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J. Biol. Chem., Vol. 282, Issue 10, 7710-7722, March 9, 2007

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The Glucose Transporter 4-regulating Protein TUG Is Essential for Highly Insulin-responsive Glucose Uptake in 3T3-L1 Adipocytes^*

Chenfei Yu, James Cresswell, Michael G. Löffler, and Jonathan S. Bogan¹

From the Section of Endocrinology and Metabolism, Department of Internal Medicine, and the Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut 06520

Insulin stimulates glucose uptake in fat and muscle by redistributing GLUT4 glucose transporters from intracellular membranes to the cell surface. We previously proposed that, in 3T3-L1 adipocytes, TUG retains GLUT4 within unstimulated cells and insulin mobilizes this retained GLUT4 by stimulating its dissociation from TUG. Yet the relative importance of this action in the overall control of glucose uptake remains uncertain. Here we report that transient, small interfering RNA-mediated depletion of TUG causes GLUT4 translocation and enhances glucose uptake in unstimulated 3T3-L1 adipocytes, similar to insulin. Stable TUG depletion or expression of a dominant negative fragment likewise stimulates GLUT4 redistribution and glucose uptake, and insulin causes a 2-fold further increase. Microscopy shows that TUG governs the accumulation of GLUT4 in perinuclear membranes distinct from endosomes and indicates that it is this pool of GLUT4 that is mobilized by TUG disruption. Interestingly, in addition to translocating GLUT4 and enhancing glucose uptake, TUG disruption appears to accelerate the degradation of GLUT4 in lysosomes. Finally, we find that TUG binds directly and specifically to a large intracellular loop in GLUT4. Together, these findings demonstrate that TUG is required to retain GLUT4 intracellularly in 3T3-L1 adipocytes in the absence of insulin and further implicate the insulin-stimulated dissociation of TUG and GLUT4 as an important action by which insulin stimulates glucose uptake.

Received for publication, November 22, 2006 , and in revised form, December 26, 2006.

^* This work was supported by American Diabetes Association, National Institutes of Health Grant R21 DK070812, the Yale Diabetes Endocrinology Research Center (DERC) Pilot and Feasibility program, the HHMI-Yale Center for Human Genetics and Genomics, and the W. M. Keck Foundation (to J. S. B.). This work used the Center for Cell Imaging and the DERC Cell Biology Core at Yale University School of Medicine. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Section of Endocrinology and Metabolism, Dept. of Internal Medicine, Yale University School of Medicine, 333 Cedar St., P. O. Box 208020, New Haven, CT 06520-8020. Tel.: 203-785-6319; Fax: 203-785-6462; E-mail: jonathan.bogan{at}yale.edu.

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