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

Citation
Remsberg, J. R., et al. “Deletion Of Histone Deacetylase 3 In Adult Beta Cells Improves Glucose Tolerance Via Increased Insulin Secretion.”. Molecular Metabolism, pp. 30-37.
Center University of Pennsylvania
Author Jarrett R Remsberg, Benjamin N Ediger, Wesley Y Ho, Manashree Damle, Zhenghui Li, Christopher Teng, Cristina Lanzillotta, Doris A Stoffers, Mitchell A Lazar
Keywords glucose tolerance, HDAC3, 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 ERT 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 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 , and therapeutic intervention may improve glucose homeostasis.

Year of Publication
2017
Journal
Molecular metabolism
Volume
6
Issue
1
Number of Pages
30-37
Date Published
12/2017
ISSN Number
2212-8778
DOI
10.1016/j.molmet.2016.11.007
Alternate Journal
Mol Metab
PMID
28123935
PMCID
PMC5220396
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