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Horm Metab Res 2013; 45(03): 213-220
DOI: 10.1055/s-0032-1327619
Original Basic
© Georg Thieme Verlag KG Stuttgart · New York

Prostaglandin A2 Enhances Cellular Insulin Sensitivity via a Mechanism that Involves the Orphan Nuclear Receptor NR4A3

X. Zhu
1   Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL, USA
,
R. G. Walton
2   Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL, USA
,
L. Tian
1   Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL, USA
,
N. Luo
2   Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL, USA
,
S-R. Ho
1   Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL, USA
,
Y. Fu
2   Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL, USA
,
W. T. Garvey
2   Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL, USA
3   Birmingham Veterans Affairs Medical Center, Birmingham, AL, USA
› Author Affiliations
Further Information

Publication History

received 14 May 2012

accepted 13 September 2012

Publication Date:
26 October 2012 (online)

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Abstract

We have previously reported that members of the NR4A family of orphan nuclear receptors can augment insulin’s ability to stimulate glucose transport in adipocytes. In the current study, we endeavored to test for an insulin-sensitizing effect in muscle cells and to identify a potential transactivator. Lentiviral constructs were used to engineer both hyperexpression and shRNA silencing of NR4A3 in C2C12 myocytes. The NR4A3 hyper-expression construct led to a significant increase in glucose transport rates in the presence of maximal insulin while the NR4A3 knock-down exhibited a significant reduction in insulin-stimulated glucose transport rates. Consistently, insulin-mediated AKT phosphorylation was increased by NR4A3 hyperexpression and decreased following shRNA NR4A3 suppression. Then, we examined effects of prostaglandin A2 (PGA2) on insulin action and NR4A3 transactivation. PGA2 augmented insulin-stimulated glucose uptake in C2C12 myocytes and AKT phosphorylation after 12-h treatment, without significant effects on basal transport or basal AKT phosphorylation. More importantly, we demonstrated that PGA2 led to a greater improvement in insulin-stimulated glucose rates in NR4A3 overexpressing C2C12 myocytes, when compared with Lac-Z controls stimulated with insulin and PGA2. Moreover, the sensitizing effect of PGA2 was significantly diminished in NR4A3 knockdown myocytes compared to scramble controls. These results show for the first time that: (i) PGA2 augments insulin action in myocytes as manifested by enhanced stimulation of glucose transport and AKT phosphorylation; and (ii) the insulin sensitizing effect is dependent upon the orphan nuclear receptor NR4A3.

Key words

NR4A3 - MINOR - insulin sensitivity - prostaglandin A2 - glucose transport - skeletal muscle - C2C12 cells

Supporting Information

 

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