MicroRNA-7a overexpression in VMH restores the sympathoadrenal response to hypoglycemia

Rahul Agrawal; Griffin Durupt; Dinesh Verma; Michael Montgomery; Adriana Vieira-De Abreu; Casey Taylor; Sankar Swaminathan; Simon J. Fisher

doi:10.1172/jci.insight.130521

MicroRNA-7a overexpression in VMH restores the sympathoadrenal response to hypoglycemia

Rahul Agrawal, Griffin Durupt, Dinesh Verma, Michael Montgomery, Adriana Vieira-De Abreu, Casey Taylor, Sankar Swaminathan, Simon J. Fisher

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

Abstract

It is proposed that the impaired sympathoadrenal response to hypoglycemia induced by recurrent insulin-induced hypoglycemia (RH) is an adaptive phenomenon induced by specific changes in microRNA expression in the ventromedial hypothalamus (VMH). To test this hypothesis, genomewide microRNAomic profiling of the VMH by RNA-sequencing was performed in control rats and rats treated for RH. Differential expression analysis identified microRNA-7a-5p and microRNA-665 as potential mediators of this phenomenon. To further test this hypothesis, experiments were conducted consisting of targeted lentiviral-mediated overexpression of microRNA-7a-5p and downregulation of microRNA-665 in the VMH. Hyperinsulinemic hypoglycemic clamp experiments demonstrated that targeted overexpression of microRNA-7a-5p (but not downregulation of microRNA-665) in the VMH of RH rats restored the epinephrine response to hypoglycemia. This restored response to hypoglycemia was associated with a restoration of GABAA receptor gene expression. Finally, a direct interaction of microRNA-7a-5p with the 3′-UTR of GABAA receptor α1-subunit (Gabra1) gene was demonstrated in a luciferase assay. These findings indicate that (a) the impaired sympathoadrenal response RH induces is associated with changes in VMH microRNA expression and (b) microRNA-7a-5p, possibly via direct downregulation of GABA receptor gene expression, may serve as a mediator of the altered sympathoadrenal response to hypoglycemia.

Original language	English
Article number	e130521
Journal	JCI insight
Volume	4
Issue number	20
DOIs	https://doi.org/10.1172/jci.insight.130521
State	Published - Oct 3 2019

Bibliographical note

Funding Information:
This work was supported by funding from National Institutes of Health R01 NS070235-01A1 (to SJF) and R01DK118082 (to SJF), the Juvenile Diabetes Research Foundation 2-SRA-2014-270-M-R (to SJF), and the University of Utah’s Diabetes and Metabolism Research Center. We are grateful for support from the High-throughput Genomics and Bioinformatic Analysis core facility of Huntsman Cancer Institute and the Genomics, DNA/Peptide Synthesis, and Fluorescence Microscopy core facilities of Heath Sciences cores at the University of Utah. The authors have declared that no conflict of interest exists.

Publisher Copyright:
© 2019, American Society for Clinical Investigation.

ASJC Scopus subject areas

Medicine (all)

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10.1172/jci.insight.130521

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title = "MicroRNA-7a overexpression in VMH restores the sympathoadrenal response to hypoglycemia",

abstract = "It is proposed that the impaired sympathoadrenal response to hypoglycemia induced by recurrent insulin-induced hypoglycemia (RH) is an adaptive phenomenon induced by specific changes in microRNA expression in the ventromedial hypothalamus (VMH). To test this hypothesis, genomewide microRNAomic profiling of the VMH by RNA-sequencing was performed in control rats and rats treated for RH. Differential expression analysis identified microRNA-7a-5p and microRNA-665 as potential mediators of this phenomenon. To further test this hypothesis, experiments were conducted consisting of targeted lentiviral-mediated overexpression of microRNA-7a-5p and downregulation of microRNA-665 in the VMH. Hyperinsulinemic hypoglycemic clamp experiments demonstrated that targeted overexpression of microRNA-7a-5p (but not downregulation of microRNA-665) in the VMH of RH rats restored the epinephrine response to hypoglycemia. This restored response to hypoglycemia was associated with a restoration of GABAA receptor gene expression. Finally, a direct interaction of microRNA-7a-5p with the 3′-UTR of GABAA receptor α1-subunit (Gabra1) gene was demonstrated in a luciferase assay. These findings indicate that (a) the impaired sympathoadrenal response RH induces is associated with changes in VMH microRNA expression and (b) microRNA-7a-5p, possibly via direct downregulation of GABA receptor gene expression, may serve as a mediator of the altered sympathoadrenal response to hypoglycemia.",

author = "Rahul Agrawal and Griffin Durupt and Dinesh Verma and Michael Montgomery and {Vieira-De Abreu}, Adriana and Casey Taylor and Sankar Swaminathan and Fisher, {Simon J.}",

note = "Funding Information: This work was supported by funding from National Institutes of Health R01 NS070235-01A1 (to SJF) and R01DK118082 (to SJF), the Juvenile Diabetes Research Foundation 2-SRA-2014-270-M-R (to SJF), and the University of Utah{\textquoteright}s Diabetes and Metabolism Research Center. We are grateful for support from the High-throughput Genomics and Bioinformatic Analysis core facility of Huntsman Cancer Institute and the Genomics, DNA/Peptide Synthesis, and Fluorescence Microscopy core facilities of Heath Sciences cores at the University of Utah. The authors have declared that no conflict of interest exists. Publisher Copyright: {\textcopyright} 2019, American Society for Clinical Investigation.",

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doi = "10.1172/jci.insight.130521",

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T1 - MicroRNA-7a overexpression in VMH restores the sympathoadrenal response to hypoglycemia

AU - Agrawal, Rahul

AU - Durupt, Griffin

AU - Verma, Dinesh

AU - Montgomery, Michael

AU - Vieira-De Abreu, Adriana

AU - Taylor, Casey

AU - Swaminathan, Sankar

AU - Fisher, Simon J.

N1 - Funding Information: This work was supported by funding from National Institutes of Health R01 NS070235-01A1 (to SJF) and R01DK118082 (to SJF), the Juvenile Diabetes Research Foundation 2-SRA-2014-270-M-R (to SJF), and the University of Utah’s Diabetes and Metabolism Research Center. We are grateful for support from the High-throughput Genomics and Bioinformatic Analysis core facility of Huntsman Cancer Institute and the Genomics, DNA/Peptide Synthesis, and Fluorescence Microscopy core facilities of Heath Sciences cores at the University of Utah. The authors have declared that no conflict of interest exists. Publisher Copyright: © 2019, American Society for Clinical Investigation.

PY - 2019/10/3

Y1 - 2019/10/3

N2 - It is proposed that the impaired sympathoadrenal response to hypoglycemia induced by recurrent insulin-induced hypoglycemia (RH) is an adaptive phenomenon induced by specific changes in microRNA expression in the ventromedial hypothalamus (VMH). To test this hypothesis, genomewide microRNAomic profiling of the VMH by RNA-sequencing was performed in control rats and rats treated for RH. Differential expression analysis identified microRNA-7a-5p and microRNA-665 as potential mediators of this phenomenon. To further test this hypothesis, experiments were conducted consisting of targeted lentiviral-mediated overexpression of microRNA-7a-5p and downregulation of microRNA-665 in the VMH. Hyperinsulinemic hypoglycemic clamp experiments demonstrated that targeted overexpression of microRNA-7a-5p (but not downregulation of microRNA-665) in the VMH of RH rats restored the epinephrine response to hypoglycemia. This restored response to hypoglycemia was associated with a restoration of GABAA receptor gene expression. Finally, a direct interaction of microRNA-7a-5p with the 3′-UTR of GABAA receptor α1-subunit (Gabra1) gene was demonstrated in a luciferase assay. These findings indicate that (a) the impaired sympathoadrenal response RH induces is associated with changes in VMH microRNA expression and (b) microRNA-7a-5p, possibly via direct downregulation of GABA receptor gene expression, may serve as a mediator of the altered sympathoadrenal response to hypoglycemia.

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MicroRNA-7a overexpression in VMH restores the sympathoadrenal response to hypoglycemia

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