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Caveolin-1 Loss of Function Accelerates Glucose Transporter 4 and Insulin Receptor Degradation in 3T3-L1 Adipocytes

Departament de Bioquímica i Biologia Molecular (E.G.-M., M.P., A.Z., M.C.), Facultat de Biologia, Universitat de Barcelona, Institute for Research in Biomedicine (IRB Barcelona) (E.G.-M., M.P., A.Z.), and Unitat de Reconeixement Molecular (C.L.-I.), Serveis Cientifico-Tècnics, Universitat de Barcelona, 08028 Barcelona, Spain; and Unitat de Microscòpia Confocal (M.C.), Serveis Cientifico-Tècnics, Universitat de Barcelona, Facultat de Medicina, and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas (CIBERDEM) (A.Z., M.C.), CIBERDEM Asociadas, Mallorca 183, 08036 Barcelona, Spain

Address all correspondence and requests for reprints to: Marta Camps, Departament de Bioquímica i Biologia Molecular, Edifici Annex, Diagonal 645, 08028 Barcelona, Spain. E-mail: martacamps{at}ub.edu.

Caveolae are a specialized type of lipid rafts that are stabilized by oligomers of caveolin protein. Caveolae are particularly enriched in adipocytes. Here we analyzed the effects of caveolin-1 knockdown and caveolae ablation on adipocyte function. To this end, we obtained several multiclonal mouse 3T3-L1 cell lines with a reduced expression of caveolin-1 (95% reduction) by a small interfering RNA approach using lentiviral vectors. Control cell lines were obtained by lentiviral infection with lentiviral vectors encoding appropriate scrambled RNAs. Caveolin-1 knockdown adipocytes showed a drastic reduction in the number of caveolae (95% decrease) and cholera toxin labeling was reorganized in dynamic plasma membrane microdomains. Caveolin-1 depletion caused a specific decrease in glucose transporter 4 (GLUT4) and insulin receptor protein levels. This reduction was not the result of a generalized defect in adipocyte differentiation or altered gene expression but was explained by faster degradation of these proteins. Caveolin-1 knockdown adipocytes showed reductions in insulin-stimulated glucose transport, insulin-triggered GLUT4 recruitment to the cell surface, and insulin receptor activation. In all, our data indicate that caveolin-1 loss of function reduces maximal insulin response through lowered stability and diminished expression of insulin receptors and GLUT4. We propose that caveolin-1/caveolae control insulin action in adipose cells.