Estrada-Smith Daria, Collins Alan R, Wang Xuping, Crockett Craig, Castellani Lawrence, Lusis Aldons J, Davis Richard C
Department of Human Gentics, University of California Los Angeles, USA.
Diabetes. 2006 Aug;55(8):2265-71. doi: 10.2337/db06-0377.
Previous characterization of mouse chromosome 2 identified genomic intervals that influence obesity, insulin resistance, and dyslipidemia. For this, resistant CAST/Ei (CAST) alleles were introgressed onto a susceptible C57BL/6J background to generate congenic strains with CAST alleles encompassing 67-162 Mb (multigenic obesity 6 [MOB6]) and 84-180 Mb (MOB5) from mouse chromosome 2. To examine the effects of each congenic locus on atherosclerosis and glucose disposal, we bred each strain onto a sensitizing LDL receptor-null (LDLR(-/-)) C57BL/6J background to predispose them to hypercholesterolemia and insulin resistance. LDLR(-/-) congenics and controls were characterized for measures of atherogenesis, insulin sensitivity, and obesity. We identified a genomic interval unique to the MOB6 congenic (72-84 Mb) that dramatically decreased atherosclerosis by approximately threefold and decreased insulin resistance. This region also reduced adiposity twofold. Conversely, the congenic region unique to MOB5 (162-180 Mb) increased insulin resistance but had little effect on atherosclerosis and adiposity. The MOB congenic intervals are concordant to human and rat quantitative trait loci influencing diabetes and atherosclerosis traits. Thus, our results define a strategy for studying the poorly understood interactions between diabetes and atherosclerosis and for identifying genes underlying the cardiovascular complications of insulin resistance.
先前对小鼠2号染色体的特征分析确定了影响肥胖、胰岛素抵抗和血脂异常的基因组区间。为此，将抗性CAST/Ei（CAST）等位基因导入易感性C57BL/6J背景中，以产生携带来自小鼠2号染色体67 - 162 Mb（多基因肥胖6 [MOB6]）和84 - 180 Mb（MOB5）的CAST等位基因的近交系。为了研究每个近交系基因座对动脉粥样硬化和葡萄糖代谢的影响，我们将每个品系培育到一个致敏的低密度脂蛋白受体缺失（LDLR(-/-)）的C57BL/6J背景中，使它们易患高胆固醇血症和胰岛素抵抗。对LDLR(-/-)近交系和对照进行动脉粥样硬化形成、胰岛素敏感性和肥胖指标的特征分析。我们确定了MOB6近交系特有的一个基因组区间（72 - 84 Mb），该区间使动脉粥样硬化显著降低约三倍，并降低了胰岛素抵抗。该区域还使肥胖程度降低了两倍。相反，MOB5特有的近交系区域（162 - 180 Mb）增加了胰岛素抵抗，但对动脉粥样硬化和肥胖影响不大。MOB近交系区间与影响糖尿病和动脉粥样硬化性状的人类和大鼠数量性状基因座一致。因此，我们的结果确定了一种策略，用于研究糖尿病和动脉粥样硬化之间了解甚少的相互作用，以及用于鉴定胰岛素抵抗心血管并发症背后的基因。
