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.

Circadian rhythms in liver metabolism and disease

“…When compared to wild type mice, ob / ob mice also have intact SCN clock gene expression but abnormal peripheral clock gene expression, and these abnormalities were present prior to the onset of the metabolic phenotype 61 . It has also been shown that acetylation levels, indicative of transcriptional activation, of clock gene promoters were reduced in ob / ob mice 62 , which may partially contribute to the obese phenotype via disturbed clock function.…”

Weight cycling promotes fat gain and altered clock gene expression in adipose tissue in C57BL/6J mice

“…Conceivably, the repeated weight cycling may have evoked lasting epigenetic changes, which has been indicated to ensure specificity and plasticity in the regulation of circadian rhythm in response to metabolic cues (1,43). Differential histone H3K9 acetylation was identified recently in the promoter region of clock genes such as Dbp, Per2, and Bmal1 in mouse adipose tissue (22). The mechanism leading to altered clock gene expression could be related to the energy restriction periods, the subsequent regain periods, or both.…”

Expression of clock geneDbpin omental and mesenteric adipose tissue in patients with type 2 diabetes

“… 18 19 Our previous studies showed that acetylation level of histone H3K9 at the promoter region of Dbp and DBP mRNA expression in epididymal adipose tissue were significantly reduced in ob/ob mice, one of the animal models of human DM2. 9 10 We also found that histone deacetylases (HDACs) inhibitors increased DBP mRNA expression and decreased blood glucose in these animals with diabetes. In healthy cells, there is a tightly controlled equilibrium between the effects of histone acetyltransferases (HATs) and HDACs enabling histone (de)acetylation and the dynamic control of gene transcription.…”

“…8 We have previously reported that the acetylation of histone H3 lysine 9 (H3K9) at the promoter regions of Dbp gene and DBP mRNA expression in mice with obesity having diabetes (ob/ob) are significantly reduced in epididymal adipose tissue. 9 Recently, we showed…”

“… 8 We have previously reported that the acetylation of histone H3 lysine 9 (H3K9) at the promoter regions of Dbp gene and DBP mRNA expression in mice with obesity having diabetes (ob/ob) are significantly reduced in epididymal adipose tissue. 9 Recently, we showed that the binding of DBP to the promoter region of novel peroxisome proliferator-activated receptor ( Ppar ) -γ and the mRNA expression of PPAR-γ1sv, a splicing variant of PPAR-γ, were decreased in the fractionated preadipocytes of ob/ob mice. 10 It subsequently decreased the secretion of adiponectin, leading to the impaired insulin sensitivity in ob/ob mice.…”