Genotype-by-diet interactions determine susceptibility and resistance in T2D mouse models [Islet 2]

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。明确上述因素及其相互作用如何特异性影响T2D发病风险，仍是一项长期存在的研究挑战。小鼠模型可实现环境的精确控制与遗传背景的标准化复制，喂食不健康饮食的小鼠品系会表现出程度各异的代谢功能障碍，从显性糖尿病、饮食诱导肥胖到完全的代谢抵抗不等。当喂食高脂高糖（high-fat high-sugar, HFHS）饮食时，NZO/HlLtJ（简称NZO）小鼠会出现严重肥胖，且多数个体进展为糖尿病；C57BL/6J（简称B6J）小鼠会出现肥胖，但极少发展为显性糖尿病；而CAST/EiJ（简称CAST）小鼠则对肥胖与葡萄糖耐受不良具有抵抗性。本研究针对喂食对照饮食（低脂、无糖）与HFHS饮食的上述三种遗传多样性小鼠品系，开展了深度分子与代谢谱分析，以阐明可能影响糖尿病发病风险的代谢遗传特征。对八种组织的转录组分析（transcriptomic analysis）显示，品系间代谢差异的核心基础是显著的组织特异性分子异质性。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（lipid metabolism）与氧化磷酸化（oxidative phosphorylation）通路的差异，与各品系的肥胖及糖尿病易感性呈平行关联。在胰岛（pancreatic islets）中，NZO小鼠在HFHS饮食下会出现炎症反应，该反应被认为可导致β细胞（beta cell）功能障碍。综上，对上述遗传多样性小鼠品系的生理与分子谱分析，为深入理解代谢性疾病易感性个体差异的分子基础提供了重要研究基础。本数据集包含喂食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。