title: Rab GAPs AS160 and Tbc1d1 play nonredundant roles in the regulation of glucose and energy homeostasis in mice.
abstract: The related Rab GTPase-activating proteins (Rab GAPs) AS160 and Tbc1d1 regulate the trafficking of the glucose transporter GLUT4 that controls glucose uptake in muscle and fat cells and glucose homeostasis. AS160- and Tbc1d1-deficient mice exhibit different adipocyte- and skeletal muscle-specific defects in glucose uptake, GLUT4 expression and trafficking, and glucose homeostasis. A recent study analyzed male mice with simultaneous deletion of AS160 and Tbc1d1 (AS160(-/-)/Tbc1d1(-/-) mice). Herein, we describe abnormalities in male and female AS160(-/-)/Tbc1d1(-/-) mice on another strain background. We confirm the earlier observation that GLUT4 expression and glucose uptake defects of single-knockout mice join in AS160(-/-)/Tbc1d1(-/-) mice to affect all skeletal muscle and adipose tissues. In large mixed fiber-type skeletal muscles, changes in relative basal GLUT4 plasma membrane association in AS160(-/-) and Tbc1d1(-/-) mice also combine in AS160(-/-)/Tbc1d1(-/-) mice. However, we found different glucose uptake abnormalities in isolated skeletal muscles and adipocytes than reported previously, resulting in different interpretations of how AS160 and Tbc1d1 regulate GLUT4 translocation to the cell surface. In support of a larger role for AS160 in glucose homeostasis, in contrast with the previous study, we find similarly impaired glucose and insulin tolerance in AS160(-/-)/Tbc1d1(-/-) and AS160(-/-) mice. However, in vivo glucose uptake abnormalities in AS160(-/-)/Tbc1d1(-/-) skeletal muscles differ from those observed previously in AS160(-/-) mice, indicating additional defects due to Tbc1d1 deletion. Similar to AS160- and Tbc1d1-deficient mice, AS160(-/-)/Tbc1d1(-/-) mice show sex-specific abnormalities in glucose and energy homeostasis. In conclusion, our study supports nonredundant functions for AS160 and Tbc1d1.
authors.affiliation: Department of Medicine-Division of Endocrinology, University of Virginia, Charlottesville Virginia.
authors.forename: Stefan R
authors.initials: SR
authors.lastname: Hargett
authors.affiliation: Department of Medicine-Division of Endocrinology, University of Virginia, Charlottesville Virginia.
authors.forename: Natalie N
authors.initials: NN
authors.lastname: Walker
authors.affiliation: Department of Medicine-Division of Endocrinology, University of Virginia, Charlottesville Virginia srk4b@virginia.edu.
authors.forename: Susanna R
authors.initials: SR
authors.lastname: Keller
mesh_terms: D017667:Adipocytes / Q000378:metabolism*; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D004734:Energy Metabolism / Q000235:genetics*; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics*; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D006706:Homeostasis / Q000235:genetics*; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012737:Sex Factors
chemical_list: D001786:Blood Glucose; D020690:GTPase-Activating Proteins; D051275:Glucose Transporter Type 4; D007328:Insulin; C495693:Slc2a4 protein, mouse; C095906:Tbc1d1 protein, mouse; C505647:Tbc1d4 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose
keywords: Akt substrate of 160 kDa; Rab GTPase-activating proteins; adipocytes; glucose transporter 4; glucose uptake; skeletal muscle