title: Loss of HIF-1α impairs GLUT4 translocation and glucose uptake by the skeletal muscle cells.
abstract: Defects in glucose uptake by the skeletal muscle cause diseases linked to metabolic disturbance such as type 2 diabetes. The molecular mechanism determining glucose disposal in the skeletal muscle in response to cellular stimuli including insulin, however, remains largely unknown. The hypoxia-inducible factor-1α (HIF-1α) is a transcription factor operating in the cellular adaptive response to hypoxic conditions. Recent studies have uncovered pleiotropic actions of HIF-1α in the homeostatic response to various cellular stimuli, including insulin under normoxic conditions. Thus we hypothesized HIF-1α is involved in the regulation of glucose metabolism stimulated by insulin in the skeletal muscle. To this end, we generated C2C12 myocytes in which HIF-1α is knocked down by short-hairpin RNA and examined the intracellular signaling cascade and glucose uptake subsequent to insulin stimulation. Knockdown of HIF-1α expression in the skeletal muscle cells resulted in abrogation of insulin-stimulated glucose uptake associated with impaired mobilization of glucose transporter 4 (GLUT4) to the plasma membrane. Such defect seemed to be caused by reduced phosphorylation of the protein kinase B substrate of 160 kDa (AS160). AS160 phosphorylation and GLUT4 translocation by AMP-activated protein kinase activation were abrogated as well. In addition, expression of the constitutively active mutant of HIF-1α (CA-HIF-1α) or upregulation of endogenous HIF-1α in C2C12 cells shows AS160 phosphorylation comparable to the insulin-stimulated level even in the absence of insulin. Accordingly GLUT4 translocation was increased in the cells expressing CA-HIF1α. Taken together, HIF-1α is a determinant for GLUT4-mediated glucose uptake in the skeletal muscle cells thus as a possible target to alleviate impaired glucose metabolism in, e.g., type 2 diabetes.
authors.affiliation: Division of Metabolism and Biosystemic Science, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Hidemitsu
authors.initials: H
authors.lastname: Sakagami
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Makino
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Mizumoto
authors.forename: Tsubasa
authors.initials: T
authors.lastname: Isoe
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Takeda
authors.forename: Jun
authors.initials: J
authors.lastname: Watanabe
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Fujita
authors.forename: Yumi
authors.initials: Y
authors.lastname: Takiyama
authors.forename: Atsuko
authors.initials: A
authors.lastname: Abiko
authors.forename: Masakazu
authors.initials: M
authors.lastname: Haneda
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D020690:GTPase-Activating Proteins / Q000378:metabolism; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D007328:Insulin / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics
chemical_list: D020690:GTPase-Activating Proteins; D051275:Glucose Transporter Type 4; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007328:Insulin; C495693:Slc2a4 protein, mouse; C505647:Tbc1d4 protein, mouse; D005947:Glucose
keywords: glucose transporter 4; hypoxia-inducible factor-1; insulin action; protein kinase B substrate of 160 kilodaltons