Rheb在诱导和改善胰岛素抵抗中的作用
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摘要
Rheb是Ras超家族中GTP结合蛋白,具有调节多种生理学功能的作用。为进一步弄清楚Rheb在胰岛素抵抗发生中的作用及在胰岛素抵抗改善过程中的作用,通过先建立胰岛素抵抗小鼠为模型,再通过有氧运动改善胰岛素抵抗状况的方法,研究并检测前后两阶段小鼠组织的Rheb、mTOR和PGC-1α表达情况。结果表明在小鼠诱导胰岛素抵抗发生阶段Rheb和mTOR的表达是同步升高的,PGC-1α表达是降低的;然后经有氧运动改善其胰岛素抵抗的阶段时Rheb与mTOR是同步降低的,而PGC-1α表达是升高的。可见Rheb是通过mTOR通路在高脂饮食诱导胰岛素抵抗中也发挥着重要作用,同时其表达下降后也可有效调控机体代谢状况,改善胰岛素抵抗。
Rheb is a GTP-binding protein in the Ras superfamily and has the role of regulating many physiological functions. In order to further make certain the role of Rheb in the occurrence of insulin resistance and improvement of insulin resistance,the model of insulin resistance mice were established by high-fat diet and then the status of insulin resistance were improved through aerobic exercise. The expression of Rheb,mTOR and PGC-1α in the tissues of mice were used to investigate in the two stages. The results show that the expression of Rheb and mTOR were increased simultaneously and the expression of PGC-1α was decreased during the insulin resistance stage of mice. Then,the Rheb,mTOR expression were synchronously decreased while the PGC-1α expression is increased when the insulin resistance was improved through aerobic exercise. It can be seen that Rheb plays an important role in insulin resistance induced by high-fat diet through the m TOR pathway,and it can also effectively regulate the body's metabolism and improve insulin resistance after its expression decreases.
Rheb is a GTP-binding protein in the Ras superfamily and has the role of regulating many physiological functions. In order to further make certain the role of Rheb in the occurrence of insulin resistance and improvement of insulin resistance,the model of insulin resistance mice were established by high-fat diet and then the status of insulin resistance were improved through aerobic exercise. The expression of Rheb,mTOR and PGC-1α in the tissues of mice were used to investigate in the two stages. The results show that the expression of Rheb and mTOR were increased simultaneously and the expression of PGC-1α was decreased during the insulin resistance stage of mice. Then,the Rheb,mTOR expression were synchronously decreased while the PGC-1α expression is increased when the insulin resistance was improved through aerobic exercise. It can be seen that Rheb plays an important role in insulin resistance induced by high-fat diet through the m TOR pathway,and it can also effectively regulate the body's metabolism and improve insulin resistance after its expression decreases.
引文
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2 Heard J J,Fong V,Bathaie S Z,et al. Recent progress in the study of the Rheb family GTPases[J]. Cell Signal,2014,26(9):1950-1957
3 Jewell J L,Russell R C,Guan K L. Amino acid signaling upstream of m TOR[J]. Nature Reviews Molecular Cell Biologyl,2013,14(3):133-139
4 Tremblay F,Marette A. Amino acid and insulin signaling via the m TOR/p70 S6 kinase pathway; A negative feedback mechanism leading to insulin resistance in skeletal muscle cells[J]. Journal of Biological Chemistry,2001,41(276):38052-38060
5 苑红,牛燕媚,刘彦辉,等. m TOR/S6K1信号通路在高脂饮食诱导小鼠胰岛素抵抗发生中的作用[J].中国糖尿病杂志,2009,17(12),884-888Yuan Hong,Niu Yanmei,Liu Yanhui,et al. The effect of m TOR/S6K1 signaling pathway on the development of high fat-induced mouse insulin resistance[J]. Chinese Jourmal of Diabetes,2009; 17(12),884-888
6 Laplante M,Sabatini D M. m TOR signaling in growth control and disease[J]. Cell,2012,149(2):274-293
7 Neufeld TP. TOR-dependent control of autophagy:biting the hand that feeds[J]. Current Opinion in Cell Biology,2010,22(2):157-168
8 Linke M,Fritsch S D,Sukhbaatar N,et al. m TORC1 and m TORC2as regulators of cell metabolism in immunity[J]. FEBS Letter,2017,591(19):3089-3103
9 Zinzalla V,Stracka D,Oppliger W,et al. Activation of m TORC2 by association with the ribosome[J]. Cell,2011,144(5):757-768
10 Um S H,Frigerio F,Watanabe M,et al. Absence of S6K1 protects against age-and diet-induced obesity while enhancing insulin sensitivity[J]. Nature,2004,431(7005):200-205
11 Hanahan D,Weinberg R A. Hallmarks of cancer:The next generation[J]. Cell,2011,144(5):646-674
12 Yang H,Jiang X,Li B,et al. Mechanisms of m TORC1 activation by RHEB and inhibition by PRAS40[J]. Nature,2017,552(7685):368-373
13 刘微,邹俊杰,李晓曦,等. m TOR信号通路中上游调控蛋白Rheb在脂肪细胞分化中的作用[J].第二军医大学学报,2012,33(7):697-702Liu Wei,Zou Junjie,Li Xiaoxi,et al. Role of a regulating protein in the up stream of m TOR signaling pathway Rheb in adipocyte differentiation[J]. Academic Journal of Second Military Medical University,2012,33(7):697-702
14 Chang G R,Chiu Y S,Wu Y Y,et al. Rapamycin protects against high fat diet-induces obesity in C57BL/6J mice[J]. Jourmal of Phamacological Science,2009,109:496-503
15 Wang L,Mascher H,Psilander N,et al. Resistance exercise enhances the molecular signaling of mitochondrial biogenesis induced by endurance exercise in human skeletal muscle[J]. Journal of Applied Physiogyl,2011,111:1335-1344
16 Cunningham J T,Rodgers J T,Arlow D H,et al. m TOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex[J]. Nature,2007,450:736-740
17 Thomson D M,Fick C A,Gordon S E. AMPK activation attenuates S6K1,4E-BP1,and e EF2 signaling responses to high-frequency electrically stimulated skeletal muscle contractions[J]. Journal of Applied Physiogyl,2008,104:625-632
18 牛燕媚,苑红,刘彦辉,等.有氧运动对胰岛素抵抗小鼠骨骼肌球形脂联素和腺苷酸活化蛋白激酶的影响[J].中国运动医学杂志,2009,28(1):36-40Niu Yanmei,Yuan Hong,Liu Yanhui,et al. The effect of adiponectin and AMPK in the process of aerobic exercise improving insulin resistance[J]. Chinese Journal of Sports Medines,2009,28(1):36-40
19 Tee A R,Manning B D,Roux P P,et al. Tuberous sclerosis complex gene products,tuberin and hamartin,control m TOR signaling by acting as a GTPase-activating protein complex toward Rheb[J].Current Biology,2003,(13):1259-1268
2 Heard J J,Fong V,Bathaie S Z,et al. Recent progress in the study of the Rheb family GTPases[J]. Cell Signal,2014,26(9):1950-1957
3 Jewell J L,Russell R C,Guan K L. Amino acid signaling upstream of m TOR[J]. Nature Reviews Molecular Cell Biologyl,2013,14(3):133-139
4 Tremblay F,Marette A. Amino acid and insulin signaling via the m TOR/p70 S6 kinase pathway; A negative feedback mechanism leading to insulin resistance in skeletal muscle cells[J]. Journal of Biological Chemistry,2001,41(276):38052-38060
5 苑红,牛燕媚,刘彦辉,等. m TOR/S6K1信号通路在高脂饮食诱导小鼠胰岛素抵抗发生中的作用[J].中国糖尿病杂志,2009,17(12),884-888Yuan Hong,Niu Yanmei,Liu Yanhui,et al. The effect of m TOR/S6K1 signaling pathway on the development of high fat-induced mouse insulin resistance[J]. Chinese Jourmal of Diabetes,2009; 17(12),884-888
6 Laplante M,Sabatini D M. m TOR signaling in growth control and disease[J]. Cell,2012,149(2):274-293
7 Neufeld TP. TOR-dependent control of autophagy:biting the hand that feeds[J]. Current Opinion in Cell Biology,2010,22(2):157-168
8 Linke M,Fritsch S D,Sukhbaatar N,et al. m TORC1 and m TORC2as regulators of cell metabolism in immunity[J]. FEBS Letter,2017,591(19):3089-3103
9 Zinzalla V,Stracka D,Oppliger W,et al. Activation of m TORC2 by association with the ribosome[J]. Cell,2011,144(5):757-768
10 Um S H,Frigerio F,Watanabe M,et al. Absence of S6K1 protects against age-and diet-induced obesity while enhancing insulin sensitivity[J]. Nature,2004,431(7005):200-205
11 Hanahan D,Weinberg R A. Hallmarks of cancer:The next generation[J]. Cell,2011,144(5):646-674
12 Yang H,Jiang X,Li B,et al. Mechanisms of m TORC1 activation by RHEB and inhibition by PRAS40[J]. Nature,2017,552(7685):368-373
13 刘微,邹俊杰,李晓曦,等. m TOR信号通路中上游调控蛋白Rheb在脂肪细胞分化中的作用[J].第二军医大学学报,2012,33(7):697-702Liu Wei,Zou Junjie,Li Xiaoxi,et al. Role of a regulating protein in the up stream of m TOR signaling pathway Rheb in adipocyte differentiation[J]. Academic Journal of Second Military Medical University,2012,33(7):697-702
14 Chang G R,Chiu Y S,Wu Y Y,et al. Rapamycin protects against high fat diet-induces obesity in C57BL/6J mice[J]. Jourmal of Phamacological Science,2009,109:496-503
15 Wang L,Mascher H,Psilander N,et al. Resistance exercise enhances the molecular signaling of mitochondrial biogenesis induced by endurance exercise in human skeletal muscle[J]. Journal of Applied Physiogyl,2011,111:1335-1344
16 Cunningham J T,Rodgers J T,Arlow D H,et al. m TOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex[J]. Nature,2007,450:736-740
17 Thomson D M,Fick C A,Gordon S E. AMPK activation attenuates S6K1,4E-BP1,and e EF2 signaling responses to high-frequency electrically stimulated skeletal muscle contractions[J]. Journal of Applied Physiogyl,2008,104:625-632
18 牛燕媚,苑红,刘彦辉,等.有氧运动对胰岛素抵抗小鼠骨骼肌球形脂联素和腺苷酸活化蛋白激酶的影响[J].中国运动医学杂志,2009,28(1):36-40Niu Yanmei,Yuan Hong,Liu Yanhui,et al. The effect of adiponectin and AMPK in the process of aerobic exercise improving insulin resistance[J]. Chinese Journal of Sports Medines,2009,28(1):36-40
19 Tee A R,Manning B D,Roux P P,et al. Tuberous sclerosis complex gene products,tuberin and hamartin,control m TOR signaling by acting as a GTPase-activating protein complex toward Rheb[J].Current Biology,2003,(13):1259-1268