Metabolic Syndrome: the Influence of Adipokines on the L-Arginine-NO Synthase-Nitric Oxide Signaling Pathway

Metabolic syndrome includes the following symptoms: obesity, hyperlipidemia, hypertension, insulin resistance, and cardiovascular disease. The purpose of this review is to elucidate the role of adipokines in the regulation of the L-arginine-NO-synthas-NO signaling pathway in the pathogenesis of metabolic syndrome. The main questions raised in the review are: how adipokine secretion changes, how the level of their receptors is regulated, and which signaling pathways are involved in the transmission of adipokine signals when coupled to the L-arginine-NO-synthase-NO signaling cascade. Adipokines are peptide hormones that transmit a signal from adipose tissue to targets in the brain, blood vessels, liver, pancreas, muscles, and other tissues. Some adipokines have anti-inflammatory and insulin-sensitive effects: adiponectin, omentin, adipolin, chemerin, progranulin. Others have the negative inflammatory effect in the development ofmetabolic syndrome: visfatin, vaspin, apelin. Adipokines primarily regulate the expression and activity of endothelial NO-synthase. They either activate an enzyme involving 5-AMP protein kinase or Akt kinase, increasing its activity and synthesis of NO in the tissues of healthy patients: adiponectin, adipolin, omentin, or inhibit the activity of eNOS, which leads to a decrease in NO-synthase and suppression of mRNA bioavailability: vaspin, visfatin, apelin in metabolic syndrome, and a decrease in its activity leads to dissociation and endothelial dysfunction. It should be noted that the bioavailability of NO formed by NO-synthase is affected at many levels, including: the expression ofNO-synthase mRNA and its protein; the concentration of L-arginine; the level of cofactors of the reaction; and to detect the maximum activity of endothelial NO-synthase, dimerization of the enzyme is required, posttranslational modifications are important, in particular, phosphorylation of endothelial NO-synthase by serine 1177 with the participation of 5-AMP protein kinase, Akt kinase and other kinases. It should be noted that the participation of adiponectin, omentin, and kemerin in the regulation of the L-arginine-NO-synthase-NO cascade in metabolic syndrom opens up certain opportunities for the development of new approaches for the correction of disorders observed in this disease. The review analyzes the results of research searching in PubMed databases, starting from 2001 and up to 2020 using keywords and adipokine names, more than half of the references of the last 5 years. 

1. Reaven GM. The metabolic syndrome: Time to get off the merry-go-round? J Intern Med. 2011; 269(2): 127-136. doi: 10.1111/j.1365-2796.2010.02325.x

2. Feldman RD, Anderson TJ, Touyz RM. Metabolic syndrome sinkholes: What to do when Occam’s razor gets blunted. Can J Cardiol. 2015; 31(5): 601-604. doi: 10.1016/j.cjca.2014.12.035

3. Grundy SM. Metabolic syndrome: a multiplex cardiovascular risk factor. J Clin Endocrinol Metab. 2007; 92: 399-404. doi: 10.1210/j.c.2006-0513

4. Assumpção CR, Brunini TMC, Matsuura C, Resende AC, Mendes-Ribeiro AC. Impact of the L-arginine-Nitric Oxide pathway and oxidative stress on the pathogenesis of the metabolic syndrome. Open Biochem J. 2008; 2: 108-115. doi: 10.2174/1874091X00802010108

5. Huang PL. eNOS, metabolic syndrome and cardiovascular disease. Trends Endocrinol Metab. 2009; 20(6): 295-302. doi: 10.1016/j.tem.2009.03.005

6. Mendrick DL, Diehl AM, Topor LS, Dietert RR, Will Y, La Merrill MA, et al. Metabolic syndrome and associated diseases: from the bench to the clinic. Toxicol Sci. 2018; 162(1): 36-42. doi: 10.1093/toxsci/kfx233

7. Romeo GR, Lee J, Shoelson SE. Metabolic syndrome, insulin resistance, and roles of inflammation--mechanisms and therapeutic targets. Arterioscler Thromb Vasc Biol. 2012; 32(8): 1771-1776. doi: 10.1161FATVBAHA.111.241869

8. Chistyakova OV, Sukhov IB, Shpakov AO. Metabolic syndrome: A causal relationship between oxidative stress and chronic inflammation. Russian Journal of Physiology. 2018; 104(2): 138-155. (In Russ.)

9. Morange PE, Alessi MC. Thrombosis in central obesity and metabolic syndrome: mechanisms and epidemiology. Thromb Haemost. 2013; 110(4): 669-680. doi: 10.1160/TH13-01-0075

10. Atawia RT, Bunch KL, Toque HA, Caldwell RB, Caldwell RW. Mechanisms of obesity-induced metabolic and vascular dysfunctions. Front Bioscience (Landmark Ed). 2019; 24: 890-934.

11. Santolini J. What does “NO-Synthase” stand for? Front Bioscience (Landmark Ed). 2019; 24: 133-171.

12. Mónica FZ, Bian K, Murad F. The endothelium-dependent nitric oxide-cGMP pathway. Adv Pharmacol. 2016; 77: 1-27. doi: 10.1016/bs.apha.2016.05.001

13. Lin X, Wang Q, Sun S, Xu G, Wu Q, Qi M, et al. Astragaloside IV promotes the eNOS/NO/cGMP pathway and improves left ventricular diastolic function in rats with metabolic syndrome. J Int Med Res. 2019; 48(1): 300060519826848. doi: 10.1177/0300060519826848

14. Lacza Z, Snipes JA, Zhang J, Horváth EM, Figueroa JP, Szabó C, et al. Mitochondrial nitric oxide synthase is not eNOS, nNOS or iNOS. Free Radic Biol Med. 2003; 35(10): 1217-1228. doi: 10.1016/s0891-5849(03)00510-0

15. Assumpção CR, Brunini TM, Pereira NR, Godoy-Matos AF, Siqueira MA, Mann GE, et al. Insulin resistance in obesity and metabolic syndrome: is there a connection with platelet l-arginine transport? Blood Cells Mol Dis. 2011; 45(4): 338-342. doi: 10.1016/j.bcmd.2010.10.003

16. Lira VA, Soltow QA, Long JH, Betters JL, Sellman JE, Criswell DS. Nitric oxide increases GLUT4 expression and regulates AMPK signaling in skeletal muscle. Am. J Physiol. 2007; 293(4): E1062-E1068. doi: 10.1152/ajpendo.00045.2007

17. Whitehead JP, Richards AA, Hickman IJ, Macdonald GA, Prins JB. Adiponectin – a key adipokine in the metabolic syndrome. Diabetes Obes Metab. 2006; 8(3): 264-280. doi: 10.1111/j.1463-1326.2005.00510.x

18. Shpakov AO. Adipokines and their role in the regulation of reproductive functions. Saint Petersburg: Politekh-Press; 2018. (In Russ.)

19. Roy V, Nakamura T, Kihara S, Kumada M, Shibazaki S, Takahashi M, et al. Adiponectin as a biomarker of metabolic syndrome. Circulation J. 2004; 68(11): 975-981. doi: 10.1253/circ.j.68.975

20. Liu GZ, Liang B, Lau WB, Wang Y, Zhao J, Li R, et al. High glucose/High Lipids impair vascular adiponectin function via inhibition of caveolin-1/AdipoR1 signalsome formation. Free Radic Biol Med. 2015; 89: 473-485. doi: 10.1016/j.freeradbiolmed.2015.09.005

21. Yamauchi T, Kamon J, Ito Y, Tsuchida A, Yokomizo T, Kita S, et al. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature. 2003; 423(6941): 762-769. doi: 10.1038/nature01705

22. Engin A. Adiponectin-resistance in obesity. Adv Exp Med Biol. 2017. 960: 415-441. doi: 10.1007/978-3-319-48382-5-18

23. Fang H, Judd RL. Adiponectin regulation and function. Compr Physiol. 2018; 8(3): 1031-1063. doi: 10.1002/cphy.c170046

24. Gradinaru D, Margina D, Borsa C, Ionescu C, Ilie M, Costache M, et al. Adiponectin: possible link between metabolic stress and oxidative stress in the elderly. Aging Clin Exp Res. 2017; 29(4): 621–629. doi: 10.1007/s40520-016-0629-z

25. Ruan H, Dong LQ. Adiponectin signaling and function in insulin target tissues. J Mol Cell Biol. 2016; 8: 101-109. doi: 10.1093/jmcb/mjwo14

26. Wang ZV, Cherer PE. Adiponectin, the past two decades. J Mol Cel Biol. 2016; 8: 93-100. doi: 10.1093/jmcb/mjwo11

27. Si Y, Fan W, Sun L. A review of the relationship between CTRP family and coronary artery disease. Curr Atheroscler Rep. 2020; 22(6): 22. doi: 10.1007/s11883-020-00840-0

28. Fadaei R, Moradi N, Kazemi T, Chamani E, Azdaki N, Moezibady SA, et al. Decreased serum levels of CTRP12/adipolin in patients with coronary artery disease in relation to inflammatory cytokines and insulin resistance. Cytokine. 2019; 113: 326-331. doi: 10.1016/jcito2018.09.019

29. Enomoto T, Ohashi K, Shibata R, Higuchi A, Maruyama S, et al. Adipolin/C1qdc2/CTRP12 protein functions as an adipokine that improves glucose metabolism. J Biol Chem. 2011. 286: 34552-34558. doi: 10.1074/jbc.M111.277319

30. Tan BK, Chen J, Hu J, Amar O, Mattu HS, Ramanjaneya M, et al. Circulatory changes of the novel adipokine adipolin/CTRP12 in response to metformin treatment and an oral glucose challenge in humans. Clin Endocrinol (Oxf). 2014; 81: 841-846. doi: 10.1111/cen.12438

31. Knights AJ, Funnell APW, Pearson RCM, Crossley M, Bell-Anderson KS. Adipokines and insulin action. A sensitive issue. Adipocyte. 2014; 3(2): 88-96. doi: 10.4161/adip.27552

32. Tan BK, Lewandowski KC, O’Hare JP, Randeva HS. Insulin regulates the novel adipokine adipolin/CTRP12: in vivo and ex vivo effects. J Endocrinol. 2014; 221(1): 111-119. doi: 10.1530/JOE-13-0537

33. Tan BK, Chen J, Adya R, Ramanjaneya M, Patel V, Randeva HS. Metformin increases the novel adipokine adipolin/CTRP12: Role of the AMPK pathway. J Endocrinol. 2013; 219: 101-108. doi: 10.1530/JOE-13-0277

34. Enomoto T, Shibata R, Ohashi K, Kambara T, Kataoka Y, Uemura Y, et al. Regulation of adipolin/CTRP12 cleavage by obesity. Biochem Biophys Res Commun. 2012; 428: 155-159. doi: 10.1016/j.bbrc.2012.10.031

35. Bell-Anderson KS, Funnell AP, Williams H, Mat Jusoh H, Scully T, Lim WF, et al. Loss of Krüppel-like factor 3 (KLF3/BKLF) leads to upregulation of the insulin-sensitizing factor adipolin (FAM132A/CTRP12/C1qdc2). Diabetes. 2013; 62: 2728-2737. doi: 10.2337/db12-1745

36. Escoté X, Gómez-Zorita S, López-Yoldi M, Milton-Laskibar I, Fernández-Quintela A, Martínez JA, et al. Role of omentin, vaspin, cardiotrophin-1, TWEAK and NOV/CCN3 in obesity and diabetes development. Int J Mol Sci. 2017; 18(8): E1770. doi: 10.3390/ijms18081770

37. Watanabe T, Watanabe-Kominato K, Takahashi Y, Kojima M, Watanabe R. Adipose tissue-derived omentin-1 function and regulation. Compr Physiol. 2017; 7(3): 765-781. doi: 10.1002/cphy.c160043

38. Maruyama S, Shibata R, Kikuchi R, Izumiya Y, Rokutanda T, Araki S, et al. Fat-derived factor omentin stimulates endothelial cell function and ischemia-induced revascularization via endothelial nitric oxide synthase-dependent mechanism. J Biol Chem. 2012; 287(1): 408-417. doi: 10.1074/jbc.M111.261818

39. Qi D, Tang X, He J, Wang D, Zhao Y, Deng W, et al. Omentin protects against LPS-induced ARDS through suppressing pulmonary inflammation and promoting endothelial barrier via an Akt/ eNOS-dependent mechanism. Cell Death Dis. 2016; 7(9): e2360. doi: 10.1038/cddis.2016.265

40. Alyahya AM, Al-Masri A, Hersi A, El Eter E, Husain S, Lateef R, et al. The effects of progranulin in a rat model of acute myocardial ischemia/reperfusion are mediated by activation of the P13K/Akt signaling pathway. Med Sci Monit Basic Res. 2019; 25: 229-237. doi: 10.12659/MSMBR.916258

41. Hwang HJ, Jung TW, Hong HC, Choi HY, Seo JA, Kim SG, et al. Progranulin protects vascular endothelium against atherosclerotic inflammatory reaction via Akt/eNOS and nuclear factor-κB pathways. PLoS One. 2013; 8(9): e76679. doi: 10.1371/journal.pone.007679

42. Korolczuk A, Bełtowski J. Progranulin, a new adipokine at the crossroads of metabolic syndrome, diabetes, dyslipidemia and hypertension. Nurr Pharm Des. 2017; 23(10): 1533-1539. doi: 10.2174/13816128236661701241424

43. Townley RA, Boeve BF, Eduardo E, Benarroch EE. Progranulin. Functions and neurologic correlations. Neurology. 2018; 90(3): 118-125. doi: 10.1212/WNL0000000000004840

44. De Henau O, Degroot G-N, Imbault V, Robert V, De Poorter C, McHeik S, et al. Signaling properties of chemerin receptors CMKLR1, GPR1 and CCRL2. PLoS One. 2016; 11: e0164179. doi: 10.1371/journal.pone.0164179

45. Carracedo M, Witasp A, Qureshi AR, Laguna-Fernandez A, Brismar T, Stenvinkel P, et al. Chemerin inhibits vascular calcification through ChemR23 and is associated with lower coronary calcium in chronic kidney disease. J Intern Med. 2019; 286(4): 449-457. doi: 10.1111/joim.12940

46. Li Y, Shi B, Li S. Association between serum сhemerin concentrations and clinical indices in obesity or metabolic syndrome: a meta-analysis. PLoS One. 2014; 9: e113915. doi: 10.1371/journal.pone.0113915

47. Roguska J, Zubkiewicz-Kucharska A. Chemerin as an early marker of metabolic syndrome. Pediatr Endocrinol Diabetes Metab. 2018; 24(1): 45-51. doi: 10.18544/PEDM-24.01.0102

48. Neves KB, Nguyen Dinh CA, Alves-Lopes R, Harvey KY, Costa RMD, Lobato NS, et al. Chemerin receptor blockade improves vascular function in diabetic obese mice via redox-sensitive and Akt-dependent pathways. Am J Physiol. 2018; 315(6): 1851- 1860. doi: 10.1152/ajpheart.00285.2018

49. Kaur J, Mattu HS, Chatha K, Randeva HS. Chemerin in human cardiovascular disease. Vascul Pharmacol. 2018; 110: 1-6. doi: 10.1016/j.vph.2018.06.018

50. Kutlay Ö, Kaygısız Z, Kaygısız B. The effect of chemerin on cardiac parameters and gene expressions in isolated perfused rat heart. Balkan Med J. 2019; 36(1): 43-48. doi: 10.4274balkanmedj.2017.1787

51. Heiker JT. Vaspin (serpinA12) in obesity, insulin resistance, and inflammation. J Pept Sci. 2014; 20(5): 299-306. doi: 10.1002/psc.2621

52. Kurowska P, Mlyczyńska E, Dawid M, Dupont J, Rak A. Role of vaspin in porcine ovary: effect on signaling pathways and steroid synthesis via GRP78 receptor and protein kinase A. Biol Reprod. 2020. 102(6): 1290-1305. doi: 10.1093biolreioaa027

53. Fasshauer M, Blüher M. Adipokines in health and disease. Tr Pharmacol Sci. 2015; 36(7): 461-470. doi: 10.1016/j.tips.2015.04.014

54. Mihanfar A, Rahmati-Yamchi M, Mota A, Abediazar S, Pilehvar-Soltanahmadi Y, Zarghami N. Serum levels of vaspin and its correlation with nitric oxide in type 2 diabetic patients with nephropathy. Curr Diabetes Rev. 2018; 14(2): 162-167. doi: 10.217 4/1573399813666170530103216

55. Heiker JT, Klöting N, Kovacs P, Kuettner EB, Sträter N, Schultz S, et al. Vaspin inhibits kallikrein 7 by serpin mechanism. Cell Mol Life Sci. 2013; 70(14): 2569-2583. doi: 10.10072Fs00018-013-1258-8

56. Bao JP, Xu LH, Ran JS, Xiong Y, Wu LD. Vaspin prevents leptin-induced inflammation and catabolism by inhibiting the activation of nuclear factor-κB in rat chondrocytes. Mol Med Rep. 2017; 16(3): 2925-2930. doi: 10.3892/mmr.2017.6911

57. Fukuhara A, Matsuda M, Nishizawa M, Segawa K, Tanaka M, Kishimoto K, et al. Visfatin: a protein secreted by visceral fat that mimics the effects of insulin. Science. 2005; 307(5708): 426-30. doi: 10.1126/science.1097243

58. Abella V, Scotece M, Conde J, López V, Lazzaro V, Pino J, et al. Adipokines, metabolic syndrome and rheumatic diseases. J Immunol Res. 2014: 343746. doi: 10.1155/2014/343746

59. Olszanecka-Glinianowicz M, Kocełak P, Nylec M, Chudek J, Zahorska-Markiewicz B. Circulating visfatin level and visfatin/insulin ratio in obese women with metabolic syndrome. Arch Med Sci. 2012; 8(2): 214-218. doi: 10.51114/aoms.2012.28547

60. Adya R, Tan BK, Punn A, Chen J, Randeva HS. Visfatin induces human endothelial VEGF and MMP-2/9 production via MAPK and PI3K/Akt signalling pathways: novel insights into visfatin-induced angiogenesis. Cardiovasc Res. 2008; 78: 356-365. doi: 10.1093/cvr/cvm111

61. Gerbier R, Leroux V, Couvineau P, Alvear-Perez R, Maigret B, Llorens-Cortes C, et al. New structural insights into the apelin receptor: indentification of the key residues for apelin binding. FASEB J. 2015; 29(1): 314-322. doi: 10.1096/fj.14-256339

62. Kurowska P, Barbe A, Rozycka M, Chmielinska J, Dupont J, Rak A. Apelin in reproductive physiology and pathology of different species: a critical review. Int J Endocrinol. 2018: 9170480. doi: 10.1155/2018//9170480

63. Yue P, Jin H, Xu S, Aillaud M, Deng AC, Azuma J, et al. Apelin decreased lipolis via Gq, Gi and AMPK-dependent mechanism. Endocrinology. 2011; 152(1): 59-68. doi: 10.1210/en.2010-0576

64. DePaoli AM. 20 years of leptin: leptin in common obesity and associated disorders of metabolism. J Endocrinol. 2014; 223(1): 71-81. doi: 10.12703/P6-73

65. Park HK, Ahima RS. Leptin signaling. F1000Prime Rep. 2014, 6: 73. doi: 10.1530/JOE-14-0258

66. Myers MG, Cowley MA, Münzberg H. Mechanisms of leptin action and leptin resistance. Annu Rev Physiol. 2008, 70: 537-556. doi: 10.1111.1440-1681.2011.05623.x

67. Romanova IV, Derkach KV, Morina AYu, Sukhov IB, Kuznetsova LA, Shpakov AO. Changes in the ratio of orexigenic and anorexigenic factors in the hypothalamus of obese rats caused by the cafeteria diet. Russian Journal of Physiology. 2018; 104(6): 724-730. (In Russ.). doi: 10.7868/S0869813918-060163

68. Bełtowski J. Leptin and the regulation of endothelial function in physiological and pathological conditions. Clin Exp Pharm Physiol. 2012; 39(2): 168-178. doi: 10.1016/j.brainresbull.2012.08.003

69. Schinzari F, Tesauro M, Rovella V, Daniele ND, Mores N, Veneziani A, et al. Leptin stimulates both endothelin-1 and nitric oxide activity in lean subjects but not in patients with obesity-related metabolic syndrome. J Clin Endocrinol Metab. 2013; 98(3): 1235-1241. doi: 10.1210/jc.2012-3424 7

70. Landecho MF, Tuero C, Valentí V, Bilbao I, Higuera M, Frühbeck G. Relevance of leptin and other adipokines in obesity-associated cardiovascular risk. Nutrients. 2019; 11(11): 2664. doi: 10.3990/nu11112664

71. Vecchione C, Maffei A, Colella S, Aretini A, Poulet R, Frati G, et al. Leptin effect on endothelial nitric oxide is mediated through Akt-endothelial nitric oxide synthase phosphorylation pathway. Diabetes. 2002; 51: 168-173. doi: 10.2337/diabetes.5.1.1.168

72. Mitchell JL, Morgan DA, Correia ML, Mark AL, Sivitz WI, Haynes WG. Does leptin stimulate nitric oxide to oppose the effects of sympathetic activation? Hypertension. 2001; 38: 1081-1086. doi: 10.1111.1440-1681.2011.05623.x

73. de Boer MP, Meijer RI, Richter EA, Nieuw Amerongen GP, Sipkema P, Poelgeest EM, et al. Globular adiponectin controls insulin-mediated vasoreactivity in muscle through AMPKα2. Vascul Pharmacol. 2016. 78: 24-35. doi: 10.1016/j.vph.2015.09.002

74. Adya R, Tan BK, Randeva HS. Differential effects of leptin and adiponectin in endothelial angiogenesis. J Diabetes Res. 2015: 648239. doi: 10.1155/2015/648239

75. Grossini E, Farruggio S, Qoqaiche F, Raina G, Camillo L, Sigaudo L, et al. Monomeric adiponectin modulates nitric oxide release and calcium movements in porcine aortic endothelial cells in normal/high glucose conditions. Life Sci. 2016; 161: 1-9. doi: 10.1016/j.efs.2016.07.010

76. Xia N, Horke S, Habermeier A, Closs EI, Reifenberg G, Gericke A, et al. Uncoupling of endothelial nitric oxide synthase in perivascular adipose tissue of diet-induced obese mice. Arterioscler Thromb Vasc Biol. 2016; 36(1): 78-85. doi: 10.1161/ATVBAHA.115.306263

77. Zhao L, Fu Z, Wu J, Aylor KW, Barrett EJ, Cao W, et al. Globular adiponectin ameliorates metabolic insulin resistance via AMPK-mediated restoration of microvascular insulin responses. J Physiol. 2015; 593(17): 4067-4079. doi: 10.1113/JP270371

78. Brzoskwinia M, Pardyak L, Rak A, Kaminska A, Hejmej A, Marek S, et al. Flutamide alters the expression of chemerin, apelin, and vaspin and their respective receptors in the testes of adult rats. Int J Mol Sci. 2020; 21(12): 4439. doi: 10.3390ijms21124439

79. Ebert T, Gebhardt C, Scholz M, Wohland T, Schleinitz D, Fasshauer M, et al. Relationship between 12 adipocytokines and distinct components of the metabolic syndrome. J Clin Endocrinol Metab. 2018; 103(3): 1015-1023. doi: 10.1210/jc.2017-02085