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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.

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Glucose tolerance and insulin tolerance tests on RXRγ                            mice.(A, B) In A and B, male mice, 5 months                            of age, were used. The number of animals used was 6 for both control                            (open circles) and RXRγ (filled circles) mice of line 4-3, and 5 for                            both control (open circles) and RXRγ (filled circles) mice of line                            5-3. * P<0.05 and **                            P<0.01 compared with respective control.
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pone-0020467-g001: Glucose tolerance and insulin tolerance tests on RXRγ mice.(A, B) In A and B, male mice, 5 months of age, were used. The number of animals used was 6 for both control (open circles) and RXRγ (filled circles) mice of line 4-3, and 5 for both control (open circles) and RXRγ (filled circles) mice of line 5-3. * P<0.05 and ** P<0.01 compared with respective control.

Mentions: To elucidate the role of the skeletal muscle RXRγ in systemic glucose metabolism, we performed glucose and insulin tolerance tests in RXRγ mice. The glucose tolerance test revealed increased glucose disposal in RXRγ mice relative to control mice (Fig. 1A). On the other hand, there was no significant difference in the insulin-induced hypoglycemic response between genotypes (Fig. 1B). These observations suggest that RXRγ mice have a higher capacity for glucose disposal with no change in insulin sensitivity.


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)

Glucose tolerance and insulin tolerance tests on RXRγ                            mice.(A, B) In A and B, male mice, 5 months                            of age, were used. The number of animals used was 6 for both control                            (open circles) and RXRγ (filled circles) mice of line 4-3, and 5 for                            both control (open circles) and RXRγ (filled circles) mice of line                            5-3. * P<0.05 and **                            P<0.01 compared with respective control.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0020467-g001: Glucose tolerance and insulin tolerance tests on RXRγ mice.(A, B) In A and B, male mice, 5 months of age, were used. The number of animals used was 6 for both control (open circles) and RXRγ (filled circles) mice of line 4-3, and 5 for both control (open circles) and RXRγ (filled circles) mice of line 5-3. * P<0.05 and ** P<0.01 compared with respective control.
Mentions: To elucidate the role of the skeletal muscle RXRγ in systemic glucose metabolism, we performed glucose and insulin tolerance tests in RXRγ mice. The glucose tolerance test revealed increased glucose disposal in RXRγ mice relative to control mice (Fig. 1A). On the other hand, there was no significant difference in the insulin-induced hypoglycemic response between genotypes (Fig. 1B). These observations suggest that RXRγ mice have a higher capacity for glucose disposal with no change in insulin sensitivity.

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