Significant evidence suggests protective effects of flavonoids against obesity in animal models, but these often do not translate to humans. One explanation for this disconnect is use of a few mouse strains (notably C57BL/6 J) in obesity studies. Obesity is a multifactorial disease. The underlying causes are not fully replicated by the high-fat C57BL/6 J model, despite phenotypic similarities. Furthermore, the impact of genetic factors on the activities of flavonoids is unknown. This study was designed to explore how diverse mouse strains respond to diet-induced obesity when fed a representative flavonoid. A subset of Collaborative Cross founder strains (males and females) were placed on dietary treatments (low-fat, high-fat, high-fat with quercetin, high-fat with quercetin and antibiotics) longitudinally. Diverse responses were observed across strains and sexes. Quercetin appeared to moderately blunt weight gain in male C57 and both sexes of 129S1/SvImJ mice, and slightly increased weight gain in female C57 mice. Surprisingly, quercetin dramatically blunted weight gain in male, but not female, PWK/PhJ mice. For female mice, quercetin blunted weight gain (relative to the high-fat phase) in CAST/PhJ, PWK/EiJ and WSB/EiJ mice compared to C57. Antibiotics did not generally result in loss of protective effects of quercetin. This highlights complex interactions between genetic factors, sex, obesity stimuli, and flavonoid intake, and the need to move away from single inbred mouse models to enhance translatability to diverse humans. These data justify use of genetically diverse Collaborative Cross and Diversity Outbred models which are emerging as invaluable tools in the field of personalized nutrition.

重要证据表明类黄酮在动物模型中对肥胖具有保护作用，但这些通常不会转化为人类。这种脱节的一种解释是在肥胖研究中使用了一些小鼠品系（特别是 C57BL/6 J）。肥胖是一种多因素疾病。尽管表型相似，但高脂肪 C57BL/6 J 模型并未完全复制根本原因。此外，遗传因素对类黄酮活性的影响尚不清楚。本研究旨在探索不同的小鼠品系在喂食具有代表性的黄酮类化合物时如何对饮食诱导的肥胖做出反应。将协作交叉创建者菌株（雄性和雌性）的一个子集纵向置于饮食治疗（低脂、高脂、高脂槲皮素、高脂槲皮素和抗生素）中。在品系和性别之间观察到了不同的反应。槲皮素似乎可以适度抑制雄性 C57 和两性 129S1/SvImJ 小鼠的体重增加，并略微增加雌性 C57 小鼠的体重增加。令人惊讶的是，槲皮素显着减缓了雄性 PWK/PhJ 小鼠的体重增加，而不是雌性。对于雌性小鼠，与 C57 相比，槲皮素减缓了 CAST/PhJ、PWK/EiJ 和 WSB/EiJ 小鼠的体重增加（相对于高脂肪期）。抗生素通常不会导致槲皮素的保护作用丧失。这突出了遗传因素、性别、肥胖刺激和类黄酮摄入量之间复杂的相互作用，以及摆脱单一近交小鼠模型以提高对不同人类的可译性的必要性。