Abstract
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.
Highlights
IntroductionThe GK rat was generated through the introduction of various genetic mutations from continuous inbreeding; these rats develop diabetes spontaneously
The Goto-Kakizaki (GK) rat is an animal model of non-obese type 2 diabetes (T2D)
Type 2 diabetes (T2D), which is characterized by hyperglycaemia, insulin resistance of target tissues and insufficient insulin secretion from pancreatic β-cells, is a worldwide epidemic that affects more than 415 million people[1]
Summary
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 Goto-Kakizaki (GK) rat is one of the best characterized animal models of non-obese T2D and displays hyperglycaemia, β-cell defects and insulin resistance. GK rats spontaneously develop diabetes and were generated through repeated inbreeding of Wistar rats selected at the upper limit of the normal distribution for glucose tolerance[4]. GK rat embryos transplanted into Wistar rats still developed diabetes, indicating that genetic factors play much more important roles in pathogenesis than the gestational environment[8]. Dysfunction of the hypothalamus may result in a series of metabolic disorders, and the role of the hypothalamus in the non-obese GK rat model is unclear
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