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Published in: Journal of Endocrinological Investigation 9/2016

01-09-2016 | Original Article

Evidence for decreased expression of APPL1 associated with reduced insulin and adiponectin receptors expression in PCOS patients

Authors: R. Dehghan, M. Saidijam, M. Mehdizade, N. Shabab, M. Yavangi, T. Artimani

Published in: Journal of Endocrinological Investigation | Issue 9/2016

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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.
Literature
1.
go back to reference 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 7:1227–1238CrossRefPubMedPubMedCentral 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 7:1227–1238CrossRefPubMedPubMedCentral
2.
go back to reference 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 9:417–427CrossRef 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 9:417–427CrossRef
3.
go back to reference Deepa SS, Dong LQ (2009) APPL1: role in adiponectin signaling and beyond. Am J Physiol Endocrinol Metabol 296:E22–E36CrossRef Deepa SS, Dong LQ (2009) APPL1: role in adiponectin signaling and beyond. Am J Physiol Endocrinol Metabol 296:E22–E36CrossRef
4.
go back to reference Reverchon M, Ramé C, Bertoldo M, Dupont J (2014) Adipokines and the female reproductive tract. Int J Endocrinol Reverchon M, Ramé C, Bertoldo M, Dupont J (2014) Adipokines and the female reproductive tract. Int J Endocrinol
5.
go back to reference 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 35:3961–3973CrossRef 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 35:3961–3973CrossRef
6.
go back to reference Maleedhu P, Vijayabhaskar M, Sharma S, Kodumuri PK (2014) Status of homocysteine in polycystic ovary syndrome (PCOS). J Clin Diag Res JCDR 8:31 Maleedhu P, Vijayabhaskar M, Sharma S, Kodumuri PK (2014) Status of homocysteine in polycystic ovary syndrome (PCOS). J Clin Diag Res JCDR 8:31
7.
go back to reference 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 54:2122–2131CrossRefPubMedPubMedCentral 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 54:2122–2131CrossRefPubMedPubMedCentral
8.
go back to reference 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 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
9.
go back to reference 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 12:295–305CrossRef 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 12:295–305CrossRef
10.
go back to reference 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):e471CrossRef 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):e471CrossRef
11.
go back to reference 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 99:174–183CrossRef 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 99:174–183CrossRef
12.
go back to reference 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 16:129CrossRefPubMed 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 16:129CrossRefPubMed
13.
go back to reference 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 72:26–31CrossRef 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 72:26–31CrossRef
14.
go back to reference 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 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
15.
go back to reference 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 28:777–784CrossRefPubMed 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 28:777–784CrossRefPubMed
16.
go back to reference Diamanti-Kandarakis E, Dunaif A (2012) Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications. Endocr Rev 33:981–1030CrossRefPubMed Diamanti-Kandarakis E, Dunaif A (2012) Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications. Endocr Rev 33:981–1030CrossRefPubMed
17.
go back to reference Galluzzo A, Amato MC, Giordano C (2008) Insulin resistance and polycystic ovary syndrome. Nutr Metabol Cardiovasc Dis NMCD 18:511–518CrossRef Galluzzo A, Amato MC, Giordano C (2008) Insulin resistance and polycystic ovary syndrome. Nutr Metabol Cardiovasc Dis NMCD 18:511–518CrossRef
18.
go back to reference 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 38:791–797CrossRef 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 38:791–797CrossRef
19.
go back to reference Tam CS, Xie W, Johnson WD, Cefalu WT, Redman LM, Ravussin E (2012) Defining insulin resistance from hyperinsulinemic-euglycemic clamps. Diabet Care 35:1605–1610CrossRef Tam CS, Xie W, Johnson WD, Cefalu WT, Redman LM, Ravussin E (2012) Defining insulin resistance from hyperinsulinemic-euglycemic clamps. Diabet Care 35:1605–1610CrossRef
20.
go back to reference Amato MC, Vesco R, Vigneri E, Ciresi A, Giordano C (2015) Hyperinsulinism and polycystic ovary syndrome (PCOS): role of insulin clearance. J Endocrinol Investig 38:1319–1326CrossRef Amato MC, Vesco R, Vigneri E, Ciresi A, Giordano C (2015) Hyperinsulinism and polycystic ovary syndrome (PCOS): role of insulin clearance. J Endocrinol Investig 38:1319–1326CrossRef
21.
go back to reference Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS) (2004). Human reproduction 19:41–47 Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS) (2004). Human reproduction 19:41–47
22.
go back to reference 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 33:101–110CrossRefPubMed 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 33:101–110CrossRefPubMed
23.
go back to reference 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:e103793CrossRefPubMedPubMedCentral 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:e103793CrossRefPubMedPubMedCentral
24.
go back to reference 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 37:715–719CrossRef 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 37:715–719CrossRef
25.
go back to reference 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 61:1028–1035CrossRefPubMed 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 61:1028–1035CrossRefPubMed
26.
go back to reference 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 47:901–909CrossRef 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 47:901–909CrossRef
27.
go back to reference 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 22:1003–1010CrossRefPubMed 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 22:1003–1010CrossRefPubMed
28.
go back to reference 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:e80416CrossRefPubMedPubMedCentral 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:e80416CrossRefPubMedPubMedCentral
29.
go back to reference 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] 30:638–642CrossRef 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] 30:638–642CrossRef
30.
go back to reference 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 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
31.
go back to reference 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 2:235–245CrossRef 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 2:235–245CrossRef
32.
go back to reference Mirza SS, Shafique K, Shaikh AR, Khan NA, Anwar Qureshi M (2014) Association between circulating adiponectin levels and polycystic ovarian syndrome. J Ovarian Res 7:18CrossRefPubMedPubMedCentral Mirza SS, Shafique K, Shaikh AR, Khan NA, Anwar Qureshi M (2014) Association between circulating adiponectin levels and polycystic ovarian syndrome. J Ovarian Res 7:18CrossRefPubMedPubMedCentral
33.
go back to reference Cheng KK, Lam KS, Wang B, Xu A (2014) Signaling mechanisms underlying the insulin-sensitizing effects of adiponectin. Best Pract Res Clin Endocrinol Metabol 28:3–13CrossRef Cheng KK, Lam KS, Wang B, Xu A (2014) Signaling mechanisms underlying the insulin-sensitizing effects of adiponectin. Best Pract Res Clin Endocrinol Metabol 28:3–13CrossRef
Metadata
Title
Evidence for decreased expression of APPL1 associated with reduced insulin and adiponectin receptors expression in PCOS patients
Authors
R. Dehghan
M. Saidijam
M. Mehdizade
N. Shabab
M. Yavangi
T. Artimani
Publication date
01-09-2016
Publisher
Springer International Publishing
Published in
Journal of Endocrinological Investigation / Issue 9/2016
Electronic ISSN: 1720-8386
DOI
https://doi.org/10.1007/s40618-016-0468-y

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