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

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7 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 languageEnglish
Article numbere130521
JournalJCI insight
Volume4
Issue number20
DOIs
StatePublished - Oct 3 2019

Bibliographical note

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

ASJC Scopus subject areas

  • General Medicine

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