Chronic rapamycin treatment causes glucose intolerance and hyperlipidemia by upregulating hepatic gluconeogenesis and impairing lipid deposition in adipose tissue.
Chronic rapamycin treatment causes glucose intolerance and hyperlipidemia by upregulating hepatic gluconeogenesis and impairing lipid deposition in adipose tissue.
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作者：
Houde VP;Brûlé S;Festuccia WT;Blanchard PG;Bellmann K;Deshaies Y;Marette A
哺乳动物雷帕霉素靶蛋白（mTOR）/p70 S6激酶1（S6 K1）通路是肥胖相关胰岛素抵抗发生的关键信号传导组分，并对磷脂酰肌醇3-激酶（PI 3-kinase）/Akt通路起营养敏感负反馈作用。尽管用mTOR复合物1（mTORC 1）抑制剂雷帕霉素对胰岛素靶细胞的急性治疗可预防营养诱导的胰岛素抵抗，但雷帕霉素对体内胰岛素敏感性和葡萄糖代谢的慢性作用仍然难以捉摸。为了评估mTORC 1/S6 K1通路的慢性抑制的代谢效应，在代谢表型分析之前，用雷帕霉素（2 mg/kg/天）或媒介物处理大鼠15天。长期雷帕霉素治疗减少了肥胖和脂肪细胞数量，这与参与脂质摄取和输出的基因的协调下调有关。雷帕霉素治疗还促进胰岛素抵抗、严重的葡萄糖耐受不良和增加新生血管生成。后者与肝脏致瘤主基因PEPCK和G6 β的表达升高、转录共激活因子过氧化物酶体增殖物激活受体-γ共激活因子-1 α（PGC-1α）的表达增加以及FoxO 1、CRTC 2和CREB的核募集增强相关。尽管在雷帕霉素处理的大鼠的肝脏中胰岛素受体底物/PI 3-激酶/Akt轴正常激活，但观察到这些变化，正如从mTORC 1/S6 K1负反馈环阻断所预期的那样。这些发现揭示了mTORC 1/S6 K1通过调节几个关键转录因子来控制胚胎发生的新机制。雷帕霉素处理的大鼠肝脏中的促胰岛素生成程序的强有力的诱导是严重葡萄糖耐受不良的发展的基础，即使面对保存的肝脏胰岛素信号转导至Akt并且尽管肥胖适度减少。
The mammalian target of rapamycin (mTOR)/p70 S6 kinase 1 (S6K1) pathway is a critical signaling component in the development of obesity-linked insulin resistance and operates a nutrient-sensing negative feedback loop toward the phosphatidylinositol 3-kinase (PI 3-kinase)/Akt pathway. Whereas acute treatment of insulin target cells with the mTOR complex 1 (mTORC1) inhibitor rapamycin prevents nutrient-induced insulin resistance, the chronic effect of rapamycin on insulin sensitivity and glucose metabolism in vivo remains elusive. To assess the metabolic effects of chronic inhibition of the mTORC1/S6K1 pathway, rats were treated with rapamycin (2 mg/kg/day) or vehicle for 15 days before metabolic phenotyping. Chronic rapamycin treatment reduced adiposity and fat cell number, which was associated with a coordinated downregulation of genes involved in both lipid uptake and output. Rapamycin treatment also promoted insulin resistance, severe glucose intolerance, and increased gluconeogenesis. The latter was associated with elevated expression of hepatic gluconeogenic master genes, PEPCK and G6Pase, and increased expression of the transcriptional coactivator peroxisome proliferator–activated receptor-γ coactivator-1α (PGC-1α) as well as enhanced nuclear recruitment of FoxO1, CRTC2, and CREB. These changes were observed despite normal activation of the insulin receptor substrate/PI 3-kinase/Akt axis in liver of rapamycin-treated rats, as expected from the blockade of the mTORC1/S6K1 negative feedback loop. These findings unravel a novel mechanism by which mTORC1/S6K1 controls gluconeogenesis through modulation of several key transcriptional factors. The robust induction of the gluconeogenic program in liver of rapamycin-treated rats underlies the development of severe glucose intolerance even in the face of preserved hepatic insulin signaling to Akt and despite a modest reduction in adiposity.
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影响因子：
64.8
作者：
Liu, Yi;Dentin, Renaud;Chen, Danica;Hedrick, Susan;Ravnskjaer, Kim;Schenk, Simon;Milne, Jill;Meyers, David J.;Cole, Phil;Yates, John, III;Olefsky, Jerrold;Guarente, Leonard;Montminy, Marc
通讯作者：
Montminy, Marc
影响因子：
64.8
作者：
Cunningham, John T.;Rodgers, Joseph T.;Puigserver, Pere
通讯作者：
Puigserver, Pere
影响因子：
4.8
作者：
Giraud, J;Leshan, R;White, MF
通讯作者：
White, MF
DOI：
10.1016/j.trre.2007.09.003
发表时间：
2008-01-01
期刊：
Transplantation reviews (Orlando, Fla.)
影响因子：
--
作者：
Cruzado, Josep M
通讯作者：
Cruzado, Josep M
影响因子：
64.5
作者：
Peterson TR;Laplante M;Thoreen CC;Sancak Y;Kang SA;Kuehl WM;Gray NS;Sabatini DM
通讯作者：
Sabatini DM