Paz Avia, Midlej Kareem, Zohud Osayd, Lone Iqbal M, Iraqi Fuad A
Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Animal Model Exp Med. 2025 Jan;8(1):126-141. doi: 10.1002/ame2.12488. Epub 2024 Oct 28.
Over the past few decades, a threefold increase in obesity and type 2 diabetes (T2D) has placed a heavy burden on the health-care system and society. Previous studies have shown correlations between obesity, T2D, and neurodegenerative diseases, including dementia. It is imperative to further understand the relationship between obesity, T2D, and cognitive deficits.
This investigation tested and evaluated the cognitive impact of obesity and T2D induced by high-fat diet (HFD) and the effect of the host genetic background on the severity of cognitive decline caused by obesity and T2D in collaborative cross (CC) mice. The CC mice are a genetically diverse panel derived from eight inbred strains.
Our findings demonstrated significant variations in the recorded phenotypes across different CC lines compared to the reference mouse line, C57BL/6J. CC037 line exhibited a substantial increase in body weight on HFD, whereas line CC005 exhibited differing responses based on sex. Glucose tolerance tests revealed significant variations, with some lines like CC005 showing a marked increase in area under the curve (AUC) values on HFD. Organ weights, including brain, spleen, liver, and kidney, varied significantly among the lines and sexes in response to HFD. Behavioral tests using the Morris water maze indicated that cognitive performance was differentially affected by diet and genetic background.
Our study establishes a foundation for future quantitative trait loci mapping using CC lines and identifying genes underlying the comorbidity of Alzheimer's disease (AD), caused by obesity and T2D. The genetic components may offer new tools for early prediction and prevention.
在过去几十年中，肥胖症和2型糖尿病（T2D）增加了两倍，给医疗保健系统和社会带来了沉重负担。先前的研究表明，肥胖、T2D与包括痴呆症在内的神经退行性疾病之间存在关联。进一步了解肥胖、T2D与认知缺陷之间的关系势在必行。
本研究测试并评估了高脂饮食（HFD）诱导的肥胖和T2D对协作杂交（CC）小鼠认知的影响，以及宿主遗传背景对肥胖和T2D所致认知衰退严重程度的影响。CC小鼠是一个由八个近交系衍生而来的基因多样化群体。
我们的研究结果表明，与参考小鼠品系C57BL/6J相比，不同CC品系记录的表型存在显著差异。CC037品系在高脂饮食下体重显著增加，而CC005品系根据性别表现出不同的反应。葡萄糖耐量试验显示出显著差异，一些品系如CC005在高脂饮食下曲线下面积（AUC）值显著增加。包括脑、脾、肝和肾在内的器官重量在品系和性别之间因高脂饮食而有显著差异。使用莫里斯水迷宫进行的行为测试表明，认知表现受饮食和遗传背景的影响不同。
我们的研究为未来使用CC品系进行数量性状基因座定位以及鉴定由肥胖和T2D引起的阿尔茨海默病（AD）合并症的潜在基因奠定了基础。这些遗传成分可能为早期预测和预防提供新工具。
