Meng Yuhuan, Guan Yujia, Zhang Wenlu, Wu Yu-E, Jia Huanhuan, Zhang Yu, Zhang Xiuqing, Du Hongli, Wang Xiaoning
School of Bioscience &Bioengineering, South China University of Technology, Guangzhou, 510006, China.
BGI-Shenzhen, Shenzhen, 518031, China.
Sci Rep. 2016 Sep 28;6:34138. doi: 10.1038/srep34138.
The Goto-Kakizaki (GK) rat is an animal model of non-obese type 2 diabetes (T2D). The GK rat was generated through the introduction of various genetic mutations from continuous inbreeding; these rats develop diabetes spontaneously. The mutated genes in GK rats may play key roles in the regulation of diabetes. The hypothalamus plays a central role in systematic energy homeostasis. Here, the hypothalamic transcriptomes in GK and Wistar rats at 4, 8 and 12 weeks were investigated by RNA-seq, and multiple variants and gene expression profiles were obtained. The number of variants identified from GK rats was significantly greater than that of Wistar rats, indicating that many variants were fixed and heritable in GK rats after selective inbreeding. The differential gene expression analysis indicated that GK rats had a dysfunctional hypothalamic melanocortin system and attenuation of the hypothalamic glucose-sensing pathway. In addition, we generated integrated gene network modules by combining the protein-protein interaction (PPI) network, co-expression network and mutations in GK and Wistar rats. In the modules, GK-specific genes, such as Bad, Map2k2, Adcy3, Adcy2 and Gstm6, may play key roles in hypothalamic regulation in GK rats. Our research provides a comprehensive map of the abnormalities in the GK rat hypothalamus, which reveals the new mechanisms of pathogenesis of T2D.
Goto-Kakizaki（GK）大鼠是一种非肥胖型2型糖尿病（T2D）的动物模型。GK大鼠是通过连续近亲繁殖引入各种基因突变而培育出来的；这些大鼠会自发患上糖尿病。GK大鼠中的突变基因可能在糖尿病的调控中起关键作用。下丘脑在全身能量稳态中起核心作用。在此，通过RNA测序研究了4周、8周和12周龄的GK大鼠和Wistar大鼠的下丘脑转录组，并获得了多个变异体和基因表达谱。从GK大鼠中鉴定出的变异体数量显著多于Wistar大鼠，这表明在选择性近亲繁殖后，许多变异体在GK大鼠中是固定且可遗传的。差异基因表达分析表明，GK大鼠的下丘脑黑皮质素系统功能失调，下丘脑葡萄糖感应途径减弱。此外，我们通过结合蛋白质-蛋白质相互作用（PPI）网络、共表达网络以及GK大鼠和Wistar大鼠的突变，生成了整合基因网络模块。在这些模块中，Bad、Map2k2、Adcy3、Adcy2和Gstm6等GK特异性基因可能在GK大鼠的下丘脑调控中起关键作用。我们的研究提供了GK大鼠下丘脑异常的综合图谱，揭示了T2D发病机制的新机制。
