Elevated Corticosterone Associated with Food Deprivation Upregulates Expression in Rat Skeletal Muscle of the mTORC1 Repressor, REDD1
Elevated Corticosterone Associated with Food Deprivation Upregulates Expression in Rat Skeletal Muscle of the mTORC1 Repressor, REDD1
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DOI：
10.3945/jn.108.099846
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发表时间：
2009-05-01
影响因子：
4.2
通讯作者：
Kimball, Scot R.
中科院分区：
文献类型：
--
作者：
McGhee, Nora K.;Jefferson, Leonard S.;Kimball, Scot R.
食物缺乏导致骨骼肌蛋白质合成受到抑制，部分原因是通过哺乳动物靶标雷帕霉素复合体1(MTORC1)的信号减少。以往的研究已经证实，DNA损伤和发育调节蛋白(Redd1)的上调表达是调节mTORC1活性以响应各种胁迫的重要机制。我们在这项研究中的目标是确定Redd1表达的调节是否发生在食物剥夺和重新摄食的反应中，如果是这样的话，确定Redd1表达的变化是否与mTORC1信号的改变相关。不出所料，与自由喂养对照组相比，剥夺食物18h后mTORC1信号被抑制，并在重新喂养45min后迅速恢复。食物匮乏导致Redd1mRNA和蛋白表达急剧上升；重新摄食导致下降到基线水平。食物缺乏的特点是血清胰岛素水平低，糖皮质激素浓度升高。因此，最初，四氧嘧啶诱导的I型糖尿病被用来最大限度地减少食物剥夺和重新喂养引起的胰岛素变化。尽管与非糖尿病对照组相比，糖尿病大鼠BEDD1的表达上调，但Redd1的表达与血清胰岛素水平没有直接的相关性，糖尿病大鼠的胰岛素治疗不影响Redd1的表达。血清皮质酮水平与Redd1基因表达呈正相关(r=0.68；P=0.01)。此外，通过给予糖皮质激素受体拮抗剂RU486来抑制皮质酮介导的信号传递，可以阻止食物剥夺和糖尿病诱导的Redd1mRNA表达的增加。总体而言，结果表明，Redd1表达的变化可能有助于调节mTORC1信号在食物剥夺和重新摄食过程中的作用。J.Nutr.139：828-834,2009。
Food deprivation induces a repression of protein synthesis in skeletal muscle in part due to reduced signaling through the mammalian target of rapamycin complex 1 (mTORC1). Previous studies have identified upregulated expression of the protein Regulated in DNA Damage and Development (REDD1) as an important mechanism in the regulation of mTORC1 activity in response to a variety of stresses. Our goal in this investigation was to determine whether modulation of REDD1 expression occurs in response to food deprivation and refeeding, and, if it does, to ascertain if changes in REDD1 expression correlate with altered mTORC1 signaling. As expected, mTORC1 signaling was repressed after 18 h of food deprivation compared with freely-fed control rats and quickly recovered after refeeding for 45 min. Food deprivation caused a dramatic rise in REDD1 mRNA and protein expression; refeeding resulted in a reduction to baseline. Food deprivation is characterized by low-serum insulin and elevated glucocorticoid concentrations. Therefore, initially, alloxan-induced type I diabetes was used to minimize the food deprivation- and refeeding-induced changes in insulin. Although diabetic rats exhibited upregulated BEDD1 expression compared with nondiabetic controls, there was no direct correlation between REDD1 mRNA expression and serum insulin levels, and insulin treatment of diabetic rats did not affect REDD1 expression. In contrast, serum corticosterone levels correlated directly with REDD1 mRNA expression (r = 0.68; P = 0.01). Moreover, inhibiting corticosterone-mediated signaling via administration of the glucocorticoid receptor antagonist RU486 blocked both the food deprivation- and diabetes-induced increase in REDD1 mRNA expression. Overall, the results demonstrate that changes in REDD1 expression likely contribute to the regulation of mTORC1 signaling during food deprivation and refeeding. J. Nutr. 139: 828-834, 2009.