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

Sugita S, Kamei Y, Akaike F, Suganami T, Kanai S, Hattori M, Manabe Y, Fujii N, Takai-Igarashi T, Tadaishi M, Oka J, Aburatani H, Yamada T, Katagiri H, Kakehi S, Tamura Y, Kubo H, Nishida K, Miura S, Ezaki O, Ogawa Y - PLoS ONE (2011)

Bottom Line: Combination of RXRγ and PPARδ resulted in an increase in Glut1-Luc activity in skeletal muscle in vivo.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Medicine and Metabolism, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.

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.

Show MeSH

Related in: MedlinePlus

Levels of Glut 1 and Glut4, and glucose uptake in the skeletal muscle                            of RXRγ mice.(A) Gene expressions of RXRγ,                                Glut1, and 4 were examined by                            quantitative real-time PCR. The value for wild-type (littermates of line                            4-3) mice was set at 100, and relative values are shown.                                (B) Protein levels of Glut1 and Glut4 were examined                            by Western blotting. Results of relative densitometric signal for Glut1                            and 4 are shown. (C) Glucose uptake in the absence or                            presence of insulin and (D) glycogen content were                            increased in the skeletal muscle of RXRγ mice. Ratio of enhanced                            glucose uptake in the presence of insulin (insulin/basal) was similar in                            control and RXRγ mice. In A, B and                                D, the same samples were used. Mice were males of                            12 weeks of age. The number of animals was 6 for both control (open                            bars) and RXRγ (filled bars) mice. These samples were also used in                                Table 1. In                                C, mice were males of 24–27 weeks of age. The                            number of animals was 6 for both control (open bars) and RXRγ                            (filled bars) mice. * P<0.05 and **                                P<0.01 compared with respective control. N. S.,                            not significant.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3105070&req=5

pone-0020467-g002: Levels of Glut 1 and Glut4, and glucose uptake in the skeletal muscle of RXRγ mice.(A) Gene expressions of RXRγ, Glut1, and 4 were examined by quantitative real-time PCR. The value for wild-type (littermates of line 4-3) mice was set at 100, and relative values are shown. (B) Protein levels of Glut1 and Glut4 were examined by Western blotting. Results of relative densitometric signal for Glut1 and 4 are shown. (C) Glucose uptake in the absence or presence of insulin and (D) glycogen content were increased in the skeletal muscle of RXRγ mice. Ratio of enhanced glucose uptake in the presence of insulin (insulin/basal) was similar in control and RXRγ mice. In A, B and D, the same samples were used. Mice were males of 12 weeks of age. The number of animals was 6 for both control (open bars) and RXRγ (filled bars) mice. These samples were also used in Table 1. In C, mice were males of 24–27 weeks of age. The number of animals was 6 for both control (open bars) and RXRγ (filled bars) mice. * P<0.05 and ** P<0.01 compared with respective control. N. S., not significant.

Mentions: Values are the means ± SE. These samples were also used in Fig 2A, B, and D.


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

Sugita S, Kamei Y, Akaike F, Suganami T, Kanai S, Hattori M, Manabe Y, Fujii N, Takai-Igarashi T, Tadaishi M, Oka J, Aburatani H, Yamada T, Katagiri H, Kakehi S, Tamura Y, Kubo H, Nishida K, Miura S, Ezaki O, Ogawa Y - PLoS ONE (2011)

Levels of Glut 1 and Glut4, and glucose uptake in the skeletal muscle                            of RXRγ mice.(A) Gene expressions of RXRγ,                                Glut1, and 4 were examined by                            quantitative real-time PCR. The value for wild-type (littermates of line                            4-3) mice was set at 100, and relative values are shown.                                (B) Protein levels of Glut1 and Glut4 were examined                            by Western blotting. Results of relative densitometric signal for Glut1                            and 4 are shown. (C) Glucose uptake in the absence or                            presence of insulin and (D) glycogen content were                            increased in the skeletal muscle of RXRγ mice. Ratio of enhanced                            glucose uptake in the presence of insulin (insulin/basal) was similar in                            control and RXRγ mice. In A, B and                                D, the same samples were used. Mice were males of                            12 weeks of age. The number of animals was 6 for both control (open                            bars) and RXRγ (filled bars) mice. These samples were also used in                                Table 1. In                                C, mice were males of 24–27 weeks of age. The                            number of animals was 6 for both control (open bars) and RXRγ                            (filled bars) mice. * P<0.05 and **                                P<0.01 compared with respective control. N. S.,                            not significant.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3105070&req=5

pone-0020467-g002: Levels of Glut 1 and Glut4, and glucose uptake in the skeletal muscle of RXRγ mice.(A) Gene expressions of RXRγ, Glut1, and 4 were examined by quantitative real-time PCR. The value for wild-type (littermates of line 4-3) mice was set at 100, and relative values are shown. (B) Protein levels of Glut1 and Glut4 were examined by Western blotting. Results of relative densitometric signal for Glut1 and 4 are shown. (C) Glucose uptake in the absence or presence of insulin and (D) glycogen content were increased in the skeletal muscle of RXRγ mice. Ratio of enhanced glucose uptake in the presence of insulin (insulin/basal) was similar in control and RXRγ mice. In A, B and D, the same samples were used. Mice were males of 12 weeks of age. The number of animals was 6 for both control (open bars) and RXRγ (filled bars) mice. These samples were also used in Table 1. In C, mice were males of 24–27 weeks of age. The number of animals was 6 for both control (open bars) and RXRγ (filled bars) mice. * P<0.05 and ** P<0.01 compared with respective control. N. S., not significant.
Mentions: Values are the means ± SE. These samples were also used in Fig 2A, B, and D.

Bottom Line: Combination of RXRγ and PPARδ resulted in an increase in Glut1-Luc activity in skeletal muscle in vivo.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Medicine and Metabolism, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.

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.

Show MeSH
Related in: MedlinePlus