Single diabetic QTL derived from OLETF rat is a sufficient agent for severe diabetic phenotype in combination with leptin-signaling deficiency.

Experimental Diabetes Research Pub Date : 2012-01-01 Epub Date: 2012-12-05 DOI:10.1155/2012/858121
Hiroyuki Kose, Takahisa Yamada, Kozo Matsumoto
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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 a useful 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 the Nidd2/of congenic strain, the rat showed hyperglycemia equivalent to that of the parental OLETF rat. This suggests that the Nidd2/of locus has a strong genetic interaction with leptin signaling pathway. Furthermore, when another hyperglycemia QTL Nidd1/of is 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.

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来源于 OLETF 大鼠的单个糖尿病 QTL 是导致严重糖尿病表型和瘦素信号缺乏症的充分因素。
肥胖一直被认为是 2 型糖尿病、中风和心脏病等疾病的主要致病因素之一。由于这些疾病的病因复杂,建立一个有用的动物模型对于更好地从分子角度了解肥胖如何影响疾病的发展越来越重要。OLETF 大鼠是一种自发的 2 型糖尿病模型。我们在 OLETF 大鼠的基因组中绘制了 14 个高血糖 QTLs,随后在 F344 遗传背景下产生了一组具有 OB-R 突变的同源品系。在这里,我们发现其中一个基因位点(Nidd2/of)对肥胖具有高度敏感性。当瘦素受体突变被导入Nidd2/of同源品系时,大鼠表现出与亲代OLETF大鼠相同的高血糖。这表明 Nidd2/of 基因座与瘦素信号通路有很强的遗传相互作用。此外,当另一个高血糖QTL Nidd1/of被额外组合时,该品系会发展成明显的糖尿病。在自发模型中解剖出的单个 QTL 通常只对数量性状产生轻微影响,因此很难克隆该基因。我们的新模型不仅有助于确定致病基因,还有助于研究肥胖如何与 QTL 相互作用以调控糖尿病性状。
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来源期刊
Experimental Diabetes Research
Experimental Diabetes Research 医学-内分泌学与代谢
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3-8 weeks
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