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

Details

Serval ID
serval:BIB_9D31A168702D
Type
Article: article from journal or magazin.
Collection
Publications
Title
Enhanced fasting glucose turnover in mice with disrupted action of TUG protein in skeletal muscle.
Journal
Journal of Biological Chemistry
Author(s)
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.
ISSN
1083-351X (Electronic)
ISSN-L
0021-9258
Publication state
Published
Issued date
2013
Peer-reviewed
Oui
Volume
288
Number
28
Pages
20135-20150
Language
english
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. We predicted that transgenic mice would have GLUT4 translocation 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 TUG proteolysis 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.
Keywords
3T3-L1 Cells, Animals, Blood Glucose/metabolism, Carbon Dioxide/metabolism, Carrier Proteins/genetics, Carrier Proteins/metabolism, Deoxyglucose/metabolism, Fasting/blood, Female, Glucose/metabolism, Glucose Transporter Type 4/metabolism, Glycogen/metabolism, Hypoglycemic Agents/blood, Hypoglycemic Agents/pharmacology, Immunoblotting, Insulin/blood, Insulin/pharmacology, Male, Mice, Mice, Inbred C57BL, Mice, Inbred Strains, Mice, Transgenic, Muscle, Skeletal/drug effects, Muscle, Skeletal/metabolism, Oxygen Consumption/drug effects, Protein Transport/drug effects, Proteolysis/drug effects
Pubmed
Web of science
Open Access
Yes
Create date
10/09/2015 13:06
Last modification date
08/05/2019 22:44
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