Advertisement

Journal of Endocrinological Investigation

, Volume 39, Issue 7, pp 747–754 | Cite as

A possible connection between tumor necrosis factor alpha and adropin levels in polycystic ovary syndrome

  • T. Kume
  • M. CalanEmail author
  • O. Yilmaz
  • G. U. Kocabas
  • P. Yesil
  • M. Temur
  • M. Bicer
  • O. G. Calan
Original Article

Abstract

Context

Adropin is a peptide hormone implicated in the regulation of insulin sensitivity and energy homeostasis. Polycystic ovary syndrome (PCOS) is a metabolic and reproductive disease associated with insulin resistance. It has been demonstrated that various inflammatory markers increased in PCOS including TNF-α. TNF-α regulates the secretion of certain peptides which play a crucial role in glucose and lipid homeostasis. There is also some evidence of a link between TNF-α and adropin.

Objective

To ascertain whether there is an association between circulating adropin levels and TNF-α in PCOS.

Patients and design

152 women with PCOS and 152 age- and body mass index-matched controls without PCOS were recruited for this cross-sectional study.

Main outcome measures

Adropin and TNF-α levels were measured using ELISA.

Results

Adropin levels were lower in the PCOS group compared with the control group (7.43 ± 0.79 vs. 9.42 ± 0.76 ng/ml, P < 0.001), whereas TNF-α levels were higher (49.93 ± 3.39 vs. 35.83 ± 2.47 pg/ml, P < 0.001). A strongly negative correlation was found between circulating adropin levels and TNF-α levels in women with PCOS (r = −0.407, P < 0.001). Binary logistic regression analysis revealed that decreased adropin levels were significantly associated with high odds of having PCOS, although, after adjustment for TNF-α, this link vanished. Additionally, multiple linear regression analysis showed that HOMA-IR and TFN-α independently predicted adropin levels.

Conclusions

Serum adropin levels are significantly decreased in PCOS and are inversely associated with TNF-α. Further dissection of the nature of this association can open new therapeutic options for metabolic diseases.

Keywords

Polycystic ovary syndrome Adropin Tumor necrosis factor-α Insulin resistance Cytokine 

Abbreviations

AdrKO

Adropin knockout mice

BMI

Body mass index

CI

Confidence interval

CV

Coefficient of variability

E2

Estradiol

FBG

Fasting blood glucose

FG

Ferriman-Gallwey

HDL-C

High density lipoprotein cholesterol

HOMA-IR

Homeostasis model assessment of insulin resistance

hs-CRP

High sensitivity C-reactive protein

HUVECs

Human umbilical vein endothelial cells

LDL-C

Low density lipoprotein cholesterol

OR

Odds ratio

PCOS

Polycystic ovary syndrome

TNF-α

Tumor necrosis factor alpha

VIF

Variance inflation factor

Notes

Author contributions

T.K., M.C., G.U.K., and O.G.C. participated in study design and performed ELISA. T.K., M.C., P.Y. and M.B. participated in study design, analyzed the data, wrote, reviewed and edited the manuscript. O.Y, M.T. provided serum samples and contributed to discussions of data interpretation. M.C. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The study was conducted in compliance with the Declaration of Helsinki.

Informed consent

Informed consent was obtained from all individual participants included in the study.

References

  1. 1.
    Azziz R, Woods KS, Reyna R, Key TJ, Knochenhauer ES, Yildiz BO (2004) The prevalence and features of the polycystic ovary syndrome in an unselected population. J Clin Endocrinol Metab 89:2745–2749. doi: 10.1210/jc.2003-032046 CrossRefPubMedGoogle Scholar
  2. 2.
    Ehrmann DA (2005) Polycystic ovary syndrome. N Engl J Med 352:1223–1236. doi: 10.1056/NEJMra041536 CrossRefPubMedGoogle Scholar
  3. 3.
    Kumar KG, Trevaskis JL, Lam DD, Sutton GM, Koza RA, Chouljenko VN et al (2008) Identification of adropin as a secreted factor linking dietary macronutrient intake with energy homeostasis and lipid metabolism. Cell Metab 8:468–481. doi: 10.1016/j.cmet.2008.10.011 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Lovren F, Pan Y, Quan A, Singh KK, Shukla PC, Gupta M et al (2010) Adropin is a novel regulator of endothelial function. Circulation 122:S185–S192. doi: 10.1161/CIRCULATIONAHA.109.931782 CrossRefPubMedGoogle Scholar
  5. 5.
    Aydin S, Kuloglu T, Aydin S, Eren MN, Yilmaz M, Kalayci M et al (2013) Expression of adropin in rat brain, cerebellum, kidneys, heart, liver, and pancreas in streptozotocin-induced diabetes. Mol Cell Biochem 380:73–81. doi: 10.1007/s11010-013-1660-4 CrossRefPubMedGoogle Scholar
  6. 6.
    Yildirim B, Celik O, Aydin S (2014) Adropin: a key component and potential gatekeeper of metabolic disturbances in policystic ovarian syndrome. Clin Exp Obstet Gynecol 41:310–312PubMedGoogle Scholar
  7. 7.
    Sayın O, Tokgöz Y, Arslan N (2014) Investigation of adropin and leptin levels in pediatric obesity-related nonalcoholic fatty liver disease. J Pediatr Endocrinol Metab 27:479–484. doi: 10.1515/jpem-2013-0296 PubMedGoogle Scholar
  8. 8.
    Celik A, Balin M, Kobat MA, Erdem K, Baydas A, Bulut M et al (2013) Deficiency of a new protein associated with cardiac syndrome X; called adropin. Cardiovasc Ther 31:174–178. doi: 10.1111/1755-5922.12025 CrossRefPubMedGoogle Scholar
  9. 9.
    Celik E, Yilmaz E, Celik O, Ulas M, Turkcuoglu I, Karaer A et al (2013) Maternal and fetal adropin levels in gestational diabetes mellitus. J Perinat Med 41:375–380. doi: 10.1515/jpm-2012-0227 CrossRefPubMedGoogle Scholar
  10. 10.
    Wu L, Fang J, Chen L, Zhao Z, Luo Y, Lin C et al (2014) Low serum adropin is associated with coronary atherosclerosis in type 2 diabetic and non-diabetic patients. Clin Chem Lab Med 52:751–758. doi: 10.1515/cclm-2013-0844 PubMedGoogle Scholar
  11. 11.
    Bradley JR (2008) TNF-mediated inflammatory disease. J Pathol 214:149–160. doi: 10.1002/path.2287 CrossRefPubMedGoogle Scholar
  12. 12.
    Popa C, Netea MG, van Riel PLCM, van der Meer JWM, Stalenhoef AFH (2007) The role of TNF-alpha in chronic inflammatory conditions, intermediary metabolism, and cardiovascular risk. J Lipid Res 48:751–762. doi: 10.1194/jlr.R600021-JLR200 CrossRefPubMedGoogle Scholar
  13. 13.
    Cesari M, Penninx BWJH, Newman AB, Kritchevsky SB, Nicklas BJ, Sutton-Tyrrell K et al (2003) Inflammatory markers and onset of cardiovascular events: results from the Health ABC study. Circulation 108:2317–2322. doi: 10.1161/01.CIR.0000097109.90783.FC CrossRefPubMedGoogle Scholar
  14. 14.
    Rui L, Aguirre V, Kim JK, Shulman GI, Lee A, Corbould A et al (2001) Insulin/IGF-1 and TNF-alpha stimulate phosphorylation of IRS-1 at inhibitory Ser307 via distinct pathways. J Clin Invest 107:181–189. doi: 10.1172/JCI10934 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Chazenbalk G, Trivax BS, Yildiz BO, Bertolotto C, Mathur R, Heneidi S et al (2010) Regulation of adiponectin secretion by adipocytes in the polycystic ovary syndrome: role of tumor necrosis factor-{alpha}. J Clin Endocrinol Metab 95:935–942. doi: 10.1210/jc.2009-1158 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Kirchgessner TG, Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS (1997) Tumor necrosis factor-alpha contributes to obesity-related hyperleptinemia by regulating leptin release from adipocytes. J Clin Invest 100:2777–2782. doi: 10.1172/JCI119824 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Fasshauer M, Klein J, Neumann S, Eszlinger M, Paschke R (2001) Tumor necrosis factor alpha is a negative regulator of resistin gene expression and secretion in 3T3-L1 adipocytes. Biochem Biophys Res Commun 288:1027–1031. doi: 10.1006/bbrc.2001.5874 CrossRefPubMedGoogle Scholar
  18. 18.
    Toulis KA, Goulis DG, Mintziori G, Kintiraki E, Eukarpidis E, Mouratoglou S-A et al (2011) Meta-analysis of cardiovascular disease risk markers in women with polycystic ovary syndrome. Hum Reprod 17:741–760. doi: 10.1093/humupd/dmr025 CrossRefGoogle Scholar
  19. 19.
    Gonzalez F, Thusu K, Abdel-Rahman E, Prabhala A, Tomani M, Dandona P (1999) Elevated serum levels of tumor necrosis factor alpha in normal-weight women with polycystic ovary syndrome. Metabolism 48:437–441CrossRefPubMedGoogle Scholar
  20. 20.
    Vgontzas AN, Trakada G, Bixler EO, Lin H-M, Pejovic S, Zoumakis E et al (2006) Plasma interleukin 6 levels are elevated in polycystic ovary syndrome independently of obesity or sleep apnea. Metabolism 55:1076–1082. doi: 10.1016/j.metabol.2006.04.002 CrossRefPubMedGoogle Scholar
  21. 21.
    Tarlatzis R, Fauser B, Chang J, Azziz R. (2004) Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). The Rotterdam ESHRE/ASRM. Hum ReprodGoogle Scholar
  22. 22.
    Ferriman D, Gallwey JD (1961) Clinical assessment of body hair growth in women. J Clin Endocrinol Metab 21:1440–1447. doi: 10.1210/jcem-21-11-1440 CrossRefPubMedGoogle Scholar
  23. 23.
    Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412–419CrossRefPubMedGoogle Scholar
  24. 24.
    Ganesh Kumar K, Zhang J, Gao S, Rossi J, McGuinness OP, Halem HH et al (2012) Adropin deficiency is associated with increased adiposity and insulin resistance. Obesity (Silver Spring) 20:1394–1402. doi: 10.1038/oby.2012.31 CrossRefGoogle Scholar
  25. 25.
    Gao S, McMillan RP, Jacas J, Zhu Q, Li X, Kumar GK et al (2014) Regulation of substrate oxidation preferences in muscle by the Peptide hormone adropin. Diabetes 63:3242–3252. doi: 10.2337/db14-0388 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Butler AA, Tam CS, Stanhope KL, Wolfe BM, Ali MR, O’Keeffe M et al (2012) Low circulating adropin concentrations with obesity and aging correlate with risk factors for metabolic disease and increase after gastric bypass surgery in humans. J Clin Endocrinol Metab 97:3783–3791. doi: 10.1210/jc.2012-2194 CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Topuz M, Celik A, Aslantas T, Demir AK, Aydin S, Aydin S (2013) Plasma adropin levels predict endothelial dysfunction like flow-mediated dilatation in patients with type 2 diabetes mellitus. J Investig Med 61:1161–1164. doi: 10.231/JIM.0000000000000003 CrossRefPubMedGoogle Scholar
  28. 28.
    Chen X, Xun K, Chen L, Wang Y (2009) TNF-alpha, a potent lipid metabolism regulator. Cell Biochem Funct 27:407–416. doi: 10.1002/cbf.1596 CrossRefPubMedGoogle Scholar
  29. 29.
    Ronti T, Lupattelli G, Mannarino E (2006) The endocrine function of adipose tissue: an update. Clin Endocrinol (Oxf) 64:355–365. doi: 10.1111/j.1365-2265.2006.02474.x Google Scholar
  30. 30.
    Gupta-Ganguli M, Cox K, Means B, Gerling I, Solomon SS (2011) Does therapy with anti-TNF-alpha improve glucose tolerance and control in patients with type 2 diabetes? Diabetes Care 34:e121. doi: 10.2337/dc10-1334 CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Liu M, Liu F (2010) Transcriptional and post-translational regulation of adiponectin. Biochem J 425:41–52. doi: 10.1042/BJ20091045 CrossRefGoogle Scholar
  32. 32.
    Gan L, Guo K, Cremona ML, McGraw TE, Leibel RL, Zhang Y (2012) TNF-α up-regulates protein level and cell surface expression of the leptin receptor by stimulating its export via a PKC-dependent mechanism. Endocrinology 153:5821–5833. doi: 10.1210/en.2012-1510 CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Finck BN, Johnson RW (2000) Tumor necrosis factor-alpha regulates secretion of the adipocyte-derived cytokine, leptin. Microsc Res Tech 50:209–215. doi: 10.1002/1097-0029(20000801)50:3<209:AID-JEMT4>3.0.CO;2-T CrossRefPubMedGoogle Scholar
  34. 34.
    Rask-Madsen C, Domínguez H, Ihlemann N, Hermann T, Køber L, Torp-Pedersen C (2003) Tumor necrosis factor-alpha inhibits insulin’s stimulating effect on glucose uptake and endothelium-dependent vasodilation in humans. Circulation 108:1815–1821. doi: 10.1161/01.CIR.0000091406.72832.11 CrossRefPubMedGoogle Scholar
  35. 35.
    Plomgaard P, Bouzakri K, Krogh-Madsen R, Mittendorfer B, Zierath JR, Pedersen BK (2005) Tumor necrosis factor-alpha induces skeletal muscle insulin resistance in healthy human subjects via inhibition of Akt substrate 160 phosphorylation. Diabetes 54:2939–2945CrossRefPubMedGoogle Scholar

Copyright information

© Italian Society of Endocrinology (SIE) 2016

Authors and Affiliations

  • T. Kume
    • 1
  • M. Calan
    • 2
    Email author
  • O. Yilmaz
    • 3
  • G. U. Kocabas
    • 4
  • P. Yesil
    • 5
  • M. Temur
    • 3
  • M. Bicer
    • 6
  • O. G. Calan
    • 1
  1. 1.Department of Biochemistry and Clinical BiochemistryDokuz Eylul University Faculty of MedicineInciraltiTurkey
  2. 2.Division of Endocrinology and Metabolism (PCOS Research Group), Department of Internal MedicineDokuz Eylul University Faculty of MedicineInciraltiTurkey
  3. 3.Department of Obstetrics and GynecologyManisa Merkezefendi State HospitalMerkezefendiTurkey
  4. 4.Division of Endocrinology and Metabolism, Department of Internal Medicine (PCOS Research Group)Izmir Bozyaka Training and Research HospitalBozyakaTurkey
  5. 5.Department of BioengineeringEge UniversityBornovaTurkey
  6. 6.Department of Obstetrics and Gynecology, Medical Park HospitalIzmir University Faculty of MedicineIzmirTurkey

Personalised recommendations