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

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ID: 197216
2017
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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. Author Video: Author Video Watch what authors say about their articles Keywords: HDAC3, Glucose tolerance, Insulin secretion
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remsberg2017moleculardeletion Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Jarrett R. Remsberg, Benjamin N. Ediger, Wesley Y. Ho, Manashree Damle, Zhenghui Li, Christopher Teng, Cristina Lanzillotta, Doris A. Stoffers, Mitchell A. Lazar
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Journal Small (Weinheim an der Bergstrasse, Germany)
Year 2017
DOI
DOI not found
URL
http://www.sciencedirect.com/science/article/pii/S221287781630223X
Keywords
internal medicine

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