinant of the acute regulation of glucose transport in these cells. The machinery that regulates GLUT4 trafficking could be altered in insulin-responsive cells of diabetic patients. 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 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
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