title: Deletion of histone deacetylase 3 in adult beta cells improves glucose tolerance via increased insulin secretion.
abstract: 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.
  
  
  
  An HDAC3 β-cell specific knockout was generated in adultMIP-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.
  
  
  
  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 secretionin vivoas 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.
  
  
  
  HDAC3 plays an important role in regulating insulin secretionin vivo, and therapeutic intervention may improve glucose homeostasis.
authors.affiliation: Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Jarrett R
authors.initials: JR
authors.lastname: Remsberg
authors.affiliation: Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Benjamin N
authors.initials: BN
authors.lastname: Ediger
authors.affiliation: Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Wesley Y
authors.initials: WY
authors.lastname: Ho
authors.affiliation: Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Manashree
authors.initials: M
authors.lastname: Damle
authors.affiliation: Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Zhenghui
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Teng
authors.affiliation: Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Cristina
authors.initials: C
authors.lastname: Lanzillotta
authors.affiliation: Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Doris A
authors.initials: DA
authors.lastname: Stoffers
authors.affiliation: Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: lazar@mail.med.upenn.edu.
authors.forename: Mitchell A
authors.initials: MA
authors.lastname: Lazar
mesh_terms: D000818:Animals; D005947:Glucose / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000378:metabolism; D006655:Histone Deacetylases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010179:Pancreas / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D017384:Sequence Deletion; D000099186:Histone Deacetylase 3
chemical_list: D005947:Glucose; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D007328:Insulin; D000099186:Histone Deacetylase 3
keywords: Glucose tolerance; HDAC3; Insulin secretion