iNOS调节Rab8参与肥胖诱导的胰岛素抵抗
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摘要
目的:探究诱导型一氧化氮合酶(iNOS)对Rab8的调节与胰岛素抵抗的关系。方法:用普通饮食和高脂饮食分别喂养野生型和iNOS~(-/-)小鼠12周,在第12周进行腹腔注射葡萄糖耐量实验和胰岛素耐量实验,测定体质量、附睾脂肪质量,Western blot检测骨骼肌中Rab8蛋白表达。结果:高脂饮食诱发小鼠肥胖和胰岛素抵抗。相比于野生型小鼠,iNOS~(-/-)小鼠的体质量、附睾脂肪质量均显著降低,分别降低10.36 g和0.29 g(均P<0.001),胰岛素抵抗有显著改善,而骨骼肌Rab8蛋白水平显著升高,增高2.14倍(P<0.000 1)。结论:iNOS可能通过调节Rab8参与高脂饮食诱导的胰岛素抵抗。
Objective: To investigate the relationship between the regulation of Rab8 by iNOS and insulin resistance. Methods: Wild-type and iNOS~(-/-)mice were fed with chow diet and high-fat diet for 12 weeks, respectively. Intraperitoneal glucose tolerance test(ipGTT) and insulin tolerance test(ITT) were performed separately at the12 th week. Body weight and epididymal adipose weight were measured. The protein level of Rab8 in skeletal muscle was detected by Western blot. Results: High-fat diet induced insulin resistance and obesity in mice. Compared with wild-type mice, iNOS~(-/-)mice had significantly lower body weight, epididymal adipose weight decreased by10.36 g and 0.29 g(P <0.001), and insulin resistence was significantly improved while Rab8 protein levels in skeletal muscle were significantly increased, increased by 2.14 times. Conclusion: iNOS may regulates Rab8 in insulin resistance induced by high fat diet in mice.
Objective: To investigate the relationship between the regulation of Rab8 by iNOS and insulin resistance. Methods: Wild-type and iNOS~(-/-)mice were fed with chow diet and high-fat diet for 12 weeks, respectively. Intraperitoneal glucose tolerance test(ipGTT) and insulin tolerance test(ITT) were performed separately at the12 th week. Body weight and epididymal adipose weight were measured. The protein level of Rab8 in skeletal muscle was detected by Western blot. Results: High-fat diet induced insulin resistance and obesity in mice. Compared with wild-type mice, iNOS~(-/-)mice had significantly lower body weight, epididymal adipose weight decreased by10.36 g and 0.29 g(P <0.001), and insulin resistence was significantly improved while Rab8 protein levels in skeletal muscle were significantly increased, increased by 2.14 times. Conclusion: iNOS may regulates Rab8 in insulin resistance induced by high fat diet in mice.
引文
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[11] Zhu D, Wang H, Zhang J, et al. Irisin improves endothelial function in type 2 diabetes through reducing oxidative/nitrative stresses[J]. J Mol Cell Cardiol, 2015, 87:138
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[13] Bolado-Carrancio A, Riancho J A, Sainz J, et al. Activation of nuclear receptor NR5A2 increases Glut4 expression and glucose metabolism in muscle cells[J]. Biochem Biophys Res Commun, 2014,446(2):614
[14] Samovski D, Su X, Xu Y, et al. Insulin and AMPK regulate FA translocase/CD36 plasma membrane recruitment in cardiomyocytes via Rab GAP AS160 and Rab8a Rab GTPase[J]. J Lipid Res, 2012,53(4):709
[15] Arora D K, Syed I, Machhadieh B, et al. Rab-geranylgeranyl transferase regulates glucose-stimulated insulin secretion from pancreaticβcells[J]. Islets, 2012, 4(5):354
[16] Chadt A, Immisch A, de Wendt C, et al. Deletion of both rab-GTpase-activating proteins TBC1D1 and TBC1D4 in mice eliminates insulin-and AICAR-stimulated glucose transport[J]. Diabetes, 2015,64:746
[17] Ishikura S, Klip A. Muscle cells engage Rab8A and myosin Vb in insulin-dependent GLUT4 translocation[J]. Am J Physiol Cell Physiol, 2008, 295(4):C1016
[2] Wei Y, Gao J, Qin L, et al. Tanshinone I alleviates insulin resistance in type 2 diabetes mellitus rats through IRS-1 pathway[J]. Biomed Pharmacother, 2017, 93:352
[3] Boden G, Homko C, Barrero C A, et al. Excessive caloric intake acutely causes oxidative stress, GLUT4 carbonylation, and insulin resistance in healthy men[J]. Sci Transl Med, 2015, 7(304):304re7
[4] Chen Y, Wang Y, Zhang J, et al. Rab10 and myosin-Va mediate insulin-stimulated GLUT4 storage vesicle translocation in adipocytes[J].J Cell Biol, 2012,198(4):545
[5] L u G, Zhang R, Geng S, et al. Myeloid cell-derived inducible nitric oxide synthase suppresses M1 macrophage polarization[J]. Nat Commun, 2015, 6:6676
[6]李园园,徐文清.诱导性一氧化氮合酶抑制剂的研究进展[J].中国药物化学杂志, 2017(6):10
[7] Boettger M K, Uceyler N, Zelenka M, et al. Differences in inflammatory pain in n NOS-, iNOS-and eNOS-deficient mice[J]. Eur J Pain,2007, 11(7):810
[8] Liu B, Kuang L, Liu J. Bariatric surgery relieves type 2 diabetes and modulates inflammatory factors and coronary endothelium eNOS/iNOS expression in db/db mice[J]. Can J Physiol Pharmacol, 2014,92(1):70
[9] Eghbalzadeh K, Brixius K, Bloch W, et al. Skeletal muscle nitric oxide(NO)synthases and NO-signaling in“diabesity”–What about the relevance of exercise training interventions[J]. Nitric Oxide,2014, 37:2
[10] SalvadóL, Barroso E, Gómez-Foix A M, et al. PPARβ/δprevents endoplasmic reticulum stress-associated inflammation and insulin resistance in skeletal muscle cells through an AMPK-dependent mechanism[J]. Diabetologia, 2014, 57(10):2126
[11] Zhu D, Wang H, Zhang J, et al. Irisin improves endothelial function in type 2 diabetes through reducing oxidative/nitrative stresses[J]. J Mol Cell Cardiol, 2015, 87:138
[12] McConell G K, Bradley S J, Stephens T J, et al. Skeletal muscle nNOS protein content is increased by exercise training in humans[J].Am J Physiol Regul Integr Comp Physiol, 2007, 293(2):R821
[13] Bolado-Carrancio A, Riancho J A, Sainz J, et al. Activation of nuclear receptor NR5A2 increases Glut4 expression and glucose metabolism in muscle cells[J]. Biochem Biophys Res Commun, 2014,446(2):614
[14] Samovski D, Su X, Xu Y, et al. Insulin and AMPK regulate FA translocase/CD36 plasma membrane recruitment in cardiomyocytes via Rab GAP AS160 and Rab8a Rab GTPase[J]. J Lipid Res, 2012,53(4):709
[15] Arora D K, Syed I, Machhadieh B, et al. Rab-geranylgeranyl transferase regulates glucose-stimulated insulin secretion from pancreaticβcells[J]. Islets, 2012, 4(5):354
[16] Chadt A, Immisch A, de Wendt C, et al. Deletion of both rab-GTpase-activating proteins TBC1D1 and TBC1D4 in mice eliminates insulin-and AICAR-stimulated glucose transport[J]. Diabetes, 2015,64:746
[17] Ishikura S, Klip A. Muscle cells engage Rab8A and myosin Vb in insulin-dependent GLUT4 translocation[J]. Am J Physiol Cell Physiol, 2008, 295(4):C1016