Ghrelin Enhances The Sensitivity of Insulin in L6 Rat Skeletal Muscle Via PI3K/Akt/GSK-3βSignaling Pathway_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

 SUNYing-dong , ZHOUYong , WANGYong ,  LIUJin-gang

Department of Biliary, Herniary, and Obesity Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China;

Corresponding author：

LIUJin-gang, Email: liujg@sj-hospital.org

Keywords：

Ghrelin; Glucose transporter 4; Protein kinase B; Glycogen synthase kinase

DOI：

10.7507/1007-9424.20140195

Video：

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Objective To study the effects of Ghrelin for glucose metabolism and insulin sensitivity of L6 rat myoblasts in palmitic acid induced, and to explore its possible mechanisms. Methods The L6 rat myoblasts were cultured until differentiation, then using palmitic acid(0.3 mmol/L) for 16 hours. The experimental group was treated with different doses of Ghrelin(1, 10, and 100 nmol/L) for 8 hours, then the glucose uptake was detected by using glucose oxidase peroxidase method(GOD-POD), the cell membrane glucose transporter 4(GLUT-4) protein staining was observated under confocal microscopy, and the expressions of total protein kinase B(Akt), phosphorylated protein kinase B(pAkt), total glycogen synthase kinase-3β(GSK-3β), and phosphorylated glycogen synthase kinase-3β(pGSK-3β) were detected by using immunoblotting(Western blot). Results Ghrelin enhanced the glucose uptake of L6 rat myoblasts with insulin resistance, the cell membrane Glut-4 stain was deepen, the expressions of pAkt and pGSK-3βprotein increased, and this effect could be PI3K blocker(LY294002) eliminated. Conclusion Ghrelin promotes the glucose uptake of L6 rat myoblasts through PI3K/Akt/GSK-3βsignaling pathway, so as to improve the sensitivity of insulin in L6 rats muscle cells.

Citation： SUNYing-dong, ZHOUYong, WANGYong, LIUJin-gang. Ghrelin Enhances The Sensitivity of Insulin in L6 Rat Skeletal Muscle Via PI3K/Akt/GSK-3βSignaling Pathway. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2014, 21(7): 816-821. doi: 10.7507/1007-9424.20140195 Copy

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2.	Karolina PS, Caroline H, Emil E, et al. Role of ghrelin in food reward:impact of ghrelin on sucrose self-administration and mesolimbic dopamine and acetylcholine receptor gene expression[J]. Addict Biol, 2012, 17(1):95-107.
3.	Chung TL, Blerina K, Ashley G, et al. The expression of ghrelin O-acyltransferase (GOAT) in human tissues[J]. Endocr J, 2011, 58(8):707-710.
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7.	Walia P, Asadi A, Kieffer TJ, et al. Ontogeny of Ghrelin, obestatin, prepro-ghrelin, and prohormone convertases in rat pancreas and stomach[J]. Pediatr Res, 2009, 65(1):39-44.
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12.	Wenying Y, Juming L, Jianping W, et al. Prevalence of diabetes among men and women in China[J]. N Engl J Med, 2010, 362(12):1090-1101.
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14.	Rocco B, Michela Z, Maria RC, et al. Ghrelin enhances in vivo skeletal muscle but not liver AKT signaling in rats[J]. Obesity, 2007, 11(15):2614-2623.
15.	Katarina TB, Elizabeth W, Kimberly K, et al. Appetite responds to changes in meal content, whereas ghrelin, leptin, and insulin track changes in energy availability[J]. J Clin Endocrinol Metab, 2009, 94(7):2290-2298.
16.	Zhang Z, Zhao M, Li Q, et al. Acetyl-l-carnitine inhibits TNFalpha-induced insulin resistance via AMPK pathway in rat skeletal muscle cells[J]. FEBS Lett, 2009, 583(2):470-474.
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18.	Amanda EB, Andrew JH, Lauren EW, et al. The evolution of insulin resistance in muscle of the glucose infused rat[J]. Arch Biochem Biophys, 2011, 509(2):133-141.
19.	Brand C, Cipok M, Attali V, et al. Protein kinase Cdelta participates in insulin-induced activation of PKB via PDK1[J]. Biochem Biophys Res Commun, 2006, 349(3):954-962.
20.	Hajduch E, Litherland GJ, Hundal HS. Protein kinase B(PKB/ Akt)-a key regulator of glucose transport[J]. FEBS Lett, 2001, 492(3):199-203.
21.	Taniguchi CM, Emanuelli B, Kahn CR. Critical nodes in signalling pathways:insights into insulin action[J]. Nat Rev Mol Cell Biol, 2006, 7(2):85-96.
22.	Gonzalez E, McGraw TE. Insulin signaling diverges into Akt-dependent and-independent signals to regulate the recruitment/docking and the fusion of GLUT4 vesicles to the plasma membrane[J]. Mol Biol Cell, 2006, 17(10):4484-4493.
23.	Wakashin H, Hirose K, Maezawa Y, et al. IL-23 and Th17 cells enhance Th2-cell-mediated eosinophilic airway inflammation in Mice[J]. Am J Respir Cirt Care Med, 2008, 178(10):1023-1032.
24.	Kaidanovich O, Eldar-Finkelman H. The role of glycogen synthase kinase-3 in insulin resistance and type 2 diabetes[J]. Expert Opin Ther Targets, 2002, 6(5) :555-561.
25.	Granata R, Volante M, Settanni F, et al. Unacylated ghrelin and obestatin increase islet cell mass and prevent diabetes in streptozotocin-treated newbornrats[J]. J Mol Endocrinol, 2010, 45(1): 9-17.

1. Kiewiet RM, Aken MO, Weerd K, et al. Effects of acute administration of acylated and unacylated ghrelin on glucose and insulin concentrations in morbidly obese subjects without overt diabetes[J]. Eur J Endocrinol, 2009, 161(4):567-573.
2. Karolina PS, Caroline H, Emil E, et al. Role of ghrelin in food reward:impact of ghrelin on sucrose self-administration and mesolimbic dopamine and acetylcholine receptor gene expression[J]. Addict Biol, 2012, 17(1):95-107.
3. Chung TL, Blerina K, Ashley G, et al. The expression of ghrelin O-acyltransferase (GOAT) in human tissues[J]. Endocr J, 2011, 58(8):707-710.
4. Kojima M, Hosoda H, Date Y, et al. Ghrelin is a growth hormonereleasing acylated peptide from stomach[J]. Nature, 1999, 402(6762):656-660.
5. Frangioudakis G, Cooney GJ. Acute elevation of circulating fatty acids impairs downstream insulin signalling in rat skeletal muscle in vivo independent of effects on stress signaling[J]. J Endocrinol, 2008, 197(2):277-285.
6. Qader SS, Hakanson R, Rehfeld JF, et al. Proghrelin-derived peptides influence the secretion of insulin, glucagon, pancreatic polypeptide and somatostatin:a study on isolated islets from mouse and rat pancreas[J]. Regul Pept, 2008, 146(1-3):230-237.
7. Walia P, Asadi A, Kieffer TJ, et al. Ontogeny of Ghrelin, obestatin, prepro-ghrelin, and prohormone convertases in rat pancreas and stomach[J]. Pediatr Res, 2009, 65(1):39-44.
8. Cowley MA, Smith RG, Diano S. The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis[J]. Neuron, 2003, 37(4): 649-661.
9. Nikoulina SE, Ciaraldi TP, Mudaliar S, et al. Potential role of glycogen syntbase kinase-3 in skeletal muscle insulin resistance of type 2 diabetes[J]. Diabetes, 2000, 49(2):263-271.
10. 于一凡, 周勇, 王勇, 等. Ghrelin对大鼠离体胰腺胰岛素分泌及Glut-2蛋白表达的影响[J].中国普外基础与临床杂志, 2013, 20(3):251-258.
11. Kerem M, Salman B, Ozsoy S, et al. Exogenous Ghrelin enhances endocrine and exocrine regeneration in pancreatectomized rats[J]. J Gastrointest Surg, 2009, 13(4):775-783.
12. Wenying Y, Juming L, Jianping W, et al. Prevalence of diabetes among men and women in China[J]. N Engl J Med, 2010, 362(12):1090-1101.
13. Katsiki N, Mikhailidis DP, Gotzamani-Psarrakou A, et al. Effects of improving glycemic control with insulin on leptin, adiponectin, ghrelin and neuropeptidey levels inpatients with type 2 diabetes mellitus:a pilot study[J]. Open Cardiovasc Med J, 2011, 5(5): 136-147.
14. Rocco B, Michela Z, Maria RC, et al. Ghrelin enhances in vivo skeletal muscle but not liver AKT signaling in rats[J]. Obesity, 2007, 11(15):2614-2623.
15. Katarina TB, Elizabeth W, Kimberly K, et al. Appetite responds to changes in meal content, whereas ghrelin, leptin, and insulin track changes in energy availability[J]. J Clin Endocrinol Metab, 2009, 94(7):2290-2298.
16. Zhang Z, Zhao M, Li Q, et al. Acetyl-l-carnitine inhibits TNFalpha-induced insulin resistance via AMPK pathway in rat skeletal muscle cells[J]. FEBS Lett, 2009, 583(2):470-474.
17. Martins AR, Nachbar RT, Gorjao R, et al. Mechanisms underlying skeletal muscle insulin resistance induced by fatty acids: importance of the mitochondrial function[J]. Lipids Health Dis, 2012, 11(30):1-11.
18. Amanda EB, Andrew JH, Lauren EW, et al. The evolution of insulin resistance in muscle of the glucose infused rat[J]. Arch Biochem Biophys, 2011, 509(2):133-141.
19. Brand C, Cipok M, Attali V, et al. Protein kinase Cdelta participates in insulin-induced activation of PKB via PDK1[J]. Biochem Biophys Res Commun, 2006, 349(3):954-962.
20. Hajduch E, Litherland GJ, Hundal HS. Protein kinase B(PKB/ Akt)-a key regulator of glucose transport[J]. FEBS Lett, 2001, 492(3):199-203.
21. Taniguchi CM, Emanuelli B, Kahn CR. Critical nodes in signalling pathways:insights into insulin action[J]. Nat Rev Mol Cell Biol, 2006, 7(2):85-96.
22. Gonzalez E, McGraw TE. Insulin signaling diverges into Akt-dependent and-independent signals to regulate the recruitment/docking and the fusion of GLUT4 vesicles to the plasma membrane[J]. Mol Biol Cell, 2006, 17(10):4484-4493.
23. Wakashin H, Hirose K, Maezawa Y, et al. IL-23 and Th17 cells enhance Th2-cell-mediated eosinophilic airway inflammation in Mice[J]. Am J Respir Cirt Care Med, 2008, 178(10):1023-1032.
24. Kaidanovich O, Eldar-Finkelman H. The role of glycogen synthase kinase-3 in insulin resistance and type 2 diabetes[J]. Expert Opin Ther Targets, 2002, 6(5) :555-561.
25. Granata R, Volante M, Settanni F, et al. Unacylated ghrelin and obestatin increase islet cell mass and prevent diabetes in streptozotocin-treated newbornrats[J]. J Mol Endocrinol, 2010, 45(1): 9-17.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Ghrelin Enhances The Sensitivity of Insulin in L6 Rat Skeletal Muscle Via PI3K/Akt/GSK-3βSignaling Pathway

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