Enhanced fasting glucose turnover in mice with disrupted action of TUG protein in skeletal muscle

Michael G. Löffler, Andreas L. Birkenfeld, Katerina M. Philbrick, Jonathan P. Belman, Estifanos N. Habtemichael, Carmen J. Booth, Carlos M. Castorena, Cheol Soo Choi, Francois R. Jornayvaz, Brandon M. Gassaway, Hui Young Lee, Gregory D. Cartee, William Philbrick, Gerald I. Shulman, Varman T. Samuel, Jonathan S. Bogan

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Abstract

Insulin stimulates glucose uptake in 3T3-L1 adipocytes in part by causing endoproteolytic cleavage of TUG (tether containing a ubiquitin regulatory X (UBX) domain for glucose transporter 4 (GLUT4)). Cleavage liberates intracellularly sequestered GLUT4 glucose transporters for translocation to the cell surface. To test the role of this regulation in muscle, we used mice with muscle-specific transgenic expression of a truncated TUG fragment, UBX-Cter. This fragment causes GLUT4 translocation in unstimulated 3T3-L1 adipocytes.Wepredicted that transgenic mice would haveGLUT4translocation in muscle during fasting. UBX-Cter expression caused depletion of PIST (PDZ domain protein interacting specifically with TC10), which transmits an insulin signal to TUG. Whereas insulin stimulated TUGproteolysis in control muscles, proteolysis was constitutive in transgenic muscles. Fasting transgenic mice had decreased plasma glucose and insulin concentrations compared with controls. Whole-body glucose turnover was increased during fasting but not during hyperinsulinemic clamp studies. In muscles with the greatest UBX-Cter expression, 2-deoxyglucose uptake during fasting was similar to that in control muscles during hyperinsulinemic clamp studies. Fasting transgenic mice had increased muscle glycogen, and GLUT4 targeting to T-tubule fractions was increased 5.7-fold. Whole-body oxygen consumption (VO2), carbon dioxide production (VCO2), and energy expenditure were increased by 12-13%. After 3 weeks on a high fat diet, the decreased fasting plasma glucose in transgenic mice compared with controls was more marked, and increased glucose turnover was not observed; the transgenic mice continued to have an increased metabolic rate. We conclude that insulin stimulates TUG proteolysis to translocate GLUT4 in muscle, that this pathway impacts systemic glucose homeostasis and energy metabolism, and that the effects of activating this pathway are maintained during high fat diet-induced insulin resistance in mice.

Original languageEnglish (US)
Pages (from-to)20135-20150
Number of pages16
JournalJournal of Biological Chemistry
Volume288
Issue number28
DOIs
StatePublished - Jul 12 2013

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Löffler, M. G., Birkenfeld, A. L., Philbrick, K. M., Belman, J. P., Habtemichael, E. N., Booth, C. J., Castorena, C. M., Choi, C. S., Jornayvaz, F. R., Gassaway, B. M., Lee, H. Y., Cartee, G. D., Philbrick, W., Shulman, G. I., Samuel, V. T., & Bogan, J. S. (2013). Enhanced fasting glucose turnover in mice with disrupted action of TUG protein in skeletal muscle. Journal of Biological Chemistry, 288(28), 20135-20150. https://doi.org/10.1074/jbc.M113.458075