Leiter Edward H, Reifsnyder Peter C
Jackson Laboratory, Bar Harbor, Maine 04609, USA.
Diabetes. 2004 Feb;53 Suppl 1:S4-11. doi: 10.2337/diabetes.53.2007.s4.
The genetic basis for the more common forms of human obesity predisposing to insulin resistance and development of type 2 diabetes is multigenic rather than monogenic in origin. New mouse "diabesity" models have been created by combining independent diabetes risk-conferring quantitative trait loci from two unrelated parental strains: New Zealand Obese (NZO/HlLt) and Nonobese Nondiabetic (NON/Lt). F1 hybrid males, heterozygous at all polymorphic autosomal loci distinguishing the two parental strains, are driven to obesity-induced diabetes (diabesity) at high frequencies. This review focuses on two new recombinant congenic strains (RCSs) developed by introgressing multiple NZO/HlLt chromosomal segments into the nominally diabesity-resistant NON/Lt strain background. Both RCSs gain more weight than NON animals. Although exhibiting comparable weight gain and adiposity, only one of the two RCSs develops diabetes. Hence, these two RCSs will be instructive in elucidating genetic and pathophysiological differences underlying uncomplicated obesity syndromes versus diabetogenic obesity (diabesity) syndromes. Unlike mice with null mutations in a single gene producing morbid obesity, the new models develop a more moderate obesity produced by the interaction of numerous genes with relatively small effects. These RCSs are differentially sensitive to adverse side effects of thiazolidinediones and thus should be particularly useful for pharmacogenetic analyses.
导致胰岛素抵抗和2型糖尿病发生的常见人类肥胖形式的遗传基础是多基因的，而非单基因起源。通过将来自两个不相关亲本品系（新西兰肥胖品系（NZO/HlLt）和非肥胖非糖尿病品系（NON/Lt））的独立糖尿病风险相关数量性状基因座进行组合，已创建了新的小鼠“糖尿病肥胖症”模型。在区分两个亲本品系的所有多态性常染色体位点上均为杂合子的F1代杂种雄性小鼠，会以高频率发展为肥胖诱导型糖尿病（糖尿病肥胖症）。本综述聚焦于通过将多个NZO/HlLt染色体片段渗入名义上抗糖尿病肥胖症的NON/Lt品系背景而培育出的两个新的重组近交系（RCS）。两个RCS的体重均比NON动物增加得更多。尽管二者体重增加和肥胖程度相当，但两个RCS中只有一个会发展为糖尿病。因此，这两个RCS对于阐明单纯性肥胖综合征与致糖尿病性肥胖（糖尿病肥胖症）综合征背后的遗传和病理生理差异具有指导意义。与单基因无效突变导致病态肥胖的小鼠不同，新模型产生的肥胖程度更为适中，是由众多效应相对较小的基因相互作用所致。这些RCS对噻唑烷二酮类药物的不良副作用具有不同的敏感性，因此对于药物遗传学分析应特别有用。
