Data_Sheet_1_Genetic Background Shapes Phenotypic Response to Diet for Adiposity in the Collaborative Cross.docx

Defined as chronic excessive accumulation of adiposity, obesity results from long-term imbalance between energy intake and expenditure. The mechanisms behind how caloric imbalance occurs are complex and influenced by numerous biological and environmental factors, especially genetics, and diet. Population-based diet recommendations have had limited success partly due to the wide variation in physiological responses across individuals when they consume the same diet. Thus, it is necessary to broaden our understanding of how individual genetics and diet interact relative to the development of obesity for improving weight loss treatment. To determine how consumption of diets with different macronutrient composition alter adiposity and other obesity-related traits in a genetically diverse population, we analyzed body composition, metabolic rate, clinical blood chemistries, and circulating metabolites in 22 strains of mice from the Collaborative Cross (CC), a highly diverse recombinant inbred mouse population, before and after 8 weeks of feeding either a high protein or high fat high sucrose diet. At both baseline and post-diet, adiposity and other obesity-related traits exhibited a broad range of phenotypic variation based on CC strain; diet-induced changes in adiposity and other traits also depended largely on CC strain. In addition to estimating heritability at baseline, we also quantified the effect size of diet for each trait, which varied by trait and experimental diet. Our findings identified CC strains prone to developing obesity, demonstrate the genotypic and phenotypic diversity of the CC for studying complex traits, and highlight the importance of accounting for genetic differences when making dietary recommendations.

肥胖被定义为脂肪组织长期过度蓄积，其本质是能量摄入与消耗长期失衡的结果。能量失衡的发生机制极为复杂，受诸多生物与环境因素影响，其中尤以遗传与膳食因素最为关键。基于人群的膳食推荐效果往往有限，部分原因在于个体间对同一膳食的生理反应存在显著差异。因此，为优化减重治疗方案，我们亟需深化对个体遗传与膳食交互作用如何影响肥胖发生发展的认知。为探明不同宏量营养素组成的膳食对遗传多样性群体的脂肪蓄积及其他肥胖相关性状的影响，本研究针对协作杂交（Collaborative Cross, CC）这一高度多样化的重组近交系小鼠群体中的22个品系，分别在饲喂高蛋白膳食或高脂高蔗糖膳食8周前后，检测分析了其体成分、代谢率、临床血液生化指标及循环代谢物水平。无论是在基线状态还是膳食干预后，脂肪蓄积及其他肥胖相关表型均因CC品系不同而呈现出广泛的表型变异；膳食诱导的脂肪蓄积及其他性状变化同样主要依赖于CC品系背景。除了估算基线状态下的遗传力之外，我们还量化了不同性状对膳食干预的效应量，该效应量因性状与实验膳食类型而异。本研究不仅鉴定出易发生肥胖的CC品系，证实了协作杂交群体在复杂性状研究中所具备的基因型与表型多样性，同时也凸显了在制定膳食推荐方案时考虑遗传差异的重要性。