Department of Life Sciences, National Cheng Kung University, Tainan, Taiwan; Department of Physical education, National Taiwan Normal University, Taipei, Taiwan.
Department of Food and Nutrition, Providence University, Taichung, Taiwan.
Exp Gerontol. 2017 Dec 1;99:61-68. doi: 10.1016/j.exger.2017.08.023. Epub 2017 Aug 23.
Rodent animal models take at least 18months to develop aging phenotypes for researchers to investigate the mechanism of age-related metabolic complications. Senescence-accelerated mouse prone 8 (SAMP8) shortens the process of aging and may facilitate an alternative model for studying age-related insulin resistance. The short-lived strain SAMP8 and two long-lived strains SAM resistant 1 (SAMR1) mice and C57BL/6 mice at 12 (young) and 40weeks old (old) were used in the present study. Glucose tolerance test, histology and signaling pathways involved in lipid metabolism in adipose tissue and liver and key components of insulin signaling pathway in the skeletal muscle were determined in these three strains. We found that short-lived SAMP8 mice developed symptoms of insulin resistance including hyperglycemia, hyperinsulinemia, and impaired glucose tolerance in association with adipocyte hypertrophy and ectopic lipid accumulation in liver and muscle at 40-wk.-old. Significantly increased serum IL-6, leptin, and resistin levels and adipogenic transcription factor PPARγ and macrophage marker F4/80 mRNA expression in adipose tissues were observed in old SAMP8 mice, compared with that in young SAMP8 mice. Marked increases in SREBP1 and PPARγ and a decrease in PPARα at mRNA level in accordance with activation of mTOR/Akt pathway were contributed to hepatic lipid accumulation in old SAMP8 mice. Down-regulation of insulin signaling pathway including IRβ, IRS1, and AS160 at protein level in skeletal muscle was observed in old SAMP8 mice. At 40-wk.-old, both long-lived SAMR1 and C57BL/6 mice have not been fully developed age-related metabolic disorders including insulin resistance and visceral fat expansion in line with fewer defects in lipid metabolism and skeletal muscle insulin signaling pathway. In conclusion, our data suggest the suitability of the SAMP8 mice as a model for studying age-related metabolic complications.
啮齿动物动物模型需要至少 18 个月才能发展出衰老表型，以供研究人员研究与年龄相关的代谢并发症的机制。快速衰老品系 8 （SAMP8）缩短了衰老过程，可能为研究与年龄相关的胰岛素抵抗提供了替代模型。本研究使用了寿命较短的 SAMP8 品系和两种寿命较长的 SAM 抗性 1 （SAMR1）小鼠和 C57BL/6 小鼠，分别在 12（年轻）和 40 周龄（年老）时进行研究。在这三种品系中，测定了葡萄糖耐量试验、脂肪组织和肝脏中涉及脂质代谢的组织学和信号通路以及骨骼肌中胰岛素信号通路的关键组成部分。我们发现，寿命较短的 SAMP8 小鼠在 40 周龄时出现了胰岛素抵抗的症状，包括高血糖、高胰岛素血症和葡萄糖耐量受损，同时伴有脂肪细胞肥大和肝脏和肌肉中的异位脂质积累。与年轻的 SAMP8 小鼠相比，年老的 SAMP8 小鼠的血清 IL-6、瘦素和抵抗素水平以及脂肪形成转录因子 PPARγ 和巨噬细胞标记物 F4/80 mRNA 表达显著增加。在年老的 SAMP8 小鼠中，SREBP1 和 PPARγ 的显著增加和 PPARα 的减少与 mTOR/Akt 通路的激活相一致，导致肝脏脂质积累。在年老的 SAMP8 小鼠中，胰岛素信号通路包括 IRβ、IRS1 和 AS160 的下调在蛋白质水平上观察到。在 40 周龄时，两种长寿的 SAMR1 和 C57BL/6 小鼠尚未完全发展出与年龄相关的代谢紊乱，包括胰岛素抵抗和内脏脂肪扩张，这与脂质代谢和骨骼肌胰岛素信号通路的缺陷较少有关。总之，我们的数据表明，SAMP8 小鼠适合作为研究与年龄相关的代谢并发症的模型。
