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

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科研挑战。小鼠模型可实现环境与遗传背景的精准控制及重复验证，且喂食不健康饮食的不同小鼠品系会表现出各异的代谢功能异常表型，范围从显性糖尿病、饮食诱导肥胖直至完全的代谢抵抗。当喂食高脂高糖（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）小鼠虽会出现肥胖，但极少发展为显性糖尿病；而CAST/EiJ（CAST）小鼠则可抵抗肥胖与葡萄糖不耐受。本研究对喂食对照（低脂无糖）饮食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，旨在明确可能影响糖尿病发病风险的遗传代谢特征。对八种组织的转录组学分析显示，品系间代谢差异的核心分子基础存在显著的组织特异性变异。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、脂质代谢以及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平行对应关系。在胰岛中，NZO小鼠喂食HFHS饮食后会出现炎症反应，该反应被认为可促进β细胞功能异常。综上，对这些遗传背景各异的小鼠品系进行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。本数据集包含对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测序数据进行基因表达谱分析的结果。