Abstract
Purpose
To investigate the expression of Adaptor protein containing a PH domain, PTB domain and leucine zipper motif 1 (APPL1), insulin receptor (INSR), adiponectin and adiponectin receptors (adipoR1 and R2) and their possible associations in granulosa cells (GCs) of 22 polycystic ovary syndrome (PCOS) women compared to the 22 non-PCOS controls with normal ovulatory function matched for BMI (body mass index).
Methods
In this study, 44 infertile women aged 18-40 years undergoing in vitro fertilization (IVF) protocol were recruited. After follicular fluid collection, GCs were isolated and then purified with MACS (Micro Beads conjugated to monoclonal anti-human CD45 antibodies). RNA was extracted from GCs and quantitative real-time PCR (qRT-PCR) was performed to assess APPL1 gene expression.
Results
Expression of APPL1, insulin receptor and adiponectin system genes was significantly decreased in PCOS group compared to the controls.
Conclusions
Reduction of APPL1, insulin receptor and adiponectin system genes in GCs could be involved in the development of PCOS.
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References
Ryu J, Galan AK, Xin X, Dong F, Abdul-Ghani MA, Zhou L, Wang C, Li C, Holmes BM, Sloane LB (2014) APPL1 potentiates insulin sensitivity by facilitating the binding of IRS1/2 to the insulin receptor. Cell Rep 7:1227–1238
Cheng KK, Iglesias MA, Lam KS, Wang Y, Sweeney G, Zhu W, Vanhoutte PM, Kraegen EW, Xu A (2009) APPL1 potentiates insulin-mediated inhibition of hepatic glucose production and alleviates diabetes via Akt activation in mice. Cell Metabol 9:417–427
Deepa SS, Dong LQ (2009) APPL1: role in adiponectin signaling and beyond. Am J Physiol Endocrinol Metabol 296:E22–E36
Reverchon M, Ramé C, Bertoldo M, Dupont J (2014) Adipokines and the female reproductive tract. Int J Endocrinol
Li S, Huang X, Zhong H, Peng Q, Chen S, Xie Y, Qin X, Qin A (2014) Low circulating adiponectin levels in women with polycystic ovary syndrome: an updated meta-analysis. Tumor Biol 35:3961–3973
Maleedhu P, Vijayabhaskar M, Sharma S, Kodumuri PK (2014) Status of homocysteine in polycystic ovary syndrome (PCOS). J Clin Diag Res JCDR 8:31
Holmes R, Yi Z, De Filippis E, Berria R, Shahani S, Sathyanarayana P, Sherman V, Fujiwara K, Meyer C, Christ-Roberts C (2011) Increased abundance of the adaptor protein containing pleckstrin homology domain, phosphotyrosine binding domain and leucine zipper motif (APPL1) in patients with obesity and type 2 diabetes: evidence for altered adiponectin signalling. Diabetologia 54:2122–2131
Maillard V, Uzbekova S, Guignot F, Perreau C, Ramé C, Coyral-Castel S, Dupont J (2010) Effect of adiponectin on bovine granulosa cell steroidogenesis, oocyte maturation and embryo development. Reprod Biol Endocrinol 8(10):1186
Brothers KJ, Wu S, DiVall SA, Messmer MR, Kahn CR, Miller RS, Radovick S, Wondisford FE, Wolfe A (2010) Rescue of obesity-induced infertility in female mice due to a pituitary-specific knockout of the insulin receptor. Cell Metabol 12:295–305
Richards JS, Liu Z, Kawai T, Tabata K, Watanabe H, Suresh D, Kuo F-T, Pisarska MD, Shimada M (2012) Adiponectin and its receptors modulate granulosa cell and cumulus cell functions, fertility, and early embryo development in the mouse and human. Fertil Steril 98(471–479):e471
Ioannidis A, Ikonomi E, Dimou NL, Douma L, Bagos PG (2010) Polymorphisms of the insulin receptor and the insulin receptor substrates genes in polycystic ovary syndrome: a Mendelian randomization meta-analysis. Mol Genet Metabol 99:174–183
Fornes R, Ormazabal P, Rosas C, Gabler F, Vantman D, Romero C, Vega M (2010) Changes in the expression of insulin signaling pathway molecules in endometria from polycystic ovary syndrome women with or without hyperinsulinemia. Mol Med 16:129
Park HT, Cho GJ, Ahn KH, Shin JH, Kim YT, Hur JY, Kim SH, Lee KW, Kim T (2010) Association of insulin resistance with anti-Mullerian hormone levels in women without polycystic ovary syndrome (PCOS). Clin Endocrinol 72:26–31
Wang Y-X, Xie X-M, Dai M, Zhu W-J (2010) Relationship between insulin resistance and adiponectin expression in a rat model of polycystic ovary syndrome. Sci Res Essays 5:1632–1639
Stepto NK, Cassar S, Joham AE, Hutchison SK, Harrison CL, Goldstein RF, Teede HJ (2013) Women with polycystic ovary syndrome have intrinsic insulin resistance on euglycaemic-hyperinsulaemic clamp. Hum Reprod 28:777–784
Diamanti-Kandarakis E, Dunaif A (2012) Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications. Endocr Rev 33:981–1030
Galluzzo A, Amato MC, Giordano C (2008) Insulin resistance and polycystic ovary syndrome. Nutr Metabol Cardiovasc Dis NMCD 18:511–518
Meczekalski B, Nawrot R, Nowak W, Czyzyk A, Kedzia H, Gozdzicka-Jozefiak A (2015) Study on the zona pellucida 4 (ZP4) gene sequence and its expression in the ovaries of patients with polycystic ovary syndrome. J Endocrinol Investig 38:791–797
Tam CS, Xie W, Johnson WD, Cefalu WT, Redman LM, Ravussin E (2012) Defining insulin resistance from hyperinsulinemic-euglycemic clamps. Diabet Care 35:1605–1610
Amato MC, Vesco R, Vigneri E, Ciresi A, Giordano C (2015) Hyperinsulinism and polycystic ovary syndrome (PCOS): role of insulin clearance. J Endocrinol Investig 38:1319–1326
Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS) (2004). Human reproduction 19:41–47
Artimani T, Saidijam M, Aflatoonian R, Ashrafi M, Amiri I, Yavangi M, SoleimaniAsl S, Shabab N, Karimi J, Mehdizadeh M (2015) Downregulation of adiponectin system in granulosa cells and low levels of HMW adiponectin in PCOS. J Assist Reprod Genet 33:101–110
Cao T, Gao Z, Gu L, Chen M, Yang B, Cao K, Huang H, Li M (2014) AdipoR1/APPL1 potentiates the protective effects of globular adiponectin on angiotensin II-induced cardiac hypertrophy and fibrosis in neonatal rat atrial myocytes and fibroblasts. PLoS ONE 9:e103793
Ademoglu EN, Gorar S, Carlioglu A, Yazici H, Dellal FD, Berberoglu Z, Akdeniz D, Uysal S, Karakurt F (2014) Plasma nesfatin-1 levels are increased in patients with polycystic ovary syndrome. J Endocrinol Investig 37:715–719
Xing W, Yan W, Liu P, Ji L, Li Y, Sun L, Tao L, Zhang H, Gao F (2013) A novel mechanism for vascular insulin resistance in normotensive young SHRs hypoadiponectinemia and resultant APPL1 downregulation. Hypertension 61:1028–1035
Garcia V, Orostica L, Poblete C, Rosas C, Astorga I, Romero C, Vega M (2015) Endometria from Obese PCOS Women with Hyperinsulinemia Exhibit Altered Adiponectin Signaling. Horm Metabol Res 47:901–909
Seow K-M, Juan C-C, Hsu Y-P, Hwang J-L, Huang L-W, Ho L-T (2007) Amelioration of insulin resistance in women with PCOS via reduced insulin receptor substrate-1 Ser312 phosphorylation following laparoscopic ovarian electrocautery. Hum Reprod 22:1003–1010
Comim FV, Hardy K, Franks S (2013) Adiponectin and its receptors in the ovary: further evidence for a link between obesity and hyperandrogenism in polycystic ovary syndrome. PLoS ONE 8:e80416
Wang Y, Xie X, Zhu W (2010) Serum adiponectin and resistin levels in patients with polycystic ovarian syndrome and their clinical implications. J Huazhong Univ Sci Technol [Medical Sciences] 30:638–642
Hamed HO, Salama RH (2013) Adiponectin and Adiponectin Receptor-1 in Patients with Polycystic Ovarian Syndrome: impact of Insulin Sensitization by Metformin. Ibnosina J Med Biomed Sci 5:52–61
Pangaribuan B, Yusuf I, Mansyur M, Wijaya A (2011) Serum adiponectin and resistin in relation to insulin resistance and markers of hyperandrogenism in lean and obese women with polycystic ovary syndrome. Ther Adv Endocrinol Metabol 2:235–245
Mirza SS, Shafique K, Shaikh AR, Khan NA, Anwar Qureshi M (2014) Association between circulating adiponectin levels and polycystic ovarian syndrome. J Ovarian Res 7:18
Cheng KK, Lam KS, Wang B, Xu A (2014) Signaling mechanisms underlying the insulin-sensitizing effects of adiponectin. Best Pract Res Clin Endocrinol Metabol 28:3–13
Acknowledgments
This work was supported by Research and Technology Deputy of Hamadan University of Medical Sciences as a M.S thesis. The authors thank the Endometrium and Endometriosis Research Center for clinical evaluation of patients and also the Research Center for Molecular Medicine, Hamadan university of Medical Sciences for technical assistance.
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The authors declare that they have no conflict of interest.
Ethical approval
In accordance with the ethical standards of research, study protocol was approved by Hamadan University of Medical Sciences Ethics Committee (number: 16.35.9.5431).
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All the participants were fully justified for the study and a written informed consent was obtained from each of them.
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Dehghan, R., Saidijam, M., Mehdizade, M. et al. Evidence for decreased expression of APPL1 associated with reduced insulin and adiponectin receptors expression in PCOS patients. J Endocrinol Invest 39, 1075–1082 (2016). https://doi.org/10.1007/s40618-016-0468-y
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DOI: https://doi.org/10.1007/s40618-016-0468-y