Single Diabetic QTL Derived from OLETF Rat Is a Sufficient Agent for Severe Diabetic Phenotype in Combination with Leptin-Signaling Deficiency

Abstract

Obesity has been considered one of the leading causative agents for diseases such as type 2 diabetes, stroke, and heart attack. Due to their complex etiology, establishing auseful animal model is increasingly crucial for better molecular understanding of how obesity influences on disease development. OLETF rat is a spontaneous model of type 2 diabetes. We mapped 14 hyperglycemia QTLs in the genome of the OLETF rat and subsequently generated a panel of congenic strains each possessing OB-R mutation in F344 genetic background. Here we show that one of the loci,Nidd2/of, is highly responsive to obesity. When leptin receptor mutation is introgressed into theNidd2/ofcongenic strain, the rat showed hyperglycemia equivalent to that of the parental OLETF rat. This suggests that theNidd2/oflocus has a strong genetic interaction with leptin signaling pathway. Furthermore, when another hyperglycemiaQTL Nidd1/ofis additionally combined, the strain developed overt diabetes. A single QTL dissected out in spontaneous model normally exerts only mild effect on the quantitative trait, which makes it difficult to clone the gene. Our new model may help not only to identify the causative gene but also to investigate how obesity interacts with a QTL to regulate diabetic traits.