Age-dependent alterations of glucose clearance and homeostasis are temporally separated and modulated by dietary fat

Diet- and age-dependent changes in glucose regulation in mice occur, but the temporal development, mechanisms and influence of dietary fat source remainto be defined. We followed metabolic changes in three groups of mice including a low-fat diet (LFD) reference group and two high-fat, high-sucrose diets based on eitherfish oil (FOD) or soybean oil (SOD), rich in ?3- and ?6-polyunsaturated fatty acids, respectively, to closely monitor the age-dependent development in glucose regulation in both obese (SOD-fed) and lean (LFD- and FOD-fed) mice. We assessed glucose homeostasis and glucose clearance at week 8, 12, 16, 24, 31, and39 and performed an insulin tolerance test at week 40. We further analyzed correlations between the gut microbiota and key metabolic parameters. Interestingly, alterations in glucose homeostasis and glucose clearance were temporally separated, while 16S ribosomal gene amplicon sequencing revealedthat gut microbial alterations formed correlation clusters with fat mass and either glucose homeostasis or glucose clearance, but rarely both. Importantly, effective glucose clearance was maintained in FOD- and even increased in LFD-fed mice, whereas SOD-fed mice rapidly developed impaired glucose clearance followed by a gradual improvement from week 8 to week 39. All groups had similar responses to insulin 40 weeks post diet initiation despite severe nonalcoholic steatohepatitis in SOD-fed mice. We conclude that age-related alterations in glucose regulation may occur in both lean and obese mice and are modulated by dietary fat as indicated by thesustained metabolic homeostasis observed in mice fed ?3-polyunsaturated fatty acids.

小鼠的血糖调节会出现饮食与年龄依赖性变化，但其时间动态进程、潜在机制以及膳食脂肪来源的影响仍有待阐明。本研究追踪了三组小鼠的代谢变化：包括低脂饮食（low-fat diet, LFD）对照组，以及分别以鱼油（fish oil, FOD）和大豆油（soybean oil, SOD）为脂肪来源的高脂高蔗糖饮食组，其中鱼油与大豆油分别富含ω3多不饱和脂肪酸与ω6多不饱和脂肪酸；借此我们可密切监测肥胖（饲喂SOD）与消瘦（饲喂LFD或FOD）小鼠血糖调节的年龄依赖性变化进程。我们分别在饮食干预第8、12、16、24、31及39周评估了小鼠的血糖稳态与葡萄糖清除能力，并在干预第40周开展了胰岛素耐量试验。我们还进一步分析了肠道菌群与核心代谢参数之间的相关性。值得注意的是，血糖稳态与葡萄糖清除能力的变化呈现出时间上的分离；而16S核糖体基因扩增子测序结果显示，肠道菌群的变化可与脂肪量以及血糖稳态或葡萄糖清除能力形成关联簇，但极少同时与两者相关。重要的是，饲喂FOD的小鼠可维持有效的葡萄糖清除能力，而饲喂LFD的小鼠该能力甚至有所提升；与之相反，饲喂SOD的小鼠葡萄糖清除能力会快速受损，并在第8周至39周期间逐步改善。尽管饲喂SOD的小鼠出现了严重的非酒精性脂肪性肝炎，但所有组别在饮食干预40周后对胰岛素的响应均较为相似。综上，我们认为消瘦与肥胖小鼠均可能出现年龄相关的血糖调节变化，且该变化受膳食脂肪的调控——这一点可从饲喂ω3多不饱和脂肪酸的小鼠维持稳定的代谢稳态得到佐证。