title: Increased systemic glucose tolerance with increased muscle glucose uptake in transgenic mice overexpressing RXRγ in skeletal muscle.
abstract: BACKGROUND
  Retinoid X receptor (RXR) γ is a nuclear receptor-type transcription factor expressed mostly in skeletal muscle, and regulated by nutritional conditions. Previously, we established transgenic mice overexpressing RXRγ in skeletal muscle (RXRγ mice), which showed lower blood glucose than the control mice. Here we investigated their glucose metabolism.
  
  
  RESULTS
  RXRγ mice were subjected to glucose and insulin tolerance tests, and glucose transporter expression levels, hyperinsulinemic-euglycemic clamp and glucose uptake were analyzed. Microarray and bioinformatics analyses were done. The glucose tolerance test revealed higher glucose disposal in RXRγ mice than in control mice, but insulin tolerance test revealed no difference in the insulin-induced hypoglycemic response. In the hyperinsulinemic-euglycemic clamp study, the basal glucose disposal rate was higher in RXRγ mice than in control mice, indicating an insulin-independent increase in glucose uptake. There was no difference in the rate of glucose infusion needed to maintain euglycemia (glucose infusion rate) between the RXRγ and control mice, which is consistent with the result of the insulin tolerance test. Skeletal muscle from RXRγ mice showed increased Glut1 expression, with increased glucose uptake, in an insulin-independent manner. Moreover, we performed in vivo luciferase reporter analysis using Glut1 promoter (Glut1-Luc). Combination of RXRγ and PPARδ resulted in an increase in Glut1-Luc activity in skeletal muscle in vivo. Microarray data showed that RXRγ overexpression increased a diverse set of genes, including glucose metabolism genes, whose promoter contained putative PPAR-binding motifs.
  
  
  CONCLUSIONS
  Systemic glucose metabolism was increased in transgenic mice overexpressing RXRγ. The enhanced glucose tolerance in RXRγ mice may be mediated at least in part by increased Glut1 in skeletal muscle. These results show the importance of skeletal muscle gene regulation in systemic glucose metabolism. Increasing RXRγ expression may be a novel therapeutic strategy against type 2 diabetes.
authors.affiliation: Department of Molecular Medicine and Metabolism, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Sugita
authors.forename: Yasutomi
authors.initials: Y
authors.lastname: Kamei
authors.forename: Fumiko
authors.initials: F
authors.lastname: Akaike
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Suganami
authors.forename: Sayaka
authors.initials: S
authors.lastname: Kanai
authors.forename: Maki
authors.initials: M
authors.lastname: Hattori
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Manabe
authors.forename: Nobuharu
authors.initials: N
authors.lastname: Fujii
authors.forename: Takako
authors.initials: T
authors.lastname: Takai-Igarashi
authors.forename: Miki
authors.initials: M
authors.lastname: Tadaishi
authors.forename: Jun-ichiro
authors.initials: J
authors.lastname: Oka
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Yamada
authors.forename: Hideki
authors.initials: H
authors.lastname: Katagiri
authors.forename: Saori
authors.initials: S
authors.lastname: Kakehi
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Tamura
authors.forename: Hideo
authors.initials: H
authors.lastname: Kubo
authors.forename: Kenichi
authors.initials: K
authors.lastname: Nishida
authors.forename: Shinji
authors.initials: S
authors.lastname: Miura
authors.forename: Osamu
authors.initials: O
authors.lastname: Ezaki
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ogawa
mesh_terms: D000818:Animals; D001665:Binding Sites; D018274:Electroporation; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D047491:Retinoid X Receptor gamma / Q000235:genetics / Q000378:metabolism*
chemical_list: D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D047491:Retinoid X Receptor gamma; D006003:Glycogen; D005947:Glucose