title: Enhanced fasting glucose turnover in mice with disrupted action of TUG protein in skeletal muscle.
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.
authors.affiliation: Section of Endocrinology and Metabolism, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520-8020, USA.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Löffler
authors.forename: Andreas L
authors.initials: AL
authors.lastname: Birkenfeld
authors.forename: Katerina M
authors.initials: KM
authors.lastname: Philbrick
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Belman
authors.forename: Estifanos N
authors.initials: EN
authors.lastname: Habtemichael
authors.forename: Carmen J
authors.initials: CJ
authors.lastname: Booth
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Castorena
authors.forename: Cheol Soo
authors.initials: CS
authors.lastname: Choi
authors.forename: Francois R
authors.initials: FR
authors.lastname: Jornayvaz
authors.forename: Brandon M
authors.initials: BM
authors.lastname: Gassaway
authors.forename: Hui-Young
authors.initials: HY
authors.lastname: Lee
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Cartee
authors.forename: William
authors.initials: W
authors.lastname: Philbrick
authors.forename: Gerald I
authors.initials: GI
authors.lastname: Shulman
authors.forename: Varman T
authors.initials: VT
authors.lastname: Samuel
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Bogan
mesh_terms: D041721:3T3-L1 Cells; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002245:Carbon Dioxide / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D003847:Deoxyglucose / Q000378:metabolism; D005215:Fasting / Q000097:blood; D005260:Female; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D006003:Glycogen / Q000378:metabolism; D000077614:Golgi Matrix Proteins; D007004:Hypoglycemic Agents / Q000097:blood / Q000494:pharmacology; D015151:Immunoblotting; D007328:Insulin / Q000097:blood / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C478539:Aspscr1 protein, mouse; D001786:Blood Glucose; D002352:Carrier Proteins; D051275:Glucose Transporter Type 4; D000077614:Golgi Matrix Proteins; C435484:Gopc protein, mouse; D007004:Hypoglycemic Agents; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D002245:Carbon Dioxide; D006003:Glycogen; D003847:Deoxyglucose; D005947:Glucose
keywords: Diabetes; Energy Metabolism; Glucose Metabolism; Glucose Transport; Glut4; Insulin; Insulin Resistance; Membrane Trafficking; Nutrition; Transgenic Mice