Elsevier

Molecular Metabolism

Volume 6, Issue 1, January 2017, Pages 30-37
Molecular Metabolism

Original Article
Deletion of histone deacetylase 3 in adult beta cells improves glucose tolerance via increased insulin secretion

https://doi.org/10.1016/j.molmet.2016.11.007Get rights and content
Under a Creative Commons license
open access

Highlights

  • HDAC3 ablation in adult mouse β-cells improves glucose tolerance.

  • Improved glucose tolerance is due to increased insulin secretion.

  • HDAC3 targets multiple genes involved in potentiating insulin secretion.

Abstract

Objective

Histone deacetylases are epigenetic regulators known to control gene transcription in various tissues. A member of this family, histone deacetylase 3 (HDAC3), has been shown to regulate metabolic genes. Cell culture studies with HDAC-specific inhibitors and siRNA suggest that HDAC3 plays a role in pancreatic β-cell function, but a recent genetic study in mice has been contradictory. Here we address the functional role of HDAC3 in β-cells of adult mice.

Methods

An HDAC3 β-cell specific knockout was generated in adult MIP-CreERT transgenic mice using the Cre-loxP system. Induction of HDAC3 deletion was initiated at 8 weeks of age with administration of tamoxifen in corn oil (2 mg/day for 5 days). Mice were assayed for glucose tolerance, glucose-stimulated insulin secretion, and islet function 2 weeks after induction of the knockout. Transcriptional functions of HDAC3 were assessed by ChIP-seq as well as RNA-seq comparing control and β-cell knockout islets.

Results

HDAC3 β-cell specific knockout (HDAC3βKO) did not increase total pancreatic insulin content or β-cell mass. However, HDAC3βKO mice demonstrated markedly improved glucose tolerance. This improved glucose metabolism coincided with increased basal and glucose-stimulated insulin secretion in vivo as well as in isolated islets. Cistromic and transcriptomic analyses of pancreatic islets revealed that HDAC3 regulates multiple genes that contribute to glucose-stimulated insulin secretion.

Conclusions

HDAC3 plays an important role in regulating insulin secretion in vivo, and therapeutic intervention may improve glucose homeostasis.

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Keywords

HDAC3
Glucose tolerance
Insulin secretion

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