Deconstructing and reconstructing obesity-induced diabetes (Diabesity) in mice
Deconstructing and reconstructing obesity-induced diabetes (Diabesity) in mice
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DOI：
10.2337/diabetes.51.3.825
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发表时间：
2002-03-01
期刊：
影响因子：
7.7
通讯作者：
Leiter, EH
中科院分区：
文献类型：
--
作者：
Reifsnyder, PC;Leiter, EH
肥胖驱动的2型糖尿病（糖尿病）涉及复杂的遗传和环境相互作用，以触发疾病。在这里，我们结合联合收割机变量数量的已知数量的数量性状位点（QTL）的肥胖和糖尿病的贡献新西兰肥胖（NZO/HLt）和非肥胖非糖尿病（NON/Lt）菌株的形式，10个区间定向重组同源株（RCS），与NON/Lt作为背景菌株，剖析所涉及的遗传相互作用。所有10个RCS的体重增加都比NON亲本品系显著更多，但没有一个像亲本、糖尿病倾向的NZO那样肥胖。这些RCS在F12的糖尿病发展范围在0和100%之间，取决于遗传构成。RCS-2、RCS-1和RCS-10代表特定致糖尿病QTL数量的逐步增加，导致糖尿病发病率的逐步增加。RCS-10重现了在（NZOxNON）F1雄性中观察到的100%发生率，但体重增加较少。类似地，RCS-6、RCS-7、RCS-8和RCS-9代表具有不同致糖尿病QTL组合的糖尿病易感菌株。RCS-3、-4和-5代表不转变为糖尿病的肥胖菌株。因为这些肥胖和糖尿病综合征反映了不同的QTL集合，而不是瘦素或瘦素受体基因中的无效突变，所以它们作为人类多基因肥胖/糖尿病综合征的模型是非常相关的。
Obesity-driven type 2 diabetes (diabesity) involves complex genetic and environmental interactions to trigger disease. Here, we combine variable numbers of known quantitative trait loci (QTL) for obesity and diabetes contributed by New Zealand Obese (NZO/HlLt) and Nonobese Nondiabetic (NON/Lt) strains in the form of 10 interval-directed recombinant congenic strains (RCS), with NON/Lt as the background strain, to dissect the genetic interactions involved. All 10 RCS gain significantly more weight than the NON parental strain, but none are as obese as the parental, diabetes-prone NZO. Diabetes development in these RCS at F12 ranges between 0 and 100%, depending on genetic constitution. RCS-2, -1, and -10 represent a step-wise increase in numbers of specific diabetogenic QTL, resulting in a step-wise increase in diabetes incidence. RCS-10 recreates the 100% incidence seen in (NZOxNON)F1 males, but with less weight gain. Similarly, RCS-6, -7, -8, and -9 represent diabetes-prone strains with different combinations of diabetogenic QTL. RCS-3, -4, and -5 represent obese strains that do not transit to diabetes. Because these obesity and diabetes syndromes reflect different collections of QTL, rather than null mutations in the leptin or leptin receptor genes, they are extremely relevant as models for the polygenic obesity/ diabesity syndromes in humans.