Abstract:
Histone deacetylase (HDAC) 9 is a negative regulator of adipogenic differentiation, which is required for maintenance of healthy adipose tissues. We reported that HDAC9 expression is upregulated in adipose tissues during obesity, in conjunction with impaired adipogenic differentiation, adipocyte hypertrophy, insulin resistance, and hepatic steatosis, all of which were alleviated by global genetic deletion of Hdac9. Here, we developed a novel transgenic (TG) mouse model to test whether overexpression of Hdac9 is sufficient to induce adipocyte hypertrophy, insulin resistance, and hepatic steatosis in the absence of obesity. HDAC9 TG mice gained less body weight than wild-type (WT) mice when fed a standard laboratory diet for up to 40 weeks, which was attributed to reduced fat mass (primarily inguinal adipose tissue). There was no difference in insulin sensitivity or glucose tolerance in 18-week-old WT and HDAC9 TG mice; however, at 40 weeks of age, HDAC9 TG mice exhibited impaired insulin sensitivity and glucose intolerance. Tissue histology demonstrated adipocyte hypertrophy, along with reduced numbers of mature adipocytes and stromovascular cells, in the HDAC9 TG mouse adipose tissue. Moreover, increased lipids were detected in the livers of aging HDAC9 TG mice, as evaluated by oil red O staining. In conclusion, the experimental aging HDAC9 TG mice developed adipocyte hypertrophy, insulin resistance, and hepatic steatosis, independent of obesity. This novel mouse model may be useful in the investigation of the impact of Hdac9 overexpression associated with metabolic and aging-related diseases.
摘要:
组蛋白去乙酰化酶(HDAC)9是脂肪分化的负调节因子,这是维持健康脂肪组织所必需的。我们报道了HDAC9在肥胖期间脂肪组织中的表达上调,与受损的成脂分化相结合,脂肪细胞肥大,胰岛素抵抗,和肝脏脂肪变性,所有这些都通过Hdac9的全球遗传缺失得到缓解。这里,我们开发了一种新的转基因(TG)小鼠模型来测试Hdac9的过表达是否足以诱导脂肪细胞肥大,胰岛素抵抗,和没有肥胖的肝脏脂肪变性。HDAC9TG小鼠在喂食标准实验室饮食长达40周时,体重增加比野生型(WT)小鼠少,这归因于脂肪量减少(主要是腹股沟脂肪组织)。18周龄WT和HDAC9TG小鼠的胰岛素敏感性或糖耐量无差异;然而,在40周大的时候,HDAC9TG小鼠表现出胰岛素敏感性和葡萄糖耐受不良。组织组织学显示脂肪细胞肥大,随着成熟脂肪细胞和基质血管细胞数量的减少,在HDAC9TG小鼠脂肪组织中。此外,在衰老的HDAC9TG小鼠的肝脏中检测到脂质增加,通过油红O染色评估。总之,实验性衰老HDAC9TG小鼠出现脂肪细胞肥大,胰岛素抵抗,和肝脏脂肪变性,独立于肥胖。这种新型小鼠模型可用于研究与代谢和衰老相关疾病相关的Hdac9过表达的影响。