Ingvorsen C, Karp N A, Lelliott C J
Mouse Pipelines, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Robinson Way, Cambridge, UK.
Nutr Diabetes. 2017 Apr 10;7(4):e261. doi: 10.1038/nutd.2017.6.
Metabolic disorders are commonly investigated using knockout and transgenic mouse models on the C57BL/6N genetic background due to its genetic susceptibility to the deleterious metabolic effects of high-fat diet (HFD). There is growing awareness of the need to consider sex in disease progression, but limited attention has been paid to sexual dimorphism in mouse models and its impact in metabolic phenotypes. We assessed the effect of HFD and the impact of sex on metabolic variables in this strain.
We generated a reference data set encompassing glucose tolerance, body composition and plasma chemistry data from 586 C57BL/6N mice fed a standard chow and 733 fed a HFD collected as part of a high-throughput phenotyping pipeline. Linear mixed model regression analysis was used in a dual analysis to assess the effect of HFD as an absolute change in phenotype, but also as a relative change accounting for the potential confounding effect of body weight.
HFD had a significant impact on all variables tested with an average absolute effect size of 29%. For the majority of variables (78%), the treatment effect was modified by sex and this was dominated by male-specific or a male stronger effect. On average, there was a 13.2% difference in the effect size between the male and female mice for sexually dimorphic variables. HFD led to a significant body weight phenotype (24% increase), which acts as a confounding effect on the other analysed variables. For 79% of the variables, body weight was found to be a significant source of variation, but even after accounting for this confounding effect, similar HFD-induced phenotypic changes were found to when not accounting for weight.
HFD and sex are powerful modifiers of metabolic parameters in C57BL/6N mice. We also demonstrate the value of considering body size as a covariate to obtain a richer understanding of metabolic phenotypes.
由于C57BL/6N基因背景对高脂饮食（HFD）的有害代谢影响具有遗传易感性，因此代谢紊乱通常使用该基因背景的基因敲除和转基因小鼠模型进行研究。人们越来越意识到在疾病进展中需要考虑性别因素，但对小鼠模型中的性别二态性及其对代谢表型的影响关注有限。我们评估了高脂饮食对该品系代谢变量的影响以及性别对其的影响。
我们生成了一个参考数据集，涵盖了作为高通量表型分析流程一部分收集的586只喂食标准饲料的C57BL/6N小鼠和733只喂食高脂饮食的小鼠的葡萄糖耐量、身体组成和血浆化学数据。线性混合模型回归分析用于双重分析，以评估高脂饮食作为表型的绝对变化的影响，同时也作为考虑体重潜在混杂效应的相对变化。
高脂饮食对所有测试变量都有显著影响，平均绝对效应大小为29%。对于大多数变量（78%），治疗效果因性别而异，且主要表现为雄性特异性或雄性更强的效应。对于具有性别二态性的变量，雄性和雌性小鼠的效应大小平均相差13.2%。高脂饮食导致显著的体重表型（增加24%），这对其他分析变量产生混杂效应。对于79%的变量，体重被发现是一个显著的变异来源，但即使考虑了这种混杂效应，与不考虑体重时相比，仍发现了类似的高脂饮食诱导的表型变化。
高脂饮食和性别是C57BL/6N小鼠代谢参数的有力调节因素。我们还证明了将体型作为协变量来更深入理解代谢表型的价值。
