Long-lived growth hormone receptor knockout mice: Interaction of reduced insulin-like growth factor I/insulin signaling and caloric restriction
Long-lived growth hormone receptor knockout mice: Interaction of reduced insulin-like growth factor I/insulin signaling and caloric restriction
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DOI：
10.1210/en.2004-1120
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发表时间：
2005-02-01
期刊：
影响因子：
4.8
通讯作者：
Bartke, A
中科院分区：
文献类型：
--
作者：
Al-Regaiey, KA;Masternak, MM;Bartke, A
胰岛素样生长因子-I/胰岛素信号的减少和热量限制(CR)被认为可以延长寿命和延缓与年龄相关的疾病。为了解决这两种干预措施的相互作用，我们让正常(N)和长期存活的生长激素受体基因敲除(GHRKO)小鼠在断奶时开始接受为期20个月的CR。我们还使用了转基因牛生长激素(BGH TG)小鼠进行比较，这些小鼠过表达GH，寿命短，胰岛素抵抗。N组动物的循环胰岛素和IGF-I水平被CR降低，而GHRKO组动物表现出非常低的胰岛素和检测不到的IGF-I。在GHRKO小鼠中，肝脏Akt的磷酸化一直被CR降低，并且非常低。BGH转基因小鼠的Akt活性增加。CR和GHRKO在mRNA水平上增加了叉头盒O1(Foxo1)转录因子的表达。然而，Foxo1蛋白水平只在GHRKO小鼠中升高。在GHRKO小鼠中，共激活物--过氧化物酶体增殖物激活受体--γ-共激活物1α在基因和蛋白水平上均增加。与自由喂养的N-CR和GHRKO小鼠相比，N-CR和GHRKO小鼠的磷酸化cAMP反应元件结合蛋白和活性p38也显著增加，而BGH-TG小鼠的这些蛋白水平显著降低。脱乙酰酶sirtuin1(SIRT1)的蛋白水平在两个CR组中升高，出人意料的是，在BGH TG小鼠中也是如此。这些结果表明Akt/Foxo1通路在调节啮齿动物寿命方面发挥了重要作用。糖异生途径的激活和脂肪代谢的增加可能参与了促生长激素和胰岛素信号减弱对长寿的影响。这些结果也增加了GH受体/GH结合蛋白基因和CR的靶向破坏通过重叠但不同的机制起作用的证据。
Reduced IGF-I/insulin signaling and caloric restriction (CR) are known to extend the life span and delay age-related diseases. To address the interaction of these two interventions, we subjected normal (N) and long-lived GH receptor knockout (GHRKO) mice to CR for 20 months starting at weaning. We also used bovine GH transgenic (bGH Tg) mice, which overexpress GH and are short-lived and insulin resistant, for comparison. Circulating insulin and IGF-I levels were reduced by CR in N animals, whereas GHRKO animals exhibited very low insulin and undetectable IGF-I. Consistently, hepatic Akt phosphorylation was reduced by CR and was very low in GHRKO mice. bGH Tg mice exhibited increased active Akt. The forkhead box O1 (Foxo1) transcription factor was additively increased by CR and GHRKO at the mRNA level. However, Foxo1 protein levels were only elevated in GHRKO mice. The coactivator peroxisome proliferator-activated receptor-gamma coactivator 1alpha was increased at both gene and protein levels in GHRKO mice. N-CR and GHRKO mice also exhibited increased phosphorylated cAMP response element-binding protein and active p38 compared with the N ad libitum-fed mice, and the levels of these proteins were greatly diminished in bGH Tg mice. The protein levels of the deacetylase sirtuin 1 (SIRT1) were elevated in the two CR groups and, unexpectedly, also in bGH Tg mice. These results suggest a major role for the Akt/Foxo1 pathway in the regulation of longevity in rodents. An activated gluconeogenic pathway and increased fat metabolism may be involved in mediating the effects of reduced somatotropic and insulin signaling on longevity. These results also add to the evidence that targeted disruption of the GH receptor/GH-binding protein gene and CR act via overlapping, but distinct, mechanisms.