Estrogen, insulin, and dietary signals cooperatively regulate longevity signals to enhance resistance to oxidative stress in mice
Estrogen, insulin, and dietary signals cooperatively regulate longevity signals to enhance resistance to oxidative stress in mice
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DOI：
10.1074/jbc.m500924200
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发表时间：
2005-04-22
影响因子：
4.8
通讯作者：
Shirasawa, T
中科院分区：
文献类型：
--
作者：
Baba, T;Shimizu, T;Shirasawa, T
为了研究秀丽隐杆线虫daf-2中发现的长寿突变的生物学意义，我们通过使用靶向敲入策略将胰岛素受体的Pro-1195替换为Leu来产生同源小鼠模型。纯合子小鼠在新生期死于糖尿病酮症酸中毒，而杂合子小鼠显示胰岛素受体激酶活性受到抑制，但在成年期生长正常，不会自发发展为糖尿病。我们研究了杂合子胰岛素受体突变小鼠的长寿表型。在80%的氧气下，突变雌性小鼠比野生型雌性小鼠存活时间长33.3%，而突变雄性小鼠比野生型雄性小鼠存活时间长18.2%。这些结果表明，突变小鼠获得了更强的抗氧化应激能力，但长寿突变的益处在雌性小鼠中比雄性小鼠更明显。突变小鼠的锰超氧化物歧化酶活性显著上调，表明抑制胰岛素信号传导导致增强的抗氧化防御。为了分析性别差异的分子基础，我们给突变小鼠注射了雌激素。结果发现，当给予雌二醇时，小鼠在80%氧气下的存活时间延长。相比之下，突变型和野生型雌性小鼠在卵巢被切除后的存活时间缩短。与野生型小鼠相比，雌激素的影响在突变小鼠中是显著的，这表明雌激素调节突变小鼠中的胰岛素信号传导。此外，我们发现，当他们的饮食受到限制时，在氧化条件下的生存时间会进一步延长。总的来说，我们发现三种不同的信号：胰岛素，雌激素和饮食信号以独立和合作的方式发挥作用，以增强小鼠对氧化应激的抵抗力。
To investigate the biological significance of a longevity mutation found in daf-2 of Caenorhabditis elegans, we generated a homologous murine model by replacing Pro-1195 of insulin receptors with Leu using a targeted knock-in strategy. Homozygous mice died in the neonatal stage from diabetic ketoacidosis, whereas heterozygous mice showed the suppressed kinase activity of the insulin receptor but grew normally without spontaneously developing diabetes during adulthood. We examined heterozygous insulin receptor mutant mice for longevity phenotypes. Under 80% oxygen, mutant female mice survived 33.3% longer than wild-type female mice, whereas mutant male mice survived 18.2% longer than wild-type male mice. These results suggested that mutant mice acquired more resistance to oxidative stress, but the benefit of the longevity mutation was more pronounced in females than males. Manganese superoxide dismutase activity in mutant mice was significantly upregulated, suggesting that the suppressed insulin signaling leads to an enhanced antioxidant defense. To analyze the molecular basis of the gender difference, we administered estrogen to mutant mice. It was found that the survival of mice under 80% oxygen was extended when they were administered estradiol. In contrast, mutant and wild-type female mice showed shortened survivals when their ovaries were removed. The influence of estrogen is remarkable in mutant mice compared with wild-type mice, suggesting that estrogen modulates insulin signaling in mutant mice. Furthermore, we showed additional extension of survival under oxidative conditions when their diet was restricted. Collectively, we show that three distinct signals; insulin, estrogen, and dietary signals work in independent and cooperative ways to enhance the resistance to oxidative stress in mice.