Genotype-by-diet interactions determine susceptibility and resistance in T2D mouse models [kidney]

Genetic and lifestyle factors greatly impact the development of metabolic diseases including Type 2 Diabetes (T2D). It is an ongoing challenge to determine how these factors and their interplay specifically contribute to risk of T2D. Mouse models allow precise control of environment and genetic replication, and mouse strains fed an unhealthy diet show variable signs of metabolic dysfunction ranging from overt diabetes to diet-induced obesity to complete resistance. When fed a high-fat high-sugar (HFHS) diet, NZO/HlLtJ (NZO) mice become severely obese and many become diabetic, C57BL/6J (B6J) mice develop obesity but seldom overt diabetes, and CAST/EiJ (CAST) mice are resistant to obesity and glucose intolerance. We present deep molecular and metabolic profiling of these three genetically diverse mouse strains fed control (low fat, no sugar) and HFHS diets to define inherited aspects of metabolism that may impact diabetes risk. Transcriptomic analysis of eight tissues revealed significant tissue-specific molecular variability underpinning the metabolic differences across strains. The most distinct diet responses were observed in adipose and pancreas. In adipose tissue, differences in immunometabolism, lipid metabolism, and oxidative phosphorylation pathways parallel the susceptibility to obesity and diabetes across strains. In pancreatic islets, there was inflammation associated with HFHS diet in NZO mice that is expected to contribute to beta cell dysfunction. Taken together, physiological and molecular profiling of these genetically diverse mouse strains provides a foundation for deeper understanding the molecular basis of individual differences in susceptibility to metabolic diseases. Gene expression profiling analysis of RNA-seq data for male and female C57BL/6J, NZO/HlLtJ, and CAST/EiJ animals fed either a high fat, high sugar diet or control diet.遗传与生活方式因素对包括2型糖尿病（Type 2 Diabetes, T2D）在内的代谢性疾病的发生发展具有显著影响。明确上述因素及其交互作用如何特异性影响2型糖尿病的患病风险，仍是一项长期存在的研究挑战。小鼠模型可实现环境的精准控制与遗传背景的重复构建，饲喂不健康饮食的不同小鼠品系会表现出程度各异的代谢功能障碍表型，从显性糖尿病、饮食诱导肥胖直至完全的代谢抵抗。当饲喂高脂高糖（high-fat high-sugar, HFHS）饮食时，NZO/HlLtJ（NZO）小鼠会出现严重肥胖，且多数个体进展为糖尿病；C57BL/6J（B6J）小鼠可出现肥胖，但极少发展为显性糖尿病；而CAST/EiJ（CAST）小鼠则表现出肥胖抵抗与葡萄糖耐受不良。本研究对饲喂对照饮食（低脂、无糖）与高脂高糖饮食的上述三种遗传背景各异的小鼠品系开展了深度分子与代谢谱分析，以阐明可能影响糖尿病患病风险的代谢遗传特征。对八种组织开展的转录组学（Transcriptomic）分析显示，品系间代谢差异的核心基础是组织特异性分子异质性，其中脂肪组织与胰腺中观察到最为显著的饮食应答差异。在脂肪组织中，免疫代谢（immunometabolism）、脂质代谢与氧化磷酸化通路的差异与各品系的肥胖及糖尿病易感性呈对应关系。在胰岛中，NZO小鼠饲喂高脂高糖饮食后会出现炎症反应，该反应被认为可促进β细胞功能障碍。综上，对这些遗传背景各异的小鼠品系开展的生理与分子表征研究，为深入理解代谢性疾病易感性个体差异的分子机制奠定了重要基础。本数据集包含了饲喂高脂高糖饮食或对照饮食的雌雄C57BL/6J、NZO/HlLtJ及CAST/EiJ小鼠的RNA测序（RNA-seq）数据的基因表达谱分析结果。