Deletion of histone deacetylase 3 in adult beta cells improves glucose tolerance via increased insulin secretion
| Autor: | Manashree Damle, Jarrett R. Remsberg, Christopher Teng, Doris A. Stoffers, Mitchell A. Lazar, Cristina Lanzillotta, Zhenghui Li, Benjamin Ediger, Wesley Y. Ho |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Genetically modified mouse Male lcsh:Internal medicine medicine.medical_specialty Mice Transgenic Carbohydrate metabolism Histone Deacetylases 03 medical and health sciences Mice Internal medicine Insulin-Secreting Cells medicine Glucose homeostasis Animals Insulin Epigenetics lcsh:RC31-1245 Molecular Biology Pancreas Sequence Deletion Mice Knockout geography geography.geographical_feature_category biology Pancreatic islets Insulin secretion HDAC3 Glucose tolerance Cell Biology Islet 3. Good health Histone Deacetylase Inhibitors 030104 developmental biology Endocrinology medicine.anatomical_structure Histone Glucose biology.protein Original Article |
| Zdroj: | Molecular Metabolism Molecular Metabolism, Vol 6, Iss 1, Pp 30-37 (2017) |
| ISSN: | 2212-8778 |
| Popis: | 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. 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. |
| Databáze: | OpenAIRE |
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