Increased systemic glucose tolerance with increased muscle glucose uptake in transgenic mice overexpressing RXRγ in skeletal muscle

Satoshi Sugita, Yasutomi Kamei, Fumiko Akaike, Takayoshi Suganami, Sayaka Kanai, Maki Hattori, Yasuko Manabe, Nobuharu Fujii, Takako Takai-Igarashi, Miki Tadaishi, Jun Ichiro Oka, Hiroyuki Aburatani, Tetsuya Yamada, Hideki Katagiri, Saori Kakehi, Yoshifumi Tamura, Hideo Kubo, Kenichi Nishida, Shinji Miura, Osamu EzakiYoshihiro Ogawa

Research output: Contribution to journalArticle

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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. Methodology/Principal Findings: 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/Significance: 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.

Original languageEnglish
Article numbere20467
JournalPloS one
Volume6
Issue number5
DOIs
Publication statusPublished - Jun 7 2011

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Retinoid X Receptors
retinoids
glucose tolerance
Transgenic Mice
Muscle
skeletal muscle
Skeletal Muscle
genetically modified organisms
uptake mechanisms
Glucose
Muscles
muscles
receptors
glucose
mice
Insulin
Metabolism
Peroxisome Proliferator-Activated Receptors
Glucose Clamp Technique
metabolism

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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Increased systemic glucose tolerance with increased muscle glucose uptake in transgenic mice overexpressing RXRγ in skeletal muscle. / Sugita, Satoshi; Kamei, Yasutomi; Akaike, Fumiko; Suganami, Takayoshi; Kanai, Sayaka; Hattori, Maki; Manabe, Yasuko; Fujii, Nobuharu; Takai-Igarashi, Takako; Tadaishi, Miki; Oka, Jun Ichiro; Aburatani, Hiroyuki; Yamada, Tetsuya; Katagiri, Hideki; Kakehi, Saori; Tamura, Yoshifumi; Kubo, Hideo; Nishida, Kenichi; Miura, Shinji; Ezaki, Osamu; Ogawa, Yoshihiro.

In: PloS one, Vol. 6, No. 5, e20467, 07.06.2011.

Research output: Contribution to journalArticle

Sugita, S, Kamei, Y, Akaike, F, Suganami, T, Kanai, S, Hattori, M, Manabe, Y, Fujii, N, Takai-Igarashi, T, Tadaishi, M, Oka, JI, Aburatani, H, Yamada, T, Katagiri, H, Kakehi, S, Tamura, Y, Kubo, H, Nishida, K, Miura, S, Ezaki, O & Ogawa, Y 2011, 'Increased systemic glucose tolerance with increased muscle glucose uptake in transgenic mice overexpressing RXRγ in skeletal muscle', PloS one, vol. 6, no. 5, e20467. https://doi.org/10.1371/journal.pone.0020467
Sugita, Satoshi ; Kamei, Yasutomi ; Akaike, Fumiko ; Suganami, Takayoshi ; Kanai, Sayaka ; Hattori, Maki ; Manabe, Yasuko ; Fujii, Nobuharu ; Takai-Igarashi, Takako ; Tadaishi, Miki ; Oka, Jun Ichiro ; Aburatani, Hiroyuki ; Yamada, Tetsuya ; Katagiri, Hideki ; Kakehi, Saori ; Tamura, Yoshifumi ; Kubo, Hideo ; Nishida, Kenichi ; Miura, Shinji ; Ezaki, Osamu ; Ogawa, Yoshihiro. / Increased systemic glucose tolerance with increased muscle glucose uptake in transgenic mice overexpressing RXRγ in skeletal muscle. In: PloS one. 2011 ; Vol. 6, No. 5.
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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. Methodology/Principal Findings: 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/Significance: 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.",
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AU - Sugita, Satoshi

AU - Kamei, Yasutomi

AU - Akaike, Fumiko

AU - Suganami, Takayoshi

AU - Kanai, Sayaka

AU - Hattori, Maki

AU - Manabe, Yasuko

AU - Fujii, Nobuharu

AU - Takai-Igarashi, Takako

AU - Tadaishi, Miki

AU - Oka, Jun Ichiro

AU - Aburatani, Hiroyuki

AU - Yamada, Tetsuya

AU - Katagiri, Hideki

AU - Kakehi, Saori

AU - Tamura, Yoshifumi

AU - Kubo, Hideo

AU - Nishida, Kenichi

AU - Miura, Shinji

AU - Ezaki, Osamu

AU - Ogawa, Yoshihiro

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N2 - 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. Methodology/Principal Findings: 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/Significance: 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.

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