Disruption of growth hormone receptor prevents calorie restriction from improving insulin action and longevity.
Disruption of growth hormone receptor prevents calorie restriction from improving insulin action and longevity.
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生长激素受体的破坏可防止卡路里的限制改善胰岛素作用和寿命。
DOI：
10.1371/journal.pone.0004567
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发表时间：
2009
期刊：
影响因子：
3.7
通讯作者：
Bartke A
中科院分区：
文献类型：
--
作者：
Bonkowski MS;Dominici FP;Arum O;Rocha JS;Al Regaiey KA;Westbrook R;Spong A;Panici J;Masternak MM;Kopchick JJ;Bartke A
大多数延迟小鼠衰老和延长寿命的突变都与生长激素和/或胰岛素信号有关。热量限制（CR）是唯一能可靠延长小鼠寿命的干预措施。在慢性 CR 方面，长寿突变小鼠和正常小鼠之间存在相当大的表型重叠。因此，我们研究了 CR 和靶向破坏或敲除小鼠生长激素受体 (GHRKO) 对寿命和胰岛素信号级联的相互作用影响。每隔一天喂食相当于轻度（即 15%）CR，这会增加正常小鼠的中位寿命，但不会增加 GHRKO 小鼠的中位寿命，这证实了我们之前关于中度（30%）CR 对这些动物寿命影响的发现。为了确定为什么正常小鼠而非 GHRKO 小鼠对 30% CR 的胰岛素敏感性没有改善，我们在 CR 一年后进行了胰岛素刺激实验。在正常小鼠中，CR 增加了肝脏和肌肉中胰岛素刺激的胰岛素信号级联 (IR/IRS/PI3K/AKT) 的激活。 GHRKO 小鼠的肝脏通过增加胰岛素信号传导早期步骤的激活来对胰岛素作出反应，而这种信号通过 PI3K 亚基丰度的改变而消除，而 PI3K 亚基丰度的改变可能会抑制 AKT 的激活。在 GHRKO 小鼠的肌肉中，在没有升高 IR 激活的情况下，胰岛素信号级联 (IRS/PI3K/AKT) 的下游激活升高。此外，我们发现仅在 GHRKO 肌肉中观察到的 IRS-1 抑制性 Ser 磷酸化显着减少，这可能是其胰岛素敏感性升高的基础。与正常小鼠相比，慢性 CR 未能进一步改变 GHRKO 小鼠胰岛素信号传导的变化，这可能解释或导致 CR 对这些长寿小鼠的胰岛素敏感性和寿命缺乏影响。
Most mutations that delay aging and prolong lifespan in the mouse are related to somatotropic and/or insulin signaling. Calorie restriction (CR) is the only intervention that reliably increases mouse longevity. There is considerable phenotypic overlap between long-lived mutant mice and normal mice on chronic CR. Therefore, we investigated the interactive effects of CR and targeted disruption or knock out of the growth hormone receptor (GHRKO) in mice on longevity and the insulin signaling cascade. Every other day feeding corresponds to a mild (i.e. 15%) CR which increased median lifespan in normal mice but not in GHRKO mice corroborating our previous findings on the effects of moderate (30%) CR on the longevity of these animals. To determine why insulin sensitivity improves in normal but not GHRKO mice in response to 30% CR, we conducted insulin stimulation experiments after one year of CR. In normal mice, CR increased the insulin stimulated activation of the insulin signaling cascade (IR/IRS/PI3K/AKT) in liver and muscle. Livers of GHRKO mice responded to insulin by increased activation of the early steps of insulin signaling, which was dissipated by altered PI3K subunit abundance which putatively inhibited AKT activation. In the muscle of GHRKO mice, there was elevated downstream activation of the insulin signaling cascade (IRS/PI3K/AKT) in the absence of elevated IR activation. Further, we found a major reduction of inhibitory Ser phosphorylation of IRS-1 seen exclusively in GHRKO muscle which may underpin their elevated insulin sensitivity. Chronic CR failed to further modify the alterations in insulin signaling in GHRKO mice as compared to normal mice, likely explaining or contributing to the absence of CR effects on insulin sensitivity and longevity in these long-lived mice.
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影响因子：
4.8
作者：
Coschigano, KT;Holland, AN;Kopchick, JJ
通讯作者：
Kopchick, JJ
影响因子：
--
作者：
Miller, RA;Chang, YY;Bartike, A
通讯作者：
Bartike, A
影响因子：
4.8
作者：
Al-Regaiey, KA;Masternak, MM;Bartke, A
通讯作者：
Bartke, A
DOI：
10.1093/gerona/60.3.293
发表时间：
2005-03-01
影响因子：
5.1
作者：
Sharp, ZD;Bartke, A
通讯作者：
Bartke, A
影响因子：
64.8
作者：
Bartke, A;Wright, JC;Roth, GS
通讯作者：
Roth, GS