Reduced Histone H3K9 Acetylation of Clock Genes and Abnormal Glucose Metabolism in ob/ob Mice

Abstract

Recent chronobiological studies found significant correlation between lack of clock function and metabolic abnormalities. We previously showed that clock gene expressions were dampened in the peripheral tissues of obese and diabetic ob/ob mice. However, the molecular mechanism of the disturbance remained to be determined. In this study, we demonstrated for the first time that acetylation levels of histone H3 lysine 9 (H3K9) at the promoter regions of clock genes, such as Dbp, Per2, and Bmal1, in the adipose tissue of ob/ob mice were significantly reduced compared with those of its control C57BL/6J mice. Treatment with histone deacetylase (HDAC) inhibitors increased Dbp, but not Per2 or Bmal1, mRNA expression in adipose tissue, and it decreased blood glucose in these animals. In addition, 2-deoxyglucose uptake activity was significantly suppressed by silencing Dbp expression in cultured adipocytes. These results suggest that reduced H3K9 acetylation and subsequent decreased mRNA expression of the Dbp gene in adipose tissue are involved in the mechanism of development of abnormal glucose metabolism in ob/ob mice. (Author correspondence: [email protected])

Keywords:

• Adipose tissue
• Clock genes
• Dbp
• Diabetes
• Epigenetics
• Histone acetylation
• Histone deacetylase inhibitor

ACKNOWLEDGMENTS

We thank Dr. Satoru Koyanagi and Dr. Naoya Matsunaga (Graduate School of Pharmaceutical Sciences, Kyushu University) for technical advice in RNA-interference experiment.

Declaration of Interest: This study was subsidized by the Japan Keirin Association through promotion funds from Keirin Race (grant 902006), and was supported by MEXT-Supported Program for the Strategic Research Foundation at Private University (Cooperative Basic and Clinical Research on Circadian Medicine) and by Jichi Medical Uiniversity Graduate Student Start-Up Grant for Young Investigators (E.I.-K.).

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.