Maternal environment and genotype interact to establish diabesity in mice
Maternal environment and genotype interact to establish diabesity in mice
复制标题
DOI：
10.1101/gr.147000
复制
发表时间：
2000-10-01
期刊：
影响因子：
7
通讯作者：
Leiter, EH
中科院分区：
文献类型：
--
作者：
Reifsnyder, PC;Churchill, G;Leiter, EH
肥胖是II型糖尿病的一个主要危险因素，在西方人群中越来越普遍，他们在工作场所和家庭中消耗的能量都较少，但摄入的热量却很高。大多数人类肥胖，可能还有大多数II型糖尿病，反映了多基因遗传而不是单基因遗传。我们通过将肥胖的、糖尿病倾向的NZO（新西兰肥胖）/HILt品系与相对瘦的NON [非肥胖的非糖尿病的]/Lt品系异交，然后将肥胖的Fl小鼠与瘦的NON/Lt亲本品系回交，从遗传学上解剖了肥胖驱动的II型糖尿病的多基因小鼠模型。在203只首次回交雄性的群体中观察到体重的连续分布。22%的第一回交男性发展明显的糖尿病表现出最高的围青春期体重增加和最早的高胰岛素血症的发展。我们报告了一个复杂的糖尿病易感（“糖尿病”）QTL（数量性状基因座）的1号染色体上贡献显着的主要影响增加体重，血浆胰岛素和血糖。NZO贡献了对第12和第5染色体上的肥胖参数具有显著主效应的QTL。14号染色体上的NON QTL与12号染色体上的NZO肥胖QTL上位性相互作用以增加肥胖。虽然1号染色体上的致糖尿病QTL的主要作用是快速生长，而不是肥胖，但它与12号染色体上的肥胖QTL上位性相互作用，以增加血糖水平。在1号染色体上的NZO贡献的QTL与15号和17号染色体上的其他NZO贡献的QTL之间以及与2号染色体上的非贡献的QTL之间发现了引起体重和/或血糖显著增加的额外复杂上位性相互作用。我们进一步表明，某些这些基因间的相互作用的预测，或增强，产妇产后环境。我们通过交叉培养实验表明，母体环境的影响部分是因为肥胖F1母鼠乳汁中存在早期肥胖诱导因子。我们还讨论了使用重组同类菌株分离和重新组装相互作用的QTL的策略，以供将来研究。
Obesity, a major risk factor for type It diabetes, is becoming more prevalent in Western populations consuming high calorie diets while expending less energy both at the workplace and at home. Most human obesity, and probably most type II diabetes as well, reflects polygenic rather than monogenic inheritance. We have genetically dissected a polygenic mouse model of obesity-driven type ii diabetes by outcrossing the obese, diabetes-prone, NZO (New Zealand Obese)/HILt strain to the relatively lean NON [Nonobese Nondiabetic]/Lt strain, and then reciprocally backcrossing obese Fl mice to the lean NON/Lt parental strain. A continuous distribution of body weights was observed in a population of 203 first backcross males. The 22% of first backcross males developing overt diabetes showed highest peripubertal weight gains and earliest development of hyperinsulinemia. We report a complex diabetes-predisposing ("diabesity") QTL (Quantitative Trait loci) on chromosome 1 contributing significant main effects to increases in body weight, plasma insulin, and plasma glucose. NZO contributed QTL with significant main effects on adiposity parameters on chromosomes 12 and 5. A NON QTL on chromosome 14 interacted epistatically with the NZO obesity QTL on chromosome 12 to increase adiposity. Although the main effect of the diabetogenic QTL on chromosome 1 was on rapid growth rather than adiposity, it interacted epistatically with the obesity QTL on chromosome 12 to increase plasma glucose levels. Additional complex epistatic interactions eliciting significant increases in body weight and/or plasma glucose were found between the NZO-contributed QTL on chromosome 1 and other NZO-contributed QTL on chromosomes 15 and 17, as well as with an NON-contributed QTL on chromosome 2. We further show that certain of these intergenic interactions are predicated on, or enhanced by, the maternal postparturitional environment. We show by cross-fostering experiments that the maternal environmental influence in part is because of the presence of early obesity-inducing Factors in the milk of obese Fl dams. We also discuss a strategy for using recombinant congenic strains to separate and reassemble interacting QTL For future study.