CD36- and obesity-associated granulosa cells dysfunction
Ru-xing Wu A * , Ying-ying Dong B * , Pei-wen Yang A , Lan Wang A , Yun-hua Deng B , Han-wang Zhang A D and Xiao-yuan Huang
C D
+ Author Affiliations
- Author Affiliations
A Reproductive Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jie Fang Avenue, Wuhan 430030, China.
B Department of Dermatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jie Fang Avenue, Wuhan 430030, China.
C Cancer Biology Research Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jie Fang Avenue, Wuhan 430030, China.
D Corresponding authors. Emails: hwzhang605@126.com; huangxy@tjh.tjmu.edu.cn
Reproduction, Fertility and Development 31(5) 993-1001 https://doi.org/10.1071/RD18292
Submitted: 14 June 2018 Accepted: 27 December 2018 Published: 5 March 2019
Journal Compilation © CSIRO 2019 Open Access CC BY-NC-ND
Abstract
Emerging evidence indicates that obesity impairs granulosa cell (GC) function, but the underlying mechanisms remain unclear. Gene expression profiles in GC of non-polycystic ovary syndrome (PCOS) obese (NPO), PCOS obese (PO), PCOS normal weight (PN) and non-PCOS normal weight (NPN) patients were analysed by microarray analysis. Compared with the NPN group, there were 16, 545 and 416 differently expressed genes in the NPO, PO and PN groups respectively. CD36 was the only intersecting gene, with greater than two fold changes in expression between the NPO versus NPN and PO versus NPN comparisons, and was not present in the PN versus NPN comparison. In addition, levels of CD36 protein were higher in GC from obese than normal weight patients. Furthermore, CD36 overexpression in a GC line inhibited cell proliferation, as determined by the cell counting kit-8 (CCK8) test, promoted cell apoptosis, as determined by flow cytometry, and inhibited the secretion of oestradiol by depositing triglyceride in cells and increasing cellular lipid peroxide levels. These adverse effects were reduced by sulfo-N-succinimidyloleate, a specific inhibitor of CD36. Together, the findings of this study suggest that obesity with and without PCOS should be regarded as separate entities, and that CD36 overexpression in GC of obese patients is one of the mechanisms by which obesity impairs GC function.
Additional keywords: endocrinology, fatty acid, gene expression.
References
Al-Azemi, M., Omu, F. E., and Omu, A. E. (2004). The effect of obesity on the outcome of infertility management in women with polycystic ovary syndrome. Arch. Gynecol. Obstet. 270, 205–210.| The effect of obesity on the outcome of infertility management in women with polycystic ovary syndrome.Crossref | GoogleScholarGoogle Scholar | 12955532PubMed |
Álvarez-Blasco, F., Botella-Carretero, J. I., San Millán, J. L., and Escobar-Morreale, H. F. (2006). Prevalence and characteristics of the polycystic ovary syndrome in overweight and obese women. Arch. Intern. Med. 166, 2081–2086.
| Prevalence and characteristics of the polycystic ovary syndrome in overweight and obese women.Crossref | GoogleScholarGoogle Scholar | 17060537PubMed |
Angin, Y., Steinbusch, L. K., Simons, P. J., Greulich, S., Hoebers, N. T., Douma, K., van Zandvoort, M. A., Coumans, W. A., Wijnen, W., Diamant, M., Ouwens, D. M., Glatz, J. F., and Luiken, J. J. (2012). CD36 inhibition prevents lipid accumulation and contractile dysfunction in rat cardiomyocytes. Biochem. J. 448, 43–53.
| CD36 inhibition prevents lipid accumulation and contractile dysfunction in rat cardiomyocytes.Crossref | GoogleScholarGoogle Scholar | 22780108PubMed |
Barnes, R. B., Rosenfield, R. L., Namnoum, A., and Layman, L. C. (2000). Effect of follicle-stimulating hormone on ovarian androgen production in a woman with isolated follicle-stimulating hormone deficiency. N. Engl. J. Med. 343, 1197–1198.
| Effect of follicle-stimulating hormone on ovarian androgen production in a woman with isolated follicle-stimulating hormone deficiency.Crossref | GoogleScholarGoogle Scholar | 11041762PubMed |
Bolúmar, F., Olsen, J., Rebagliato, M., Sáez-Lloret, I., Bisanti, L., the European Study Group on Infertility and Subfecundity (2000). Body mass index and delayed conception: a European Multicenter Study on Infertility and Subfecundity. Am. J. Epidemiol. 151, 1072–1079.
| Body mass index and delayed conception: a European Multicenter Study on Infertility and Subfecundity.Crossref | GoogleScholarGoogle Scholar | 10873131PubMed |
Boots, C., and Stephenson, M. D. (2011). Does obesity increase the risk of miscarriage in spontaneous conception: a systematic review. Semin. Reprod. Med. 29, 507–513.
| Does obesity increase the risk of miscarriage in spontaneous conception: a systematic review.Crossref | GoogleScholarGoogle Scholar | 22161463PubMed |
Borgbo, T., Povlsen, B. B., Andersen, C. Y., Borup, R., Humaidan, P., and Grondahl, M. L. (2013). Comparison of gene expression profiles in granulosa and cumulus cells after ovulation induction with either human chorionic gonadotropin or a gonadotropin-releasing hormone agonist trigger. Fertil. Steril. 100, 994–1001.e2.
| Comparison of gene expression profiles in granulosa and cumulus cells after ovulation induction with either human chorionic gonadotropin or a gonadotropin-releasing hormone agonist trigger.Crossref | GoogleScholarGoogle Scholar | 23856575PubMed |
Buccione, R., Schroeder, A. C., and Eppig, J. J. (1990). Interactions between somatic cells and germ cells throughout mammalian oogenesis. Biol. Reprod. 43, 543–547.
| Interactions between somatic cells and germ cells throughout mammalian oogenesis.Crossref | GoogleScholarGoogle Scholar | 2289008PubMed |
Chin, K. V., Seifer, D. B., Feng, B., Lin, Y., and Shih, W. C. (2002). DNA microarray analysis of the expression profiles of luteinized granulosa cells as a function of ovarian reserve. Fertil. Steril. 77, 1214–1218.
| DNA microarray analysis of the expression profiles of luteinized granulosa cells as a function of ovarian reserve.Crossref | GoogleScholarGoogle Scholar | 12057731PubMed |
Das, M., Djahanbakhch, O., Hacihanefioglu, B., Saridogan, E., Ikram, M., Ghali, L., Raveendran, M., and Storey, A. (2008). Granulosa cell survival and proliferation are altered in polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 93, 881–887.
| Granulosa cell survival and proliferation are altered in polycystic ovary syndrome.Crossref | GoogleScholarGoogle Scholar | 18073308PubMed |
Diamanti-Kandarakis, E., and Dunaif, A. (1996). New perspectives in polycystic ovary syndrome. Trends Endocrinol. Metab. 7, 267–271.
| New perspectives in polycystic ovary syndrome.Crossref | GoogleScholarGoogle Scholar | 18406758PubMed |
Eisen, M. B., Spellman, P. T., Brown, P. O., and Botstein, D. (1998). Cluster analysis and display of genome-wide expression patterns. Proc. Natl Acad. Sci. USA 95, 14863–14868.
| Cluster analysis and display of genome-wide expression patterns.Crossref | GoogleScholarGoogle Scholar | 9843981PubMed |
Febbraio, M., Hajjar, D. P., and Silverstein, R. L. (2001). CD36: a class B scavenger receptor involved in angiogenesis, atherosclerosis, inflammation, and lipid metabolism. J. Clin. Invest. 108, 785–791.
| CD36: a class B scavenger receptor involved in angiogenesis, atherosclerosis, inflammation, and lipid metabolism.Crossref | GoogleScholarGoogle Scholar | 11560944PubMed |
Gil-Campos, M., Canete, R. R., and Gil, A. (2004). Adiponectin, the missing link in insulin resistance and obesity. Clin. Nutr. 23, 963–974.
| Adiponectin, the missing link in insulin resistance and obesity.Crossref | GoogleScholarGoogle Scholar | 15380884PubMed |
Grøndahl, M. L., Borup, R., Lee, Y. B., Myrhøj, V., Meinertz, H., and Sørensen, S. (2009). Differences in gene expression of granulosa cells from women undergoing controlled ovarian hyperstimulation with either recombinant follicle-stimulating hormone or highly purified human menopausal gonadotropin. Fertil. Steril. 91, 1820–1830.
| Differences in gene expression of granulosa cells from women undergoing controlled ovarian hyperstimulation with either recombinant follicle-stimulating hormone or highly purified human menopausal gonadotropin.Crossref | GoogleScholarGoogle Scholar | 18439596PubMed |
Habets, D. D., Coumans, W. A., Voshol, P. J., den Boer, M. A., Febbraio, M., Bonen, A., Glatz, J. F., and Luiken, J. J. (2007). AMPK-mediated increase in myocardial long-chain fatty acid uptake critically depends on sarcolemmal CD36. Biochem. Biophys. Res. Commun. 355, 204–210.
| AMPK-mediated increase in myocardial long-chain fatty acid uptake critically depends on sarcolemmal CD36.Crossref | GoogleScholarGoogle Scholar | 17292863PubMed |
Haslam, D. W., and James, W. P. (2005). Obesity. Lancet 366, 1197–1209.
| Obesity.Crossref | GoogleScholarGoogle Scholar | 16198769PubMed |
Hedley, A. A., Ogden, C. L., Johnson, C. L., Carroll, M. D., Curtin, L. R., and Flegal, K. M. (2004). Prevalence of overweight and obesity among US children, adolescents, and adults, 1999–2002. JAMA 291, 2847–2850.
| Prevalence of overweight and obesity among US children, adolescents, and adults, 1999–2002.Crossref | GoogleScholarGoogle Scholar | 15199035PubMed |
Health Industry Standard of the People’s Republic of China (2013). Criteria of weight for adults. Available at http://www.moh.gov.cn/ewebeditor/uploadfile/2013/08/20130808135715967 [verified 13 February 2019]. [In Chinese]
Homburg, R., and Crawford, G. (2014). The role of AMH in anovulation associated with PCOS: a hypothesis. Hum. Reprod. 29, 1117–1121.
| The role of AMH in anovulation associated with PCOS: a hypothesis.Crossref | GoogleScholarGoogle Scholar | 24770999PubMed |
Homburg, R., Ray, A., Bhide, P., Gudi, A., Shah, A., Timms, P., and Grayson, K. (2013). The relationship of serum anti-Mullerian hormone with polycystic ovarian morphology and polycystic ovary syndrome: a prospective cohort study. Hum. Reprod. 28, 1077–1083.
| The relationship of serum anti-Mullerian hormone with polycystic ovarian morphology and polycystic ovary syndrome: a prospective cohort study.Crossref | GoogleScholarGoogle Scholar | 23377771PubMed |
Jungheim, E. S., Lanzendorf, S. E., Odem, R. R., Moley, K. H., Chang, A. S., and Ratts, V. S. (2009). Morbid obesity is associated with lower clinical pregnancy rates after in vitro fertilization in women with polycystic ovary syndrome. Fertil. Steril. 92, 256–261.
| Morbid obesity is associated with lower clinical pregnancy rates after in vitro fertilization in women with polycystic ovary syndrome.Crossref | GoogleScholarGoogle Scholar | 18692801PubMed |
Kenigsberg, S., Bentov, Y., Chalifa-Caspi, V., Potashnik, G., Ofir, R., and Birk, O. S. (2009). Gene expression microarray profiles of cumulus cells in lean and overweight–obese polycystic ovary syndrome patients. Mol. Hum. Reprod. 15, 89–103.
| Gene expression microarray profiles of cumulus cells in lean and overweight–obese polycystic ovary syndrome patients.Crossref | GoogleScholarGoogle Scholar | 19141487PubMed |
Lan, C. W., Chen, M. J., Tai, K. Y., Yu, D. C., Yang, Y. C., Jan, P. S., Yang, Y. S., Chen, H. F., and Ho, H. N. (2015). Functional microarray analysis of differentially expressed genes in granulosa cells from women with polycystic ovary syndrome related to MAPK/ERK signaling. Sci. Rep. 5, 14994.
| Functional microarray analysis of differentially expressed genes in granulosa cells from women with polycystic ovary syndrome related to MAPK/ERK signaling.Crossref | GoogleScholarGoogle Scholar | 26459919PubMed |
Lash, M. M., and Armstrong, A. (2009). Impact of obesity on women’s health. Fertil. Steril. 91, 1712–1716.
| Impact of obesity on women’s health.Crossref | GoogleScholarGoogle Scholar | 18410940PubMed |
Linné, Y. (2004). Effects of obesity on women’s reproduction and complications during pregnancy. Obes. Rev. 5, 137–143.
| Effects of obesity on women’s reproduction and complications during pregnancy.Crossref | GoogleScholarGoogle Scholar | 15245382PubMed |
Metwally, M., Cutting, R., Tipton, A., Skull, J., Ledger, W. L., and Li, T. C. (2007a). Effect of increased body mass index on oocyte and embryo quality in IVF patients. Reprod. Biomed. Online 15, 532–538.
| Effect of increased body mass index on oocyte and embryo quality in IVF patients.Crossref | GoogleScholarGoogle Scholar | 18044034PubMed |
Metwally, M., Li, T. C., and Ledger, W. L. (2007b). The impact of obesity on female reproductive function. Obes. Rev. 8, 515–523.
| The impact of obesity on female reproductive function.Crossref | GoogleScholarGoogle Scholar | 17868286PubMed |
Morales, A. J., Laughlin, G. A., Butzow, T., Maheshwari, H., Baumann, G., and Yen, S. S. (1996). Insulin, somatotropic, and luteinizing hormone axes in lean and obese women with polycystic ovary syndrome: common and distinct features. J. Clin. Endocrinol. Metab. 81, 2854–2864.
| 8768842PubMed |
Norman, R. J., Noakes, M., Wu, R., Davies, M. J., Moran, L., and Wang, J. X. (2004). Improving reproductive performance in overweight/obese women with effective weight management. Hum. Reprod. Update 10, 267–280.
| Improving reproductive performance in overweight/obese women with effective weight management.Crossref | GoogleScholarGoogle Scholar | 15140873PubMed |
Ozgun, M. T., Uludag, S., Oner, G., Batukan, C., Aygen, E. M., and Sahin, Y. (2011). The influence of obesity on ICSI outcomes in women with polycystic ovary syndrome. J. Obstet. Gynaecol. 31, 245–249.
| The influence of obesity on ICSI outcomes in women with polycystic ovary syndrome.Crossref | GoogleScholarGoogle Scholar | 21417650PubMed |
Rittenberg, V., Seshadri, S., Sunkara, S. K., Sobaleva, S., Oteng-Ntim, E., and El-Toukhy, T. (2011). Effect of body mass index on IVF treatment outcome: an updated systematic review and meta-analysis. Reprod. Biomed. Online 23, 421–439.
| Effect of body mass index on IVF treatment outcome: an updated systematic review and meta-analysis.Crossref | GoogleScholarGoogle Scholar | 21885344PubMed |
Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group (2004). Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum. Reprod. 19, 41–47.
| Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS).Crossref | GoogleScholarGoogle Scholar | 14688154PubMed |
Schube, U., Nowicki, M., Jogschies, P., Blumenauer, V., Bechmann, I., and Serke, H. (2014). Resveratrol and desferoxamine protect human OxLDL-treated granulosa cell subtypes from degeneration. J. Clin. Endocrinol. Metab. 99, 229–239.
| Resveratrol and desferoxamine protect human OxLDL-treated granulosa cell subtypes from degeneration.Crossref | GoogleScholarGoogle Scholar | 24170104PubMed |
Tian, Y., Jiang, C., Wang, M., Cai, R., Zhang, Y., He, Z., Wang, H., Wu, D., Wang, F., Liu, X., et al. (2016). BMI, leisure-time physical activity, and physical fitness in adults in China: results from a series of national surveys, 2000–14. Lancet Diabetes Endocrinol. 4, 487–497.
| BMI, leisure-time physical activity, and physical fitness in adults in China: results from a series of national surveys, 2000–14.Crossref | GoogleScholarGoogle Scholar | 27133172PubMed |
Tusher, V. G., Tibshirani, R., and Chu, G. (2001). Significance analysis of microarrays applied to the ionizing radiation response. Proc. Natl Acad. Sci. USA 98, 5116–5121.
| Significance analysis of microarrays applied to the ionizing radiation response.Crossref | GoogleScholarGoogle Scholar | 11309499PubMed |
Valckx, S. D., Arias-Alvarez, M., De Pauw, I., Fievez, V., Vlaeminck, B., Fransen, E., Bols, P. E., and Leroy, J. L. (2014). Fatty acid composition of the follicular fluid of normal weight, overweight and obese women undergoing assisted reproductive treatment: a descriptive cross-sectional study. Reprod. Biol. Endocrinol. 12, 13.
| Fatty acid composition of the follicular fluid of normal weight, overweight and obese women undergoing assisted reproductive treatment: a descriptive cross-sectional study.Crossref | GoogleScholarGoogle Scholar | 24498875PubMed |
van‘t Erve, T. J., Lih, F. B., Kadiiska, M. B., Deterding, L. J., Eling, T. E., and Mason, R. P. (2015). Reinterpreting the best biomarker of oxidative stress: the 8-iso-PGF2α/PGF2α ratio distinguishes chemical from enzymatic lipid peroxidation. Free Radic. Biol. Med. 83, 245–251.
| Reinterpreting the best biomarker of oxidative stress: the 8-iso-PGF2α/PGF2α ratio distinguishes chemical from enzymatic lipid peroxidation.Crossref | GoogleScholarGoogle Scholar |
World Health Organization (WHO) (2000). Obesity: preventing and managing the global epidemic. Report of a WHO Consultation (WHO Technical Report Series 894). Available at https://www.who.int/nutrition/publications/obesity/WHO_TRS_894/en/ [verified 4 February 2019].
Wise, L. A., Rothman, K. J., Mikkelsen, E. M., Sorensen, H. T., Riis, A., and Hatch, E. E. (2010). An Internet-based prospective study of body size and time-to-pregnancy. Hum. Reprod. 25, 253–264.
| An Internet-based prospective study of body size and time-to-pregnancy.Crossref | GoogleScholarGoogle Scholar | 19828554PubMed |
Wu, X. Q., Wang, Y. Q., Xu, S. M., Liu, J. F., Bi, X. Y., Wang, Z. Q., and Zhang, J. P. (2017). The WNT/beta-catenin signaling pathway may be involved in granulosa cell apoptosis from patients with PCOS in North China. J. Gynecol. Obstet. Hum. Reprod. 46, 93–99.
| The WNT/beta-catenin signaling pathway may be involved in granulosa cell apoptosis from patients with PCOS in North China.Crossref | GoogleScholarGoogle Scholar | 28403963PubMed |
Yang, X., Wu, L. L., Chura, L. R., Liang, X., Lane, M., Norman, R. J., and Robker, R. L. (2012). Exposure to lipid-rich follicular fluid is associated with endoplasmic reticulum stress and impaired oocyte maturation in cumulus–oocyte complexes. Fertil. Steril. 97, 1438–1443.
| Exposure to lipid-rich follicular fluid is associated with endoplasmic reticulum stress and impaired oocyte maturation in cumulus–oocyte complexes.Crossref | GoogleScholarGoogle Scholar | 22440252PubMed |
