Bao Dan, Ma Yuanwu, Zhang Xu, Guan Feifei, Chen Wei, Gao Kai, Qin Chuan, Zhang Lianfeng
Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences &Comparative Medical Center, Peking Union Medical College, China.
Key Laboratory of Human Disease Animal Model, State Administration of Traditional Chinese Medicine, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences &Comparative Medical Center, Peking Union Medical College, China.
Sci Rep. 2015 Nov 5;5:15942. doi: 10.1038/srep15942.
Leptin receptor, which is encoded by the diabetes (db) gene and is highly expressed in the choroid plexus, regulatesenergy homeostasis, the balance between food intake and energy expenditure, fertility and bone mass. Here, using CRISPR/Cas9 technology, we created the leptin receptor knockout rat. Homozygous leptin receptor null rats are characterized by obesity, hyperphagia, hyperglycemia, glucose intolerance, hyperinsulinemia and dyslipidemia. Due to long-term poor glycemic control, the leptin receptor knockout rats also develop some diabetic complications such as pancreatic, hepatic and renal lesions. In addition, the leptin receptor knockout rats show a significant decrease in bone volume and bone mineral density of the femur compared with their wild-type littermates. Our model has rescued some deficiency of the existing rodent models, such as the transient hyperglycemia of db/db mice in the C57BL/6J genetic background and the delayed onset of glucose intolerance in the Zucker rats, and it is proven to be a useful animal model for biomedical and pharmacological research on obesity and diabetes.
瘦素受体由糖尿病（db）基因编码，在脉络丛中高度表达，它调节能量平衡，即食物摄入与能量消耗之间的平衡、生育能力和骨量。在此，我们利用CRISPR/Cas9技术创建了瘦素受体基因敲除大鼠。纯合瘦素受体缺失大鼠的特征为肥胖、食欲亢进、高血糖、葡萄糖不耐受、高胰岛素血症和血脂异常。由于长期血糖控制不佳，瘦素受体基因敲除大鼠还会出现一些糖尿病并发症，如胰腺、肝脏和肾脏病变。此外，与野生型同窝大鼠相比，瘦素受体基因敲除大鼠股骨的骨体积和骨矿物质密度显著降低。我们的模型弥补了现有啮齿动物模型的一些不足，如C57BL/6J遗传背景下db/db小鼠的短暂高血糖以及Zucker大鼠葡萄糖不耐受的延迟发作，并且已被证明是肥胖和糖尿病生物医学及药理学研究的有用动物模型。
