A closer look at the role of urotensin II in the metabolic syndrome

Frontiers in Endocrinology

Volumn 3, Issue DEC, 2012, Pages

  Barrette, Pierre Olivier ^a   Schwertani, Adel Giaid ^a  

^a MCGILL UNIVERSITY HEALTH CENTRE   (Canada)

Author keywords

Diabetes; Dyslipidemia; Hypertension; Inflammation; Insulin resistance; Metabolic syndrome; Obesity

Indexed keywords

EID: 84874427760     PISSN: None     EISSN: 16642392     Source Type: Journal    
DOI: 10.3389/fendo.2012.00165     Document Type: Review

References (172)

1. Albertin, G., Guidolin, D., Sorato, E., Spinazzi, R., Mascarin, A., Oselladore, B., et al. (2009). Pro-angiogenic activity of Urotensin-II on different human vascular endothelial cell populations. Regul. Pept. 157, 64-71.
2. Ames, R. S., Sarau, H. M., Chambers, J. K., Willette, R. N., Aiyar, N. V., Romanic, A. M., et al. (1999). Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14. Nature 401, 282-286.
3. Arnalich, F., Hernanz, A., Lopez-Maderuelo, D., Peña, J. M., Cama-Cho, J., Madero, R., et al. (2000). Enhanced acute-phase response and oxidative stress in older adults with type II diabetes. Horm. Metab. Res. 32,407-412.
4. Babihska, M., Holecki, M., Prochaczak, E, Owczarek, A., Kokocihska, D., Chudek., J., et al. (2012). Is plasma urotensin II concentration an indicator of myocardial damage in patients with acute coronary syndrome? Arch. Med. Sci. 8, 449-454.
5. Bastard, J. P., Jardel, C., Bruckert, E., Blondy, P., Capeau, J., Laville, M., et al. (2000). Elevated levels of interleukin 6 are reduced in serum and subcutaneous adipose tissue of obese women after weight loss. J. Clin. Endocrinol Metab. 85, 3338-3342.
6. Bastard, J. P., Maachi, M., Van Nhieu, J. T., Jardel, C., Bruckert, E., Grimaldi, A., et al. (2002). Adipose tissue IL-6 content correlates with resistance to insulin activation of glucose uptake both in vivo and in vitro. J. Clin. Endocrinol Metab. 87,2084-2089.
7. Bavenholm, P., de Faire, U., Landou, C., Efendic, S., Nilsson, J., Wilman, B., et al. (1998). Progression of coronary artery disease in young male postinfarction patients is linked to disturbances of carbohydrate and lipoprotein metabolism and to impaired fibrinolytic function. Eur. HeartJ. 19,402-410.
8. Behm, D. J., Doe, C. P., Johns, D. G., Maniscalco, K., Stankus, G. P., Wibberley, A., et al. (2004). Urotensin-II: a novel systemic hypertensive factor in the cat. Naunyn Schmiedebergs Arch. Pharmacol. 369, 274-280.
9. Besedovsky, H. O., and Del Rey, A. (1996). Immuneneuro-endocrine interactions. Endocr. Rev. 17, 64-102.
10. Boden, G. (1997). Role of fatty acids in the pathogenesis of insulin resistance and NIDDM. Diabetes 46, 3-10.
11. Boden, G., and Shulman, G. I. (2002). Free fatty acids in obesity and type 2 diabetes: defining their role in the development of insulin resistance and β-cell dysfunction. Eur. J. Clin. Invest. 32(Suppl. 3), 14-23.
12. Boden, G., Cheung, P., Stein, T. P., Kresge, K., and Mozzoli, M. (2002). FFA cause hepatic insulin resistance by inhibiting insulin suppression of glycogenolysis. Am. J. Physiol Endocrinol. Metab. 283, E12-E19.
13. Bousette, N., Patel, L., Douglas, S. A., Ohlstein, E. H., and Giaid, A. (2004). Increased expression of urotensin II and its cognate receptor GPR14 in atherosclerotic lesions of the human aorta. Atherosclerosis 176,117-123.
14. Brasier, A. R., Li, J., and Wimbish, K. A. (1996). Tumor necrosis factor activates angiotensinogen gene expression by the Rel A transactivator. Hypertension 27, 1009-1017.
15. Brinton, E. A., Eisenberg, S., and Bres-low, J. L. (1991). Increased apo A-I and apo A-II fractional catabolic rate in patients with low high density lipoprotein-cholesterol levels with or without hypertriglyceridemia. J. Clin. Invest. 87, 536-544.
16. Cameron, A. J., Boyko, E. J., Sicree, R. A., Zimmet, P. Z., Söderberg, S., Alberti, K. G., et al. (2008). Central obesity as a precursor to the metabolic syndrome in the AusDiab study and Mauritius. Obesity (Silver Spring) 16, 2707-2716.
17. Carey, D. G., Jenkins, A. B., Campbell, L. V., Freund, J., and Chisholm, D. J. (1996). Abdominal fat and insulin resistance in normal and overweight women: direct measurements reveal a strong relationship in subjects at both low and high risk of NIDDM. Diabetes 45, 633-638.
18. Chan, J. C., Cheung, J. C., Stehouwer, C. D., Emeis, J. J., Tong, P. C., Ko, G. T., et al. (2002). The central roles of obesity-associated dyslipidaemia, endothelial activation and cytokines in the metabolic syndrome-an analysis by structural equation modelling. Int. J. Obes. Relat. Metab. Disord. 26, 994-1008.
19. Chanalaris, A., Lawrence, K. M., Townsend, P. A., Davidson, S., Jamshidi, Y., Stephanou, A., et al. (2005). Hypertrophic effects of urocortin homologous peptides are mediated via activation of the Akt pathway. Biochem. Biophys. Res. Commun. 328, 442-448.
20. Charles, M. A., Eschwege, E., Thicult, N., Claude, J. R., Warnet, J. M., Rosselin, G. E., et al. (1997). The role of non-esterified fatty acids in the deterioration of glucose tolerance in Caucasian subjects: results of the Paris Prospective Study. Diabetologia 40,1101-1106.
21. Cheung, B. M., Leung, R., Man, Y. B., and Wong, L. Y. (2004). Plasma concentration of urotensin II is raised in hypertension. J. Hypertens. 22, 1341-1344.
22. Cho, L. W. (2011). Metabolic syndrome. Singapore Med. J. 52, 779-785.
23. Conlon, J. M., Agius, L., George, K., Alberti, M. M.,and Hazon,N. (1994). Effects of dogfish urotensin II on lipid mobilization in the fasted dogfish, Scyliorhinus canicula. Gen. Comp. Endocrinol. 93,177-180.
24. Conlon, J. M., Arnold-Reed, D., and Bal-ment, R. J. (1990). Post-translational processing of prepro-urotensin II. FEBSLett. 266, 37-40.
25. Conlon, J. M., Yano, K., Waugh, D., and Hazon, N. (1996). Distribution and molecular forms of urotensin II and its role in cardiovascular regulation in vertebrates. J. Exp. Zool. 275, 226-238.
26. Cornier, M. A., Dabelea, D., Hernandez, T. L., Lindstrom, R. C., Steig, A. J., Stob, N. R., et al. (2008). The metabolic syndrome. Endocr. Rev. 29, 777-822.
27. Coulouarn, Y., Jégou, S., Tostivint, H., Vaudry, H., and Lihrmann, I. (1999). Cloning, sequence analysis and tissue distribution of the mouse and rat urotensin II precursors. FEBS Lett. 457,28-32.
28. Das, U. N. (2001). Is obesity an inflammatory condition? Nutrition 17, 953-966.
29. Das, U. N. (2002). Is metabolic syndrome X an inflammatory condition? Exp. Biol Med. 227, 989-997.
30. DeFronzo, R. A., Gunnarsson, R., Björkman, O., Olsson, M., and Wahren, J. (1985). Effects of insulin on peripheral and splanchnic glucose metabolism in noninsulin-dependent (type II) diabetes mellitus. J. Clin. Invest. 76, 149-155.
31. Djordjevic, T., BelAiba, R. S., Bonello, S., Pfeilschifter, J., Hess, J., and Gör-lach, A. (2005). Human urotensin II is a novel activator of NADPH oxidase in human pulmonary artery smooth muscle cells. Arterioscler. Thromb. Vasc. Biol. 25,519-525.
32. Domínguez-Rodríguez, A., Díaz, I., Rodríguez-Moyano, M., Caderón-Sánchez, E., Antonio, R. J., Ordóñez, A., et al. (2012). Urotensin-II signalling mechanism in rat coronary artery: role of STIM1 and Orai1-dependant store operated calcium influx in vasoconstriction. Arterioscler. Thromb. Vasc. Biol. 35,1325-1332.
33. Dong, X., Ye, X., Song, N., Zhao, J., Di, B., Peng, F., et al. (2012). Urotensin II promotes the production of LTC(4) in rat aortic adventitial fibroblasts through NF-ΚB-5-LO pathway by p38 MAPK and ERK activations. Heart Vessels doi: 10.1007/s00380-012-0291-0 [Epub ahead of print].
34. Dörffel, Y., Lätsch, C., Stuhlmüller, B., Schreiber, S., Scholze, S., Burmester, G. R., et al. (1999). Preactivated peripheral blood mono-cytes in patients with essential hypertension. Hypertension 34, 113-117.
35. Douglas, S. A., and Ohlstein, E. H. (2000). Human urotensin-II, the most potent mammalian vasoconstrictor identified to date, as a therapeutic target for the management of cardiovascular disease. Trends Car-diovasc. Med. 131,1262-1274.
36. Douglas, S. A., Sulpizio, A. C., Piercy, V., Sarau, H. M., Ames, R. S., Aiyar, N. V.,et al. (2000). Differential vasoconstrictor activity of human urotensin-II in vascular tissue isolated from the rat, mouse, dog, pig, marmoset and cynomolgus monkey. Br. J. Pharmacol. 131, 1262-1274.
37. Douglas, S. A., Tayara, L., Ohlstein, E. H., Halawa, N., and Giaid, A. (2002). Congestive heart failure and expression of myocardial urotensin II. Lancet 359, 1990-1997.
38. Eckel, R. H., Alberti, K. G., Grundy, S. M., and Zimmet, P. Z. (2010). The metabolic syndrome. Lancet 375, 181-183.
39. Engström, G., Hedblad, B., Stavenow, L., Lind, P., Janzon, L., and Lindgärde, F. (2003). Inflammation-sensitive plasma proteins are associated with future weight gain. Diabetes 52,2097-2101.
40. Fagot-Campagna, A., Balkau, B., Simon, D., Warnet, J. M., Claude, J. R., Ducimetiere, P., et al. (1998). High free fatty acid concentration: an independent risk factor for hypertension in the Paris Prospective Study. Int. J. Epidemiol. 27, 808-813.
41. Fernández-Real, J. M., Broch, M., Ven-drell, J., Richart, C., and Ricart, W. (2000). Interleukin 6 gene polymorphism and lipid abnormalities in healthy subjects. J. Clin. Endocrinol. Metab. 85,1334-1339.
42. Fernández-Real, J. M., Vayreda, M., Richart, C., Gutiérrez, C., Broch, M., Vendrell, J., et al. (2001). Circulating interleukin 6 levels, blood pressure and insulin sensitivity in apparently healthy men and women. J. Clin. Endocrinol. Metab. 86,1154-1159.
43. Fernández-Real, J. M., and Ricart, W. (2003). Insulin resistance and chronic cardiovascular inflammatory syndrome. Endocr. Rev. 24, 278-301.
44. Festa, A., D'Agostino, R. Jr., Williams, K., Karter, A. J., Mayer-Davis, E. J., Tracy, R. P., et al. (2001). The relation of body fat mass and distribution to markers of chronic inflammation. Int. J. Obesity 25, 1407-1415.
45. Festa, A., D'Agostino, R., Tracy, R. P., and Haffner, S. M. (2002). Elevated levels of acute-phase proteins and plasminogen activator inhibitor-1predict the development of type 2diabetes. The insulin resistance atherosclerosis study. Diabetes 51, 1131-1137.
46. Fleet, J. C., Clinton, S. K., Salomon, R. N., Loppnow, H., and Libby, P. (1992). Atherogenic diets enhance endotoxin-stimulated interleukin-1 and tumor necrosis factor gene expression in rabbit aortae. J. Nutr. 122, 294-305.
47. Ford, E. S., Li, C., and Zhao, G. (2010). Prevalence and correlates of metabolic syndrome based on a harmonious definition among adults in the US. J. Diabetes 2, 180-193.
48. Fried, S. K., Bunkin, D. A., and Green-berg, A. S. (1998). Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by gluco-corticoid. J. Clin. Endocrinol. Metab. 83,847-850.
49. Gardiner, S. M., March, J. E., Kemp, P. A., Davenport, A. P., and Bennett, T. (2001). Depressor and regionally selective vasodilator effects of human urotensin II in conscious rats. Br. J. Pharmacol. 132, 1625-1629.
50. Gibson, A. (1987). Complex effects of Gillichthys urotensin II on rat aortic strips. Br. J. Pharmacol. 91, 205-212.
51. Golden, S. H., Folsom, A. R., Coresh, J., Sharrett, A. R., Szklo, M., and Brancati,F. (2002). Risk factor groupings related to insulin resistance and their synergistic effects on subclini-cal atherosclerosis: the atherosclerosis risk in communities study. Diabetes 51,3069-3076.
52. Gram, J., Jespersen, J., Kluft, C., and Rijken, D. C. (1987). On the usefulness of fibrinolysis variables in the characterization of a risk group for myocardial reinfarction. Acta. Med. Scand. 221,149-153.
53. Greenberg, A. S., Nordan, R. P., McIn-tosh, J., Calvo, J. C., Scow, R. O., and Jablons, D. (1992). Interleukin-6 reduces lipoprotein lipase activity in adipose tissue of mice in vivo and in 3T3-L1 adipocytes: a possible role for interleukin-6 in cancer cachexia. Cancer. Res. 52,4113-4116.
54. Gregor, M. F., and Hotamisligil, G. S. (2011). Inflammatory mechanisms in obesity. Annu. Rev. Immunol. 23, 415-445.
55. Grimble, R. F. (2002). Inflammatory status and insulin resistance. Curr. Opin. Clin. Nutr. Metab. Care 5, 551-559.
56. Grundy, S. M. (1999). Hypertriglyc-eridemia, insulin resistance, and the metabolic syndrome. Am. J. Cardiol. 83,25-29.
57. Grunfeld, C., and Feingold, K. R. (1992). Role of cytokines in inducing hyperlipidemia. Diabetes 41(Suppl. 2), 97-101.
58. Gruson, D., Rousseau, M. F., Ketel-slegers, J. M., and Hermans, M. P. (2010). Raised plasma urotensin II in type 2 diabetes patients is associated with the metabolic syndrome phenotype. J. Clin. Hypertens. (Greenwich) 12, 653-660.
59. Gruson, D., Ginion, A., Decroly, N., Lause, P., Vanoverschelde, J. L., Ketelslegers, J. M., et al. (2010). Urotensin II induction of adult car-diomyocytes hypertrophy involves the Akt/GSK-3beta signaling pathway. Peptides 31, 1326-1333.
60. Gruson, D., Ginion, A., Lause, P., Ketelslegers, J. M., Thissien, J. P., and Bertrand, L. (2012). Urotensin II and urocortin trigger the expression of myostatin, a negative regulator of cardiac growth, in cardiomyocytes. Peptides 33, 351-353.
61. Hamsten, A., Wiman, B., Defaire, U., and Blomback, M. (1985). Increased plasmalevel of a rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction. N. Engl. J. Med. 313, 1557-1563.
62. Hamsten, A., Defaire, U., Walldius, G., Dahlen, G., Szamosi, A., Landov, C., et al. (1987). Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet 2, 3-9.
63. Han, S. N., Leka, L. S., Lichtenstein, A. H., Ausman, L. M., Schaefer, E. J., and Meydani, S. N. (2002). Effect of hydrogenated and saturated, relative to polyunsaturated, fat on immune and inflammatory responses of adults with moderate hypercholesterolemia. J. Lipid. Res. 43, 445-452.
64. Hassan, G. S., Chouiali, F., Saito, T., Hu, E, Douglas, S. A., Ao, Z., et al. (2003). Effect of human urotensin-II infusion on hemo dynamics and cardiac function. Can. J. Physiol. Pharmacol. 81,125-128.
65. Hassan, G. S., Douglas, S. A., Ohlstein, E. H., and Giaid, A. (2005). Expression of urotensin-II in human coronary atherosclerosis. Peptides 26, 2462-2472.
66. Heller, J., Schepke, M., Neef, M., Woitas, R., Rabe, C., and Sauerbruch, T. (2002). Increased urotensin II plasma levels in patients with cirrhosis and portal hypertension. J. Hepatol. 37, 767-772.
67. Hodis, H. N., Mack, W. J., LaBree, L., Selzer, R. H., Liu, C. R., Liu, C. H., et al. (1998). The role of carotid arterial intima-media thickness in predicting clinical coronary events. Ann. Intern. Med. 128, 262-269.
68. Hotamisligil, G. S., Budavari, A., Murray, D., and Spiegelman, B. M. (1994). Reduced tyrosine kinase activity of the insulin receptor in obesity-diabetes. J. Clin. Invest. 94, 1543-1549.
69. Hotamisligil, G. S., Peraldi, P., Budavari, A., Ellis, R., White, M. F., and Spiegel-man, B. M. (1996). IRS-1-mediated inhibition of insulin receptor tyro-sine kinase activity in TNF-α and obesity-induced insulin resistance. Science 271, 665-668.
70. Hotamisligil, G. S., Shargill, N. S., and Spiegelman, B. M. (1993). Adipose expression of tumor necrosis factor-α: direct role in obesity-linked insulin resistance. Science 259, 87-91.
71. Howard, G., O'Leary, D. H., Zaccaro, D., Haffner, S., Rewers, M., Hamman, R., et al. (1996). Insulin sensitivity and atherosclerosis. Circulation 93, 1809-1817.
72. Iglewski, M., and Grant, S. R. (2010). Urotensin II-induced signaling involved in proliferation vascular smooth muscle cells. Vasc. Health Risk. Manag. 6, 723-734.
73. Jaggers, J. R., Sui, X., Hooker, S. P., LaM-onte, M. J., Matthews, C. E., Hand, G. A., et al. (2009). Metabolic syndrome and risk of cancer mortality in men. Eur. J. Cancer 45,1831-1838.
74. Janke, J., Engeli, S., Gorzelniak, K., Feldpausch, M., Heintze, U., Böhnke, J., et al. (2006). Adipose tissue and circulating endothelial cell specific molecule-1 in human obesity. Horm. Metab. Res. 38, 28-33.
75. Jiang, Z., Michal, J. J., Tobey, D. J., Wang, Z., Macneil, M. D., and Magnuson, N. S. (2008). Comparative understanding of UTS2 and UTS2R genes for their involvement in type 2 diabetes mellitus. Int. J. Biol. Sci. 4, 96-102.
76. Johns, D. G., Ao, Z., Naselsky, D., Herold, C. L., Maniscalco, K., Sarov-Blat, L., et al. (2004). Urotensin-II-mediated cardiomy-ocyte hypertrophy: effect of receptor antagonism and role of inflammatory mediators. Arch. Pharmacol. 370, 238-250.
77. Jovinge, S., Hamsten, A., Tornvall, P., Proudler, A., Bavenholm, P., Ericsson, C. G., et al. (1998). Evidence for a role of tumor necrosis factor in disturbances of triglyceride and glucose metabolism predisposing to coronary heart disease. Metabolism 47,113-118.
78. Juhan-Vague, I., Alessi, M. C., and Vague, P. (1991). Increased plasma plasminogen activator inhibitor 1 levels. A possible link between insulin resistance and atherothrom-bosis. Diabetologia 34, 457-462.
79. Kahaleh, M. B., and Fan, P. S. (1997). Effect of cytokines on the production of endothelin by endothelial cells. Clin. Exp. Rheumatol. 15, 163-167.
80. Kahn, B. B., and Flier, J. S. (2000). Obesity and insulin resistance. J. Clin. Invest. 106,473-481.
81. Kern, P. A., Ranganathan, S., Li, C., Wood, L., and Ranganathan, G. (2001). Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. Am. J. Physiol. Endocrinol. Metab. 280,E745-E751.
82. Kiss, R. S., You, Z., Genest, J. Jr., Behm, D. J., and Giaid, A. (2011). Urotensin II differentially regulates macrophage and hepatic cholesterol homeostasis. Peptides 32, 956-963.
83. Laimer, M., Ebenbichler, C. F., Kaser, S., Sandhofer, A., Weiss, H., Nehoda, H., et al. (2002). Markers of chronic inflammation and obesity: a prospective study on the reversibility of this association in middle-aged women undergoing weight loss by surgical intervention. Int. J. Obes. Relat. Metab. Disord. 26, 659-662.
84. Lassègue, B., and Clempus, R. E. (2003). Vascular NAD(P)H oxidases: specific features, expression, and regulation. Am. J. Physiol. Regul. Integr. Comp. Physiol. 285,277-297.
85. Leinonen, E., Hurt-Camejo, E., Wiklund, O., Hulten, L. M., Hiukka, A., and Taskinen, M. R. (2003). Insulin resistance and adiposity correlate with acute-phase reaction and soluble cell adhesion molecules in type 2 diabetes. Atherosclerosis 166, 387-394.
86. Libby, P., Ridket, P. M., Hansson, G. K., and Leducq Transatlantic Network on Atherothrombosis. (2009). Inflammation in atherosclerosis: from pathophysiology to practice. J. Am. Coll. Cardiol. 54,2129-2138.
87. Lim, M., Honisett, S., Sparkes, C. D., Komesaroff, P., Kompa, A., and Krum, H. (2004). Differential effect of urotensin II on vascular tone in normal subjects and patients with chronic heart failure. Circulation 109, 1212-1214.
88. Lin, Y., Tsuchihashi, T., Matsumura, K., Fukuhara, M., Ohya, Y., Fujii, K., et al. (2003). Central cardiovascular action of urotensin II in spontaneously hypertensive rats. Hypertens. Res. 26, 839-845.
89. Liu, Q., Pong, S. S., Zeng, Z., Zhang, Q., Howard, A. D., Williams, D. L., et al. (1999). Identification of urotensin II as the endogenous ligand for the orphan G-protein-coupled receptor GPR14. Biochem. Biophys. Res. Com-mun. 266, 174-178.
90. Loirand, G., Rolli-Derkinderen, M., and Pacaud, P. (2008). Urotensin II and atherosclerosis. Peptides 29, 778-782.
91. Maguire, J. J., Kuc, R. E., and Davenport, A. P. (2000). Orphan-receptor ligand human urotensin II: receptor localization in human tissues and comparison of vasoconstrictor responses with endothelin-1. Br. J. Pharmacol. 131,441-446.
92. Maguire, J. J., Kuc, R. E., Wiley, K. E., Kleinz, M. J., and Davenport, A. P. (2004). Cellular distribution of immunoreactive urotensin-II in human tissues with evidence of increased expression in atherosclerosis and a greater constrictor response of small compared to large coronary arteries. Peptides 25, 1767-1774.
93. Mallamaci, F., Pizzini, P., Tripepi, G., and Zoccali, C. (2005). Urotensin II in end-stage renal disease: an inverse correlate of sympathetic function and cardiac natriuretic peptides. J.Nephrol. 18,727-732.
94. Matsushita, M., Shichiri, M., Imai, T., Iwashina, M., Tanaka, H., Takasu, N., et al. (2001). Co-expression of urotensin II and its receptor (GPR14) in human cardiovascular and renal tissues. J. Hypertens. 19, 2185-2190.
95. Mayer-Davis, E. J., D'Agostino, R. Jr., Karter, A. J., Haffner, S. M., Rewers, M. J., Saad, M., et al. (1998). Intensity and amount of physical activity in relation to insulin sensitivity: the Insulin Resistance Atherosclerosis Study. JAMA 279, 669-674.
96. McGarry, J. D., and Dobbins, R. L. (1999). Fatty acids, lipotoxicity and insulin secretion. Diabetologia 42, 128-138.
97. McMillan, D. E. (1989). Increased levels of acute-phase serum proteins in diabetes. Metabolism 38, 1042-1046.
98. Misra, A., and Khurana, L. (2008). Obesity and the metabolic syndrome in developing countries. J. Clin. Endocrinol. Metab. 93(Suppl. 1), S9-S30.
99. Muramaki, T., Michelagnoli, S., Longhi, R., Gianfranceschi, G., Pazzucconi, F., Calabresi, L., et al. (1995). Triglyc-erides are major determinants of cholesterol esterification/transfer and HDL remodelling in human plasma. Atherioscler. Throm. Vasc. Biol. 15, 1819-1828.
100. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). (2002). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 106,3143-3421.
101. Neumiller, J. J., Wood, L., and Campbell, R. K. (2010). Dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes mellitus. Pharmacotherapy 30,463-484.
102. Nishihama, K., Yamada, Y., Matsuo, H., Segawa, T., Watanabe, S., Kato, K., et al. (2007). Association of gene polymorphisms with myocar-dial infarction in individuals with or without conventional coronary risk factors. Int. J. Mol. Med. 19,129-141.
103. Nonogaki, K., Fuller, G. M., Fuentes, N. L., Moser, A. H., Staprans, I., and Grunfeld, C. (1995). Interleukin-6 stimulates hepatic triglyceride secretion in rats. Endocrinology 136,2143- 2149.
104. Oguri, M., Kato, K., Yokoi, K., Itoh, T., Yoshida, T., Watanabe, S., et al. (2009). Association of genetic variants with myocardial infarction in Japanese individuals with metabolic syndrome. Atherosclerosis 206, 486-493.
105. Ong, K. L., Wong, L. Y., and Cheug, B. M. (2008). The role of urotensin II in the metabolic syndrome. Peptides 29, 859-867.
106. Ong, K. L., Wong, L. Y., Man, Y. B., Leung, R. Y., Song, Y Q., Lam, K. S., et al. (2006). Haplotypes in the urotensin II gene and urotensin II receptor gene are associated with insulin resistance and impaired glucose tolerance. Peptides 27, 1659-1667.
107. Paolisso, G., Tataranni, P. A., Foley, J. E., Bogardus, C., Howard, B. V., and Ravussin, E. (1995). A high concentration of fasting plasma non-esterified fatty acids is a risk factor for the development of NIDDM. Diabetologia 38, 1213-1217.
108. Papadopoulos, P., Bousette, N., Al-Ramli, W., You, Z., Behm, D. J., Ohlstein, E. H., et al. (2009). Targeted overexpression of the human urotensin receptor transgene in smooth muscle cells: effect of UT antagonism in ApoE knockout mice fed with Western Diet. Atherosclerosis 204, 395-404.
109. Papanicolaou, D. A., Petrides, J. S., Tsigos, C., Bina, S., Kalogeras, K. T., Wilder, R., et al. (1996). Exercise stimulates interleukin-6 secretion: inhibition by glucocorticoids and correlation with catecholamines. Am. J. Physiol. 271, E601-E605.
110. Pearson, D., Shively, J. E., Clark, B. R., Geschwind, I. I., Barkley, M., Nish-ioka, R. S., et al. (1980). Urotensin II antagonist peptide in the caudal neurosecretory system of fishes. Proc. Natl. Acad. Sci. U.S.A. 77, 5021-5024.
111. Popkin, B. M., and Doak, C. M. (1998). The obesity epidemic is a worldwide phenomenon. Nutr. Rev. 56, 106-114.
112. Pradhan, A. D., Manson, J. E., Rifai, N., Buring, J. E., and Ridker, P. M. (2001). C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA 286, 327-334.
113. Randle, P. J. (1998). Regulatory interactions between lipids and carbohydrates: the glucose fatty acid cycle after 35 years. Diabetes Metab. Rev. 14,263-283.
114. Randle, P. J., Garland, P. B., Hales, C. N., and Newsholme, E. A. (1963). The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1, 785-789.
115. Reaven, G. M. (1988). Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 37, 1595-1607.
116. Reaven, G. M. (2003). Insulin resistance/compensatory hyper-insulinemia, essential hypertension, and cardiovascular disease. J. Clin. Endocrinol Metab. 88, 2399-2403.
117. Ross, B., McKendy, K., and Giaid, A. (2010). Role of urotensin II in health and disease. Am. J. Physiol. Regul. Integr. Comp. Physiol. 298, R1156-R1172.
118. Ruan, W., and Lai, M. (2010). Insulin-like growth factor binding protein: a possible marker for the metabolic syndrome? Acta. Diabetol. 47, 5-14.
119. Russell, F. D., and Molenaar, P. (2004). Investigation of signalling pathways that mediate the inotropic effect of urotensin-II in human heart. Cardio-vasc. Res. 63,673-681.
120. Sáez, M. E., Smani, T., Ramírez-Lorca, R., Díaz, I., Serrano-Ríos, M., Ruiz, A., et al. (2011). Association analysis of urotensin II gene (UTS2) and flanking regions with biochemical parameters related to insulin resistance. PLoS ONE 6:e19327. doi: 10.1371/journal.pone.0019327
121. Sako, Y., and Grill, V. E. (1990). A 48-hour lipid infusion in the rat time-dependently inhibits glucose-induced insulin secretion and B cell oxidation through a process likely coupled to fatty acid oxidation. Endocrinology 127, 1580-1589.
122. Sano, M., Fukuda, K., Kodama, H., Pan, J., Saito, M., Matsuzaki, J., et al. (2000). Interleukin-6 family of cytokines mediate angiotensin II-induced cardiac hypertrophy in rodent cardiomyocytes.J. Biol. Chem. 275,29717-22923.
123. Sartore, S., Chiavegato, A., Faggin, E., Franch, R., Puato, M., Ausoni, S., et al. (2001). Contribution of adventitial fibroblasts to neointima formation and vascular remodeling: from innocent bystander to active participant. Circ. Res. 89, 1111-1121.
124. Sauzeau, V., Le Mellionnec, E., Bertoglio, J., Scalbert, E., Pacaud, P., and Loirand, G. (2001). Human urotensin II-induced contraction and arterial smooth muscle cell proliferation are mediated by RhoA and Rho-kinase. Circ. Res. 88, 1102-1104.
125. Segain, J. P., Rolli-Derkinderen, M., Gervois, N., Raingeard de la Blétière, D., Loirand, G., and Pacaud, P. (2007). Urotensin II is a new chemo-tactic factor for UT-expressing monocytes. J. Immunol. 179, 901-909.
126. Sheridan, M. A., and Bern, H. A. (1986). Both somatostatin and the caudal neuropeptide, urotensin II, stimulate lipid mobilization from coho salmon liver incubated in vitro. Regul. Pept. 14, 333-344.
127. Sheridan, M. A., Plisetskaya, E. M., Bern, H. A., and Gorbman, A. (1987). Effects of somatostatin-25 and urotensin II on lipid and carbohydrate metabolism of coho salmon, Oncorhynchus kisutch. Gen. Comp. Endocrinol. 66, 405-414.
128. Silvestre, R. A., Egido, E. M., Hernández, R., Leprince, J., Chatenet, D., Tolle-mer, H., et al. (2004). Urotensin-II is present in pancreatic extracts and inhibits insulin release in the perfused rat pancreas. Eur. J. Endocrinol. 151, 803-809.
129. Silvestre, R. A., Rodríguez-Gallardo, J., Egido, E. M., and Marco, J. (2001). Inhibition of insulin release by urotensin II - a study on the perfused rat pancreas. Horm. Metab. Res. 33,379-381.
130. Sondermeijer, B., Komp, A., Kome-saroff, P., and Krum, H. (2005). Effects of exogenous urotensin-II on vascular tone in skin microcirculation of patients with essential hypertension. Am. J. Hypertens. 22, 1341-1344.
131. Song, N., Ding, W., Chu, S., Zhao, J., Dong, X., Di, B., et al. (2012). Urotensin II stimulates vascular endothelial growth factor secretion from advential fibroblasts in synergy with angiotensin II. Circ. J. 76, 1267-1273.
132. Sowers, J. R. (2004). Insulin resistance and hypertension. Am. J. Physiol. Heart Circ. Physiol. 286, H1597-H1602.
133. Stefan, N., Kantartzis, K., Machann, J., Schick, F., Thamer, C., Rittig, K., et al. (2008). Identification and characterization of metabolically benign obesity in humans. Arch. Intern. Med. 168, 1609-1616.
134. Stenmark, K. R., Davie, N., Frid, M., Gerasimovskaya, E., and Das, M. (2006). Role of the adventitia in pulmonary vascular remodelling. Physiology (Bethesda)21, 134-145.
135. Stirrat, A., Gallagher, M., Douglas, S. A., Ohlstein, E. H., Berry, C., Kirk, A., et al. (2001). Potent vasodilator responses to human urotensin-II in human pulmonary and abdominal resistance arteries. Am. J. Physiol. Heart Circ. Physiol. 280, H925-H928.
136. Stouthard, J. M., Romijn, J. A., Van der Poll, T., Endert, E., Klein, S., Bakker, P. J., et al. (1995). Endocrinologic and metabolic effects of interleukin-6 in humans. Am. J. Physiol. 268, E813-E819.
137. Sun, H. X., Du, W. N., Zuo, J., Wu, G. D., Shi, G. B., Shen, Y., et al. (2002). The association of two single nucleotide polymorphisms in PRKCZ and UTS2 respectively with type 2 diabetes in Han people of northern China. Zhong-guo Yi Xue Ke Xue Yuan Xue Bao 24, 223-227.
138. Sutherland, J. P., McKinley, B., and Eckel, R. H. (2004). The metabolic syndrome and inflammation. Metab. Synd. Relat. Disord. 2, 82-104.
139. Suzuki, S., Wenyi, Z., Hirai, M., Hinokio, Y., Suzuki, C., Yamada, T., et al. (2004). Genetic variations at urotensin II and urotensin II receptor genes and risk of type 2 diabetes mellitus in Japanese. Peptides 25, 1803-1808.
140. Takano, M., Itoh, N., Yayama, K., Yamano, M., Ohtani, R., and Okamoto, H. (2000). Interleukin 6 as a mediator responsible for inflammation-induced increase in plasma angiotensinogen. Biochem. Pharmacol. 45,201-206.
141. Tamura, K., Okazaki, M., Tamura, M., Isozumi, K., Tasaki, H., and Nakashima, Y. (2003). Urotensin II-induced activation of extracellular signal-regulated kinase in cultured vascular smooth muscle cells: involvement of cell adhesion-mediated integrin signalling. Life Sci. 72,1049-1060.
142. Tan, Y. J., Fan, Z. T., and Yang, H. X. (2006). Role of urotensin II gene in the genetic susceptibility to gesta-tional diabetes mellitus in northern Chinese women. Zhonghua Fu Chan KeZaZhi 41, 732-735.
143. Totsune, K., Takahashi, K., Arihara, Z., Sone, M., Ito, S., and Murakami, O. (2003). Increased plasma urotensin II levels in patients with diabetes mellitus. Clin. Sci. 104, 1-5.
144. Trayhurn, P., and Wood, I. S. (2004). Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br. J. Nutr. 92, 347-355.
145. Tsoukas, P., Kane, E., and Giaid, A. (2011). Potential clinical implications of the urotensin II receptor antagonists. Front. Pharmacol. 2:38. doi: 10.3389/fphar.2011.00038
146. Tzanidis, A., Hannan, R. D., and Thomas, W. G. (2003). Direct actions of urotensin II on the heart implications for cardiac fibro-sis and hypertrophy. Circ. Res. 93, 246-253.
147. Unger, R. H. (1995). Lipotoxicity in the pathogenesis of obesity-dependant NIDDM. Genetic and clinical implications. Diabetes 44, 863-870.
148. Vessby, B., Unsitupa, M., Hermansen, K., Riccardi, G., Rivellese, A. A., Tapsell, L. C., et al. (2001). Substituting dietary saturated for monounsat-urated fat impairs insulin sensitivity in healthy men and women: the KANWU Study. Diabetologia 44, 312-319.
149. The interleukin-6 (174) G/C promoter polymorphism is associated with type-2 diabetes mellitus in Native Americans and Caucasians
150. Wang, H. X., Zeng, X. J., Liu, Y., Wang, J., Lu, L. Q., Hao, G., et al. (2009). Elevated expression of urotensin II and its receptor in skelet al muscle of diabetic mouse. Regul. Pept. 154, 85-90.
151. Wang, Z. J., Shi, L. B., Xiong, Z. W., Zhang, L. F., Meng, L., Bu, D. E, et al. (2006). Alteration of vascular urotensin II receptor in mice with apolipoprotein E gene knockout. Peptides 27, 858-863.
152. Watanabe, T., Pakala, R., and Kata-giri, T. (2001). Synergistic effect of urotensin II with mildly oxidized LDL on DNA synthesis in vascular smooth muscle cells. Circulation 104, 16-18.
153. Watanabe, T., Pakala, R., and Kata-giri, T. (2001). Synergistic effect of urotensin II with serotonin on vascular smooth muscle cell proliferation. J. Hypertens. 19,2191-2196.
154. Watanabe, T., Suguro, T., Kanome, T., Sakamoto, Y., Kodate, S., Hagiwara, T., et al. (2005). Human urotensin II accelerates foam cell formation in human monocyte-derived macrophage. Hypertension 46, 738-744.
155. Watson, A. M., Lambert, G. W., Smith, K. J., and May, C. N. (2003). Urotensin II acts centrally to increase epinephrine and ACTH release and cause potent inotropic and chronotropic actions. Hypertension 42, 373-379.
156. Welborn, T. A., Breckenridge, A., Rubinstein, A. H., Dollery, C. T., and Fraser, T. R. (1966). Serum-insulin in essential hypertension and in peripheral vascular disease. Lancet 1, 1336- 1337.
157. Wenyi, Z., Suzuki, S., Hirai, M., Hinokio, Y., Tanizawa, Y., Mat-sutani, A., et al. (2003). Role of urotensin II gene in genetic susceptibility to Type 2 diabetes mellitus in Japanese subjects. Diabetologia 46, 972-976.
158. World Health Organization. (2008). Controlling the Global Obesity Epidemic. Available at: http://www.who.int/nutrition/topics/obesity/en/index.html [accessed August 2012].
159. Yi, L., Gu, Y. H., Wang, X. L., An, L. Z., Xie, X. D., Shao, W., et al. (2006). Association of ACE, ACE2 and UTS2 polymorphisms with essential hypertension in Han and Dongxiang populations from north-western China. J. Int.Med.Res. 34,272-283.
160. Yoshimoto, T., Matsushita, M., and Hirata, Y. (2004). Role of urotensin II in peripheral tissue as an autocrine/paracrine growth factor. Peptides25, 1775-1781.
161. You, Z., Genest, J. Jr., Barrette, P. O., Hafiane, A., Behm, D. J., D'Orleans-Juste, P., et al. (2012). Arterioscler. Thromb. Vasc. Biol. 32, 1809-1816.
162. Yudkin, J. S., Stehouwer, C. D., Emeis, J. J., and Coppack, S. W. (1999). C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue? Artherioscler. Thromb. Vasc. Biol. 19,972-978.
163. Zavaroni, I., Ardigò, D., Zuccarelli, A., Pacetti, E., Piatti, P. M., Monti, L., et al. (2006). Insulin resistance/compensatory hyperinsu-linemia predict carotid intimal media thickness in patients with essential hypertension. Nutr. Metab. Cardio-vasc. Dis. 16, 22-27.
164. Zhang, Y., Li, J., Cao, J., Chen, J., Yan, J., Zhang, Z., et al. (2002). Effect of chronic hypoxia on contents of urotensin II and its functional receptors in rat myocardium. Heart Vessels 16, 64-68.
165. Zhang, Y. G., Li, J., Li, Y. G., and Wei, R. H. (2008). Urotensin II induces phenotypic differentiation, migration and collagen synthesis of adventitial fibroblasts from rat aorta. J. Hypertens. 26, 1119-1126.
166. Zhou, P., Wu, S. Y., Yu, C. F., Wang, H., Tang, C. S., Lin, L., et al. (2003). Effects of urotensin II on isolated rat hearts under normal perfusion and ischemia reperfusion. Sheng Li Xue Bao 55, 442-448.
167. Zoccali, C., Mallamaci, F., Tripepi, G., Cutrupi, S., Pizzini, P., and Malatino, L. (2006). Urotensin II is an inverse predictor of incident cardiovascular events in endstage renal disease. Kidney Int. 69,1253-1258.
168. Zoccali, C., and Mallamaci, F. (2008). Urotensin II: a cardiovascular and renal update. Curr. Opin. Nephrol. Hypertens. 17,199-204.
169. Zhu, F., Ji, L., and Luo, B. (2002). The role of urotensin II gene in the genetic susceptibility to type 2 diabetes in Chinese population. Zhonghua Yi Xue Za Zhi 82, 1473-1475.
170. Zhu, Y., Zhu, Y., and Moore, P. (2006). The role of urotensin II in cardiovascular and renal physiology and diseases. Br. J. Pharmacol. 148, 884-901.
171. Zou, M. H., Cohen, R. A., and Ullrich, V. (2004). Peroxynitrite and vascular endothelial dysfunction in diabetes mellitus. Endothelium 11, 89-97.
172. Zuliani, G., Volpato, S., Ble, A., Bandinelli, S., Corsi, A. M., Lau-retani, F., et al. (2007). High interleukin-6 plasma levels are associated with low HDL-C levels in ommunity-dwelling older adults: the In Chianti study. Atherosclerosis 192,384-390.