Adipokines resistin and lipokalin-2 and its role in the pathogenesis of polycystic ovary syndrome and metabolic syndrome.

Authors

  • N. Yu. Voronenko Shupyk National Medical Academy of Postgraduate Education, Ukraine

DOI:

https://doi.org/10.26641/2307-0404.2013.3.19000

Keywords:

adipocytokines, lipocalin-2, resistin, metabolic syndrome, polycystic ovary syndrome

Abstract

Adipose tissues hormones resistin and lipocalin -2 play an important role in the regulation of lipid and carbohydrate metabolism, inflammation and immune disorders, fertility and reproductive mechanisms. Obesity and overweight are significantly involved in the process of fertility decline. Women with obesity and metabolic syndrome have abnormal adypokine plasma levels. The aim of the study was to investigate the relationships between the women’s of the hypothalamic-pituitary-ovarian axis and energy metabolism. Methods: basal levels of resistin, lipocalin-2, follicular stimulating, luteinizing hormones, estradiol, total and free testosterone, dihydrotestosterone, dihydroepiandrosteron sulfate, androstenedione, cortisol, anti-mullerian hormone, prolactin, insulin, folistatin, homocysteine, interleukin-6 and sex-binding globulin were determined in the serum of 35 women of reproductive age with metabolic syndrome (MS), 33 patients of reproductive age with polycystic ovary syndrome (PCOS) and in 54 healthy contols. It is found that despite the normal values of hormones lipocalin-2 and resistin even in patients with obesity, their concentrations significantly correlated with anthropometric, hormonal and metabolic parameters. We established statistically significant stimulatory effects of lipocalin-2 and resistin on the synthesis of ovarian steroids and the significant inhibitory effect of lipocalin-2 and resistin on ovarian and adrenal androgens synthesis in normal physical condition and reproductive health. In MS and PCOS these relationships are not established. The results obtained allow us to propose the assumption of the existence of metabolic changes of the sensitivity of the reproductive system and the adrenal gland to the effects of lipocalin -2 and resistin in women with PCOS and metabolic syndrome.

References

17beta-hydroxysteroid dehydrogenase (HSD)/17-ketosteroid reductase (KSR) family; nomenclature and main characteristics of the 17HSD/KSR enzymes / H. Peltoketo, V. Luu-The, J. Simard, J. Adamski // J. Mol. Endocrinol. – 1999. – Vol. 23. – P. 1-11.

A direct effect of hyperinsulinemia on serum sex hormone-binding globulin levels in obese women with the polycystic ovary syndrome / J.E. Nestler, L.P. Powers, D.W. Matt, K.A. Steingold, S.R. Plymate, R.S. Rit¬tmaster, J.N. Clore, W.G. Blackard // J. Clin. Endocrinol. Metab. – 1991. – Vol. 72. – P. 83-89.

A 25 kDa alpha 2-microglobulin- related protein is a component of the 125 kDa form of human gelatinase / S. Triebel, J. Bläser, H. Reinke, H. Tschesche // FEBS Lett. – 1992. – Vol. 314. – P. 386-388.

Acute endotoxemia is associated with upregu¬lation of lipocalin 24p3/Lcn2 in lung and liver / V.R. Sunil, K.J. Patel, M. Nilsen-Hamilton [et al.] // Exp. Mol. Pathol. – 2007. – Vol. 83. – P. 177-187.

Adiponectin and resistin serum levels in women with polycystic ovary syndrome during glucose tolerance test: A signficant reciprocal correlation between adipo¬nectin and resistin independent of insulin resistance indices / K.C. Lewandowski, K. Szosland, C. O’Cal¬laghan [et al.] // Molecular Genetics Metabolism. – 2005. – Vol. 85. – P. 61–69.

Anti-Müllerian hormone levels reflect severity of PCOS but are negatively influenced by obesity: relationship with increased luteinizing hormone levels / A. Piouka, D. Farmakiotis, I. Katsikis [et al.] // Am. J. Physiol. Endocrinol. Metab. – 2009. – Vol. 296. – P. 238-243.

A proteomic approach for identification of secreted proteins during the differentiation of 3T3-L1 preadipocytes to adipocytes / I. Kratchmarova, D.E. Ka¬lume, B. Blagoev [et al.] // Mol Cell Proteomics. – 2002. - Vol. 1. – P. 213-222.

Björntorp P.: Abdominal obesity and the me¬tabolic syndrome / P. Björntorp // Ann. Med. - 1992. – Vol. 24. – Р. 465-468.

Chen C.C. Serum resistin level among healthy subjects: Relationship to anthropometric and metabolic parameters / C.C. Chen // Metabolism. – 2005. – Vol. 54. – P. 471–475.

Cowland J.B. Molecular characterization and pattern of tissue expression of the gene for neutrophil gelatinase-associated lipocalin from humans / J.B. Cow¬land, N. Borregaard // Genomics. – 1997. – Vol. 45. – Р. 17-23.

DeFronzo R.A. Glucose clamp technique: a method for quantifying insulin secretion and resistance / R.A. DeFronzo, J.D. Tobin, R. Andres // Am. J. Physiol . – 1979. – Vol. 237. – Р. 214-223.

Deslypere JP. Fat tissue: a steroid reservoir and site of steroid metabolism. J.P. Deslypere, L. Verdonck, A. Vermeulen // J. Clin. Endocrinol. Metab. – 1985. – Vol. 61. – Р. 564-570.

Devarajan P. Neutrophil gelatinase-associated lipocalin–an emerging troponin for kidney injury / P. De¬varajan // Nephrol. Dial. Transplant. – 2008. – Vol. 23. – Р. 3737-3743.

Diamanti-Kandarakis E. Unravelling the phe¬notypic map of polycystic ovary syndrome (PCOS): a prospective study of 634 women with PCOS / E. Di¬a¬manti-Kandarakis, D. Panidis // J. Clin. Endocrinol. – 2007. – Vol. 67. – Р. 735-742.

Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanism and implications for patho¬genesis / A. Dunaif // Endocr Rev. – 1997. – N 18. – P. 774-800.

Failure of mathematical indices to accurately assess insulin resistance in lean, overweight, or obese wo¬men with polycystic ovary syndrome / E. Diamanti-Kandarakis, C. Kouli, K. Alexandraki, G. Spina // J. Clin. Endocrinol. Metab. – 2004. – Vol. 89. – Р. 1273-1276.

Flo T.H. Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron / T.H. Flo, K.D. Smith, S. Sato [et al.] // Nature. – 2004. – Vol. 432. – P. 917-921.

Goodarzi M.O. The importance of insulin resistance in polycystic ovary syndrome / M.O. Goodarzi, S.G. Korenman // Fertil Steril . – 2003. – Vol. 80. – P. 255-258.

Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man / D. Matthews, J. Hosker, A. Rudenski [et al.] // Diabetologia. – 1985. – Vol. 28. – P. 12-19.

Huang H.L. Ovarian steroids regulate 24p3 expression in mouse uterus during the natural estrous cycle and the preimplantation period / H.L. Huang, S.T. Chu, Y.H. Chen // J. Endocrinol. – 1999. – Vol. 162. – P. 11-19.

Implication of lipocalin-2 and visfatin levels in patients with coronary heart disease / K.M. Choi, J.S. Lee, E.J. Kim [et al.] // Eur. J. Endocrinol. – 2008. – Vol. 158. – Р. 203-207.

Identification of neutrophil gelatinase-associated lipocalin (NGAL) as a discriminatory marker of the hepatocyte-secreted protein response to IL-1beta: a pro¬teomic analysis / A. Jayaraman, K.A. Roberts, J. Yoon [et al.] // Biotechnol. Bioeng. – 2005. – Vol. 91. – P. 502-515.

Identification by microsequencing of lipopolysac¬charide-induced proteins secreted by mouse macrophages / L.A. Meheus, L.M. Fransen, J.G. Raymackers [et al.] // Immunol. – 1993. – Vol. 151. – P. 1535-1547.

Induction of apoptosis by a secreted lipocalin that is transcriptionally regulated by IL-3 deprivation / L.R. Devireddy, J.G. Teodoro, F.A. Richard, M.R. Green // Science. – 2001. – Vol. 293. – Р. 829-834.

Legato M.J. Gender-specific aspects of obesity / M.J. Legato // Int. J. Fertil. Womens Med. – 1997. - Vol. 42. – P. 184-197.

Lipocalin-2 is an inflammatory marker closely associated with obesity, insulin resistance, and hy¬per¬glycemia in humans / Y. Wang, K.S. Lam, E.W. Kraegen [et al.] // Clin. Chem. – 2007. – Vol. 53. – P. 34-41.

Lipocalin 2-deficient mice exhibit increased sensitivity to Escherichia coli infection but not to ischemia-reperfusion injury / T. Berger, A. Togawa, G.S. Du¬n¬can [et al.] // Proc Natl Acad Sci USA. - 2006. – Vol. 103. – P. 1834-1839.

Liu Q. Identification of a new acute phase protein / Q. Liu, M. Nilsen-Hamilton // J. Biol. Chem. – 1995. – Vol. 270. – P. 22565-22570.

Morley J.E. Evaluation of assays available to measure free testosterone / J.E. Morley, P. Patrick, H.M. Perry // Metabolism. – 2002. – N 5. – P. 554-559.

Nestler J.E. Lean women with polycystic ovary syndrome respond to insulin reduction with decreases in ovarian P450c17 alpha activity and serum androgens / J.E. Nestler, D.J. Jakubowicz // J. Clin. Endocrinol. Metab. – 1997. – Vol. 82. – P. 4075-4079.

Obesity, body composition and metabolic disturbances in polycystic ovary syndrome / P.F. Sven¬dsen, L. Nilas, K. Norgaard [et al.] // Human Repro¬duction. – 2008. – N23. – P. 2113–2121.

Osawa H. Plasma resistin, associated with single nucleotide plymorphism –402, is correlated with insulin resistance, lower HDL cholesterol, and high sensitivity C-reactive protein in the Japanese general population / H. Osa¬wa // Diabetes Care. – 2007. – Vol. 30. – P. 1501–1506.

Pervaiz S. Homology and structure-function cor¬relations between alpha 1-acid glycoprotein and serum retinol-binding protein and its relatives / S. Pervaiz, K. Brew // FASEB J. - 1987. – N 1. – P. 209-214.

Pervaiz S. Homology of beta-lactoglobulin, serum retinol-binding protein, and protein HC / S. Pervaiz, K. Brew // Science. – 1985. – Vol. 228. – P. 335-337.

Pittas A.G. Adipocyto-kines and insulin resis¬tance / A.G. Pittas, N.A. Joseph, A.S. Greenberg // J. Clin. Endocrinol. Metabolism. – 2004. – Vol. 89. – P. 447–452.

Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans / A. Katz, S.S. Nambi, K. Mather [et al.] // J. Clin. Endocrinol. Metab. – 2000. – Vol. 85. – P. 2402-2410.

Rajala M.W. Regulation of resistin expression and circulating levels in obesity, diabetes, and fasting / M.W. Rajala // Diabetes. – 2004. – Vol. 53. – P. 1671–1679.

Rasouli N. Adipocytokines and the metabolic complications of obesity / Rasouli N, Kern PA / N. Ra¬souli // J. Clin. Endocrinol. Metabolism. - 2008. – Vol. 93. – P. 64–73.

Rotterdam ESHRE/ASRM-Sponsored PCOS Con¬sensus Workshop Group: Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome / Fertil Steril. – 2004. – Vol. 81. – P. 19-25.

Rotterdam ESHRE/ASRM-Sponsored PCOS Con¬sensus Workshop Group: Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS) / Hum. Reprod. - 2004. - N19. – P. 41-47.

Serum lipocalin-2 as an insulin resistance marker in patients with polycystic ovary syndrome / D.X. Bu, A.L. Hemdahl, A. Gabrielsen [et al.] // J. Endocrinol Invest. – 2010. – N 32. – Р.38-43.

The impact of obesity on reproduction in women with polycystic ovary syndrome / R. Pasquali, A. Gam¬bineri, U. Pagotto // An. Inter. J. Obstetrics Gynaecology. – 2006. – Vol. 113. – P. 1148– 1159.

The pathogen- associated iroA gene cluster me¬diates bacterial evasion of lipocalin 2 / M.A. Fischbach, H. Lin, L. Zhou [et al.] // Proc Natl Acad Sci USA. – 2006. – Vol. 103. – P. 16502-16507.

Yang J. An iron delivery pathway mediated by a lipocalin / J. Yang, D. Goetz, J.Y. Li [et al.] // J. Mol. Cell. – 2002. – N 10. – P. 1045-1056.

Peltoketo H, Luu-The V, Simard J, Adamski J. 17beta-hydroxysteroid dehydrogenase (HSD)/17-keto¬steroid reductase (KSR) family; nomenclature and main characteristics of the 17HSD/KSR enzymes. J Mol Endocrinol. 1999;23:1-11.

Nestler JE, Powers LP, Matt DW, Steingold KA, Plymate SR, Rittmaster RS, Clore JN, Blackard WG. A direct effect of hyperinsulinemia on serum sex hormone-binding globulin levels in obese women with the polycystic ovary syndrome. J Clin Endocrinol Metab. 1991;72:83-89.

Triebel S, Bläser J, Reinke H, Tschesche H. A 25 kDa alpha 2-microglobulin- related protein is a com¬ponent of the 125 kDa form of human gelatinase. FEBS Lett. 1992;314:386-8.

Sunil VR, Patel KJ, Nilsen-Hamilton M, Heck DE, Laskin JD, Laskin DL. Acute endotoxemia is asso¬ciated with upregulation of lipocalin 24p3/Lcn2 in lung and liver. Exp Mol Pathol. 2007;83:177-87.

Lewandowski KC, Szosland K, O’Callaghan C, Tan BK, Randeva HS, Lewinski A. Adiponectin and resistin serum levels in women with polycystic ovary syndrome during glucose tolerance test: A signficant reciprocal correlation between adiponectin and resistin independent of insulin resistance indices. Molecular Genetics and Metabolism. 2005;85:61–69.

Piouka A, Farmakiotis D, Katsikis I, Macut D, Gerou S, Panidis D. Anti-Müllerian hormone levels ref¬lect severity of PCOS but are negatively influenced by obesity: relationship with increased luteinizing hormone levels. Am J Physiol Endocrinol Metab. 2009;296:238-43.

Kratchmarova I, Kalume DE, Blagoev B, Scherer PE, Podtelejnikov AV, Molina H, Bickel PE, Andersen JS, Fernandez MM, Bunkenborg J, Roepstorff P, Kris¬tiansen K, Lodish HF, Mann M, Pandey A. A proteomic approach for identification of secreted proteins during the differentiation of 3T3-L1 preadipocytes to adipocytes. Mol Cell Proteomics. 2002;1:213-22.

Björntorp P: Abdominal obesity and the meta¬bolic syndrome / Ann Med. 1992;24:465-8.

Chen CC. Serum resistin level among healthy subjects: Relationship to anthropometric and metabolic parameters. Metabolism. 2005;54:471–5.

Cowland JB. Molecular characterization and pattern of tissue expression of the gene for neutrophil gelatinase-associated lipocalin from humans / Cowland JB, Borregaard N. Genomics. 1997;45:17-23.

DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol. 1979; 237:214-23.

Deslypere JP, Verdonck L, Vermeulen A. Fat tissue: a steroid reservoir and site of steroid metabolism. J Clin Endocrinol Metab. 1985;61:564-70.

Devarajan P. Neutrophil gelatinase-associated lipocalin–an emerging troponin for kidney injury. Nephrol Dial Transplant. 2008;23:3737-43.

Diamanti-Kandarakis E, Panidis D. Unravelling the phenotypic map of polycystic ovary syndrome (PCOS): a prospective study of 634 women with PCOS . Clin Endocrinol. 2007;67:735-742.

Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocr Rev. 1997;18:774-800.

Diamanti-Kandarakis E, Kouli C, Alexandraki K, Spina G. Failure of mathematical indices to accurately assess insulin resistance in lean, overweight, or obese women with polycystic ovary syndrome. J Clin Endo¬crinol Metab. 2004; 89:1273-6.

Flo TH, Smith KD, Sato S, Rodriguez DJ, Holmes MA, Strong RK, Akira S, Aderem A. Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron. Nature. 2004; 432:917-21.

Goodarzi MO, Korenman SG. The importance of insulin resistance in polycystic ovary syndrome. Fertil Steril . 2003;80:255-8.

Matthews D, Hosker J, Rudenski A, Naylor B, Treacher D, Turner R. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28:12-19.

Huang HL, Chu ST, Chen YH. Ovarian steroids regulate 24p3 expression in mouse uterus during the natural estrous cycle and the preimplantation period. J Endocrinol. 1999;162:11-19.

Choi KM, Lee JS, Kim EJ, Baik SH, Seo HS, Choi DS, Oh DJ, Park CG. Implication of lipocalin-2 and visfatin levels in patients with coronary heart disease. Eur J Endocrinol. 2008;158:203-7.

Jayaraman A, Roberts KA, Yoon J, Yarmush DM, Duan X, Lee K, Yarmush ML. Identification of neut¬rophil gelatinase-associated lipocalin (NGAL) as a dis¬criminatory marker of the hepatocyte-secreted protein res¬ponse to IL-1beta: a proteomic analysis. 2005; 91:502-15.

Meheus LA, Fransen LM, Raymackers JG, Blockx HA, Van Beeumen JJ, Van Bun SM, Van de Voorde AJ. Identification by microsequencing of lipo¬polysaccharide-induced proteins secreted by mouse macro¬phages. Immunol. 1993;151:1535-47.

Devireddy LR, Teodoro JG, Richard FA, Green MR. Induction of apoptosis by a secreted lipocalin that is transcriptionally regulated by IL-3 deprivation. Science. 2001; 293:829-34.

Legato MJ. Gender-specific aspects of obesity. Int J Fertil Womens Med. 1997;42:184-97.

Wang Y, Lam KS, Kraegen EW, Sweeney G, Zhang J, Tso AW, Chow WS, Wat NM, Xu JY, Hoo RL, Xu A. Lipocalin-2 is an inflammatory marker closely associated with obesity, insulin resistance, and hyper¬glycemia in humans. Clin Chem. 2007;53:34-41.

Berger T, Togawa A, Duncan GS, Elia AJ, You-Ten A, Wakeham A, Fong HE, Cheung CC, Mak TW. Lipocalin 2-deficient mice exhibit increased sensitivity to Escherichia coli infection but not to ischemia-reperfusion injury. Proc Natl Acad Sci USA. 2006;103:1834-9.

Liu Q, Nilsen-Hamilton M. Identification of a new acute phase protein. J Biol Chem. 1995;270:22565-70.

Morley JE, Patrick P, Perry HM. Evaluation of assays available to measure free testosterone. Metabolism. 2002;5:554-9.

Nestler JE, Jakubowicz DJ. Lean women with polycystic ovary syndrome respond to insulin reduction with decreases in ovarian P450c17 alpha activity and serum androgens. J Clin Endocrinol Metab. 1997;82:4075-9.

Svendsen PF, Nilas L, Norgaard K, Jensen JEB, Madsbad S. Obesity, body composition and metabolic disturbances in polycystic ovary syndrome. Human Reproduction. 2008;23:2113–21.

Osawa H. Plasma resistin, associated with single nucleotide plymorphism –402, is correlated with insulin resistance, lower HDL cholesterol, and high sensitivity C-reactive protein in the Japanese general population. Diabetes Care. 2007;30:1501–6.

Pervaiz S, Brew K. Homology and structure-function

correlations between alpha 1-acid glycoprotein and serum retinol-binding protein and its relatives. FASEB J. 1987;1:209-14.

Pervaiz S, Brew K. Homology of beta-lacto¬globulin, serum retinol-binding protein, and protein HC. Science. 1985;228:335-7.

Pittas AG, Joseph NA, Greenberg AS. Adipocyto-kines and insulin resistance. Journal of Clinical Endo¬crinology and Metabolism. 2004;89:447–52.

Katz A, Nambi SS, Mather K, Baron AD, Fol¬lmann DA, Sullivan G, Quon MJ. Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab. 2000;85:2402-10.

Rajala MW, et al. Regulation of resistin expres¬sion and circulating levels in obesity, diabetes, and fasting. Diabetes. 2004;53:1671–9.

Rasouli N, Kern PA. Adipocytokines and the me¬tabolic complications of obesity. Journal of Clinical Endo¬crinology & Metabolism. 2008;93:64–73.

Rotterdam ESHRE/ASRM-Sponsored PCOS Con¬sensus Workshop Group: Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril. 2004;81:19-25.

Rotterdam ESHRE/ASRM-Sponsored PCOS Con¬sensus Workshop Group: Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS) / Hum Reprod. 2004;19:41-47.

Bu DX, Hemdahl AL, Gabrielsen A, Fuxe J, Zhu C, Eriksson P, Yan ZQ: Cakal E, Ozkaya M, Engin-Ustun Y, Ustun Y. Serum lipocalin-2 as an insulin resistance marker in patients with polycystic ovary syndrome. J Endocrinol Invest. 2010;32:38-43.

Pasquali R, Gambineri A, Pagotto U. The impact of obesity on reproduction in women with polycystic ovary syndrome. BJOG: An International Journal of Obstetrics & Gynaecology. 2006;113:1148– 59.

Fischbach MA, Lin H, Zhou L, Yu Y, Abergel RJ, Liu DR, Raymond KN, Wanner BL, Strong RK, Walsh CT, Aderem A, Smith KD. The pathogen- asso¬ciated iroA gene cluster mediates bacterial evasion of lipocalin 2. Proc Natl Acad Sci USA. 2006;103:16502-7.

Yang J, Goetz D, Li JY, Wang W, Mori K, Setlik D, Du T, Erdjument- Bromage H, Tempst P, Strong R, Barasch J. An iron delivery pathway mediated by a lipocalin. J Mol Cell. 2002;10:1045-56.

Downloads

Published

2013-10-02

How to Cite

1.
Voronenko NY. Adipokines resistin and lipokalin-2 and its role in the pathogenesis of polycystic ovary syndrome and metabolic syndrome. Med. perspekt. [Internet]. 2013Oct.2 [cited 2024Dec.2];18(3):95-110. Available from: https://journals.uran.ua/index.php/2307-0404/article/view/19000

Issue

Section

CLINICAL MEDICINE