Abstract
Background/Objectives:
A high percentage of women having polycystic ovarian syndrome (PCOS) exhibit hyperinsulinemia and obesity. Transforming necrosis factor-α (TNF-α) is an adipokine that increases in obesity and negatively affects insulin action in several tissues, including the endometrium. In fact, it has been reported that insulin signaling is altered in the endometrium of PCOS women, affecting its reproductive function. The aim of this study was to determine the proinflammatory environment and TNF-α signaling in endometrium from obese women with PCOS, and also to evaluate the effect of TNF-α on endometrial cell energy homeostasis.
Methods:
Serum and endometrial tissues were obtained from four study groups: normal-weight, normal-weight-PCOS, obese and obese-PCOS (hyperandrogenemia/hyperinsulinemia) (n=7 per group). Serum TNF-α level was assayed by enzyme-linked immunosorbent assay (ELISA); endometrial TNF-α level and its receptors (TNFR1/TNFR2) as well as nuclear factor (NF)-κB content were determined by immunohistochemistry. Finally, we evaluated TNF-α effect on glucose uptake in cultured human endometrial stromal cells (T-HESC) treated or not with testosterone/insulin resembling partially the PCOS condition.
Results:
TNF-α plasma levels were similar between groups, whereas cytokine levels and macrophage number increased in endometrium from obese-PCOS women (P<0.001). Both receptor types were higher in obese vs normal-weight women, particularly TNFR2 content in the obese-PCOS group (P<0.001). Furthermore, an increased NF-κB nuclear content in endometrium from obese-PCOS was observed (P<0.001). Finally, TNF-α treatment of T-HESC cultures exhibited a decrease of glucose uptake (P<0.05), although similar to cells treated with testosterone or testosterone/insulin/TNF-α.
Conclusions:
These results suggest that the PCOS condition induces an inflammatory state exacerbated when obesity is present, where a higher TNF-α signaling is observed, all of which could affect glucose uptake in the tissue and may cause fertility failures in these women.
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References
Diamanti-Kandarakis E . Polycystic ovarian syndrome pathophysiology, molecular aspects and clinical implications. Expert Rev Mol Med 2008; 10: e3.
Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W et al. Positions statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an Androgen Excess Society guideline. J Clin Endocrinol Metab 2006; 91: 4237–4245.
The Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 2004; 81: 19–25.
Frolova AI, Moley KH . Glucose transporters in the uterus: an analysis of tissue distribution and proposed physiological roles. Reproduction 2011; 142: 211–220.
Oróstica L, Rosas C, Plaza-Parrochia F, Astorga I, Gabler F, García V et al. Review: altered steroid metabolism and insulin signaling in PCOS endometria: impact in tissue function. Curr Pharm Des 2016; 22: 1–11.
Fornes R, Ormazabal P, Rosas C, Gabler F, Vantman D, Romero C et al. Changes in the expresión of insulin signaling pathway molecules in endometria from PCOS women with or without insulin resistance. Mol Med 2010; 16: 129–136.
Rosas C, Gabler F, Vantman D, Romero C, Vega M . Levels of Rabs and WAVE family proteins associated to translocation of GLUT4 to the cell surface in endometria from control and hyperinsulinemic PCOS women. Hum Reprod 2010; 25: 2870–2877.
Kohan K, Carvajal R, Gabler F, Vantman D, Romero C, Vega M . Role of the transcriptional factors FOXO1 and PPARG on gene expression of SLC2A4 in endometrial tissue from women with polycystic ovary syndrome. Reproduction 2010; 140: 123–131.
Ormazabal P, Romero C, Quest AFG, Vega M . Testosterone modulates the expression of molecules linked to insulin action and glucose uptake in endometrial cells. Horm Metab Res 2013; 45: 1–6.
Carvajal R, Rosas C, Kohan K, Gabler F, Vantman D, Romero C et al. Metformin augments the levels of molecules that regulate the expression of the insulin-dependent glucose transporter GLUT4 in the endometria of hyperinsulinemic PCOS patients. Hum Reprod 2013; 28: 2235–2244.
Rosas C, Oróstica L, Poblete C, Carvajal R, Gabler F, Romero C et al. Hyperandrogenism decreases GRP78 protein level and glucose uptake in human endometrial stromal cells. Reprod Sci 2015; 23: 761–770.
Mitchell M, Armstrong DT, Robker RL, Norman RJ . Adipokines: implications for female fertility and obesity. Reproduction 2005; 130: 583–597.
Cao H . Adipocytokines in obesity and metabolic disease. J Endocrinol 2014; 220: T47–T59.
Hotamisligil GS, Shargill NS, Spiegelman BM . Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 1993; 259: 87–91.
Hotamisligil GS, Budavari A, Murray D, Spiegelman BM . Reduced tyrosine kinase activity of the insulin receptor in obesity-diabetes. Central role of tumor necrosis factor-α. J Clin Invest 1994; 94: 1543–1549.
Peraldi P, Hotamisligil GS, Buurman WA, White MF, Spiegelman BM . Tumor necrosis factor (TNF)-α inhibits insulin signaling through stimulation of the p55 TNF. receptor and activation of sphingomyelinase. J Biol Chem 1996; 271: 13018–13022.
García V, Oróstica L, Poblete C, Rosas C, Astorga I, Romero C et al. Endometria from obese PCOS women with hyperinsulinemia exhibit altered adiponectin signaling. Horm Metab Res 2015; 47: 901–909.
Hajri T, Tao H, Wattacheril J, Marks-Shulman P, Abumrad NN . Regulation of adiponectin production by insulin: interactions with tumor necrosis factor-α and interleukin-6. Am J Physiol Endocrinol Metab 2011; 300: E350–E360.
Salama SA, Kamel MW, Diaz-Arrastia CR, Xu X, Veenstra TD, Salih S et al. Effect of tumor necrosis factor-ð¼ on estrogen metabolism and endometrial cells: potential physiological and pathological relevance. J Clin Endocrinol Metab 2009; 94: 285–293.
Nair S, Nguyen H, Salama S, Al-Hendy A . Obesity and the endometrium: adipocyte-secreted proinflammatory TNF α cytokine enhances the proliferation of human endometrial glandular cells. Obstet Gynecol Int 2013; 2013: 368543.
Rutledge AC, Adeli K . Fructose and the metabolic syndrome: pathophysiology and molecular mechanisms. Nutr Rev 2007; 65: S13–S23.
Cai D, Yuan M, Frantz DF, Melendez PA, Hansen L, Lee J et al. Local and systemic insulin resistance resulting from hepatic activation of IKK-β and NF-κB. Nat Med 2005; 11: 183–190.
Giudice LC . Endometrium in PCOS: implantation and predisposition to endocrine CA. Best Pract Res Clin Endocrinol Metab 2006; 20: 235–244.
Quezada S, Avellaira C, Johnson MC, Gabler F, Fuentes A, Vega M . Evaluation of steroid receptors, coregulators, and molecules associated with uterine receptivity in secretory endometria from untreated women with polycystic ovary syndrome. Fertil Steril 2006; 85: 1017–1026.
Matsuda M, DeFronzo RA . Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care 1999; 22: 1462–1470.
McAuley K, Mann J, Chase J, Lotz T, Shaw G . Point: HOMA—satisfactory for the time being: HOMA: the best bet for the simple determination of insulin sensitivity, until something better comes along. Diabetes Care 2007; 30: 2411–2413.
Noyes RN, Hertig AT, Rock J . Dating the endometrial biopsy. Fertil Steril 1950; 1: 3–25.
Chen LF, Green WC . Shaping the nuclear action of NF-kB. Nat Rev Mol Cell Biol 2004; 5: 392–401.
Krikun G, Mor G, Alvero A, Guller S, Schatz F, Sapi E et al. A novel immortalized human endometrial stromal cell line with normal progestational response. Endocrinology 2004; 145: 2291–2296.
Falini B, Flenghi L, Pileri S, Gambacorta M, Bigerna B, Durkop H et al. PG-M1: A new monoclonal antibody directed against a fixative-resistant epitope on the macrophage-restricted form of the CD68 molecule. Am J Pathol 1993; 142: 1359–1372.
Wang B, Jenkins JR, Trayhurn P . Expression and secretion of inflammation-related adipokines by human adipocytes differentiated in culture: integrated response to TNF-α. Am J Physiol Endocrinol Metab 2005; 288: E731–E740.
Guerre-Millo M . Adiponectin: an update. Diabetes Metab 2008; 34: 12–18.
Liu M, Liu F . Transcriptional and post-translational regulation of adiponectin. Biochem J 2009; 425: 41–52.
Figueroa F, Motta A, Acosta M, Mohamed F, Oliveros L, Forneris M . Role of macrophage secretions on rat polycystic ovary: its effect on apoptosis. Reproduction 2015; 150: 437–448.
wDuleba AJ, Dokras A . Is PCOS an inflammatory process? Fertil Steril 2012; 97: 7–12.
Kelly CC, Lyall H, Petrie JR, Gould GW, Connell JM, Sattar N . Low grade chronic inflammation in women with polycystic ovarian syndrome. J Clin Endocrinol Metab 2001; 86: 2453–2455.
Faulds G, Rydén M, Ek I, Wahrenberg H, Arner P . Mechanisms behind lipolytic catecholamine resistance of subcutaneous fat cells in the polycystic ovarian syndrome. J Clin Endocrinol Metab 2003; 88: 2269–2273.
Haider S, Knöfler M . Human tumour necrosis factor: physiological and pathological roles in placenta and endometrium. Placenta 2010; 30: 111–123.
Tabibzadeh S, Satyaswaroop PG, von Wolff M, Strowitzki T . Regulation of TNF-α mRNA expression in endometrial cells by TNF-α and by oestrogen withdrawal. Mol Hum Reprod 1999; 5: 1141–1149.
Jakubowicz DJ, Seppälä M, Jakubowicz S, Rodriguez-Armas O, Rivas-Santiago A, Koistinen H et al. Insulin reduction with metformin increases luteal phase serum glycodelin and insulin-like growth factor-binding protein 1 concentrations and enhances uterine vascularity and blood flow in the polycystic ovary syndrome. J Clin Endocrinol Metab 2001; 86: 1126–1133.
Yun JH, Choi JW, Lee KJ, Shin JS, Baek KH . The promoter -1031(T/C) polymorphism in tumor necrosis factor-alpha associated with polycystic ovary síndrome. Reprod Biol Endocrinol 2011; 9: 131.
Peral B, San Millán JL, Castello R, Moghetti P, Escobar-Morreale HF . The methionine 196 arginine polymorphism in exon 6 of the TNF receptor 2 gene (TNFRSF1B) is associated with the polycystic ovary syndrome and hyperandrogenism. J Clin Endocrinol Metab 2002; 87: 3977–3983.
Fernandez-Real JM, Broch M, Ricart W, Casamitjana R, Gutierrez C, Vendrell J et al. Plasma levels of the soluble fraction of tumor necrosis factor receptor 2 and insulin resistance. Diabetes 1998; 47: 1757–1762.
Johansson A, Ahrén B, Forsberg H, Olsson T . Testosterone and diurnal rhythmicity of leptin, TNF-alpha and TNF-II receptor in insulin-resistant myotonic dystrophy patients. Int J Obes Relat Metab Disord 2002; 26: 1386–1392.
Markel TA, Crisostomo PR, Wang M, Herring CM, Meldrum DR . Activation of individual tumor necrosis factor receptors differentially affects stem cell growth factor and cytokine production. Am J Physiol Gastrointest Liver Physiol 2007; 293: G657–G662.
Micheau O, Tschopp J . Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell 2003; 114: 181–190.
Karin M, Ben-Neriah Y . Phosphorylation meets ubiquitination: the control of NF-κB activity. Annu Rev Immunol 2000; 18: 621–663.
del Aguila LF, Claffey KP, Kirwan JP . TNF-alpha impairs insulin signaling and insulin stimulation of glucose uptake in C2C12 muscle cells. Am J Physiol 1999; 276: E849–E855.
Massaro M, Scoditti E, Pellegrino M, Carluccio MA, Calabriso N, Wabitsch M et al. Therapeutic potential of the dual peroxisome proliferator activated receptor (PPAR)α/γ agonist aleglitazar in attenuating TNF-α-mediated inflammation and insulin resistance in human adipocytes. Pharmacol Res 2016; 107: 125–136.
Hajri T, Tao H, Wattacheril J, Marks-Shulman P, Abumrad NN . Regulation of adiponectin production by insulin: interactions with tumor necrosis factor-α and interleukin-6. Am J Physiol Endocrinol Metab 2011; 300: E350–E360.
Fulghesu AM, Sanna F, Uda S, Magnini R, Portoghese E, Batetta B . IL-6 serum levels and production is related to an altered immune response in polycystic ovary syndrome girls with insulin resistance. Mediators Inflamm 2011. ID 389317.
Escobar-Morreale HF, Luque-Ramírez M, González F . Circulating inflammatory markers in polycystic ovary syndrome: a systematic review and metaanalysis. Fertil Steril 2011; 95: 1048–1058.
Acknowledgements
We thank the laboratory team especially Fernando Gabler for histological evaluation of endometrial samples. We are also grateful to the women who donated tissue. This study was supported by Grants 1130053 from Fondo Nacional de Desarrollo Científico y Tecnológico, Chile (to MV) and 21120541 (to LO) from Comisión Nacional de Investigación Científica y Tecnológica (Conicyt), Chile.
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Oróstica, L., Astorga, I., Plaza-Parrochia, F. et al. Proinflammatory environment and role of TNF-α in endometrial function of obese women having polycystic ovarian syndrome. Int J Obes 40, 1715–1722 (2016). https://doi.org/10.1038/ijo.2016.154
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DOI: https://doi.org/10.1038/ijo.2016.154
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