Research Summary: 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.


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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Publisher: Public Library of Science

Date Published: 31-May-2011

Author(s): 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.

Link: https://doi.org/10.1371/journal.pone.0020467

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