Horm Metab Res 2017; 49(07): 534-541
DOI: 10.1055/s-0043-107617
Endocrine Care
© Georg Thieme Verlag KG Stuttgart · New York

High Leptin Level Attenuates Embryo Development in Overweight/Obese Infertile Women by Inhibiting Proliferation and Promotes Apoptosis in Granule Cell

Xian-hua Lin*
1   The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
,
Hui Wang*
2   The Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, China
3   Department of Obstetrics and Gynecology, Taizhou Oriental Maternity Hospital, Taizhou, China
,
Dan-dan Wu*
1   The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
,
Kamran Ullah
2   The Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, China
,
Tian-tian Yu
1   The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
2   The Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, China
,
Tanzil Ur Rahman
2   The Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, China
,
He-feng Huang
1   The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
2   The Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, China
› Author Affiliations
Further Information

Publication History

received 04 January 2017

accepted 21 March 2017

Publication Date:
30 May 2017 (online)

Abstract

Obesity appears to be associated with female reproductive dysfunction and infertility. Women with obesity undergoing in vitro fertilization (IVF) had poor oocyte quality, decreased embryo development, and poor pregnancy outcome. However, the mechanism linking obesity to poor reproductive outcomes is still unclear. Obesity is frequently accompanied with elevated leptin levels. Here we aimed to evaluate the effect of high leptin level in follicular fluid (FF) on the proliferation and apoptosis in granule cells and correlate these findings with poor reproductive outcomes in infertile women with overweight or obesity who underwent IVF treatment. We investigated clinical and ongoing pregnancy rates in 189 infertile women who underwent IVF. Leptin levels were quantified in peripheral blood and FF as well. In vitro cell model was used to explore the potential effect of high leptin on the proliferation and apoptosis in granulosa cells. Results showed reduced clinical and ongoing pregnancy rates in overweight/obesity women who underwent IVF compared to control with normal BMI. On the other hand, leptin levels presented significant increase in peripheral blood and FF in overweight/obese women. Leptin level in FF was negatively correlated to good quality embryo rate. Importantly, in vitro study showed that leptin inhibited cells proliferation and promoted apoptosis by upregulation of caspase-3 and downregulation of Bcl-2 in granulosa cells in a dose dependent manner. These observations suggest that leptin may acts as a local mediator to attenuate embryo development and reduce fertility in obese patients.

* These 3 authors contributed equally to this study


 
  • References

  • 1 Ng M, Fleming T, Robinson M, Thomson B, Graetz N, Margono C, Mullany EC, Biryukov S, Abbafati C, Abera SF, Abraham JP, Abu-Rmeileh NM, Achoki T, AlBuhairan FS, Alemu ZA, Alfonso R, Ali MK, Ali R, Guzman NA, Ammar W, Anwari P, Banerjee A, Barquera S, Basu S, Bennett DA, Bhutta Z, Blore J, Cabral N, Nonato IC, Chang JC, Chowdhury R, Courville KJ, Criqui MH, Cundiff DK, Dabhadkar KC, Dandona L, Davis A, Dayama A, Dharmaratne SD, Ding EL, Durrani AM, Esteghamati A, Farzadfar F, Fay DF, Feigin VL, Flaxman A, Forouzanfar MH, Goto A, Green MA, Gupta R, Hafezi-Nejad N, Hankey GJ, Harewood HC, Havmoeller R, Hay S, Hernandez L, Husseini A, Idrisov BT, Ikeda N, Islami F, Jahangir E, Jassal SK, Jee SH, Jeffreys M, Jonas JB, Kabagambe EK, Khalifa SE, Kengne AP, Khader YS, Khang YH, Kim D, Kimokoti RW, Kinge JM, Kokubo Y, Kosen S, Kwan G, Lai T, Leinsalu M, Li Y, Liang X, Liu S, Logroscino G, Lotufo PA, Lu Y, Ma J, Mainoo NK, Mensah GA, Merriman TR, Mokdad AH, Moschandreas J, Naghavi M, Naheed A, Nand D, Narayan KM, Nelson EL, Neuhouser ML, Nisar MI, Ohkubo T, Oti SO, Pedroza A, Prabhakaran D, Roy N, Sampson U, Seo H, Sepanlou SG, Shibuya K, Shiri R, Shiue I, Singh GM, Singh JA, Skirbekk V, Stapelberg NJ, Sturua L, Sykes BL, Tobias M, Tran BX, Trasande L, Toyoshima H, van de Vijver S, Vasankari TJ, Veerman JL, Velasquez-Melendez G, Vlassov VV, Vollset SE, Vos T, Wang C, Wang X, Weiderpass E, Werdecker A, Wright JL, Yang YC, Yatsuya H, Yoon J, Yoon SJ, Zhao Y, Zhou M, Zhu S, Lopez AD, Murray CJ, Gakidou E. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: A systematic analysis for the Global Burden of Disease Study 2013. Lancet 2014; 384: 766-781
  • 2 Castillo-Martinez L, Lopez-Alvarenga JC, Villa AR, Gonzalez-Barranco J. Menstrual cycle length disorders in 18- to 40-y-old obese women. Nutrition 2003; 19: 317-320
  • 3 Boots C, Stephenson MD. Does obesity increase the risk of miscarriage in spontaneous conception: A systematic review. Semin Reprod Med 2011; 29: 507-513
  • 4 Practice Committee of American Society for Reproductive M . Obesity and reproduction: An educational bulletin. Fertil Steril 2008; 90: S21-S29
  • 5 Wang JX, Davies MJ, Norman RJ. Obesity increases the risk of spontaneous abortion during infertility treatment. Obes Res 2002; 10: 551-554
  • 6 Luke B, Brown MB, Stern JE, Missmer SA, Fujimoto VY, Leach R. Group SW . Female obesity adversely affects assisted reproductive technology (ART) pregnancy and live birth rates. Hum Reprod 2011; 26: 245-252
  • 7 Wang JX, Davies M, Norman RJ. Body mass and probability of pregnancy during assisted reproduction treatment: Retrospective study. BMJ 2000; 321: 1320-1321
  • 8 Jungheim ES, Schon SB, Schulte MB, DeUgarte DA, Fowler SA, Tuuli MG. IVF outcomes in obese donor oocyte recipients: A systematic review and meta-analysis. Hum Reprod 2013; 28: 2720-2727
  • 9 Serke H, Nowicki M, Kosacka J, Schroder T, Kloting N, Bluher M, Kallendrusch S, Spanel-Borowski K. Leptin-deficient (ob/ob) mouse ovaries show fatty degeneration, enhanced apoptosis and decreased expression of steroidogenic acute regulatory enzyme. Int J Obes (Lond) 2012; 36: 1047-1053
  • 10 Jungheim ES, Schoeller EL, Marquard KL, Louden ED, Schaffer JE, Moley KH. Diet-induced obesity model: Abnormal oocytes and persistent growth abnormalities in the offspring. Endocrinology 2010; 151: 4039-4046
  • 11 Hou YJ, Zhu CC, Duan X, Liu HL, Wang Q, Sun SC. Both diet and gene mutation induced obesity affect oocyte quality in mice. Sci Rep 2016; 6: 18858
  • 12 Pasquali R, Gambineri A. Metabolic effects of obesity on reproduction. Reprod Biomed Online 2006; 12: 542-551
  • 13 Brewer CJ, Balen AH. The adverse effects of obesity on conception and implantation. Reproduction 2010; 140: 347-364
  • 14 La Vignera S, Condorelli R, Bellanca S, La Rosa B, Mousavi A, Busa B, Vicari LO, Vicari E. Obesity is associated with a higher level of pro-inflammatory cytokines in follicular fluid of women undergoing medically assisted procreation (PMA) programs. Eur Rev Med Pharmacol Sci 2011; 15: 267-273
  • 15 Robker RL, Wu LL, Yang X. Inflammatory pathways linking obesity and ovarian dysfunction. J Reprod Immunol 2011; 88: 142-148
  • 16 Lin XH, Liu ME, Xu HY, Chen XJ, Wang H, Tian S, Sheng JZ, Huang HF. Leptin down-regulates gamma-ENaC expression: A novel mechanism involved in low endometrial receptivity. Fertil Steril 2015; 103: 228-235
  • 17 Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, Ohannesian JP, Marco CC, McKee LJ, Bauer TL, Caro JF. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 1996; 334: 292-295
  • 18 Aerts JM, Bols PE. Ovarian follicular dynamics: a review with emphasis on the bovine species. Part I: Folliculogenesis and pre-antral follicle development. Reprod Domest Anim 2010; 45: 171-179
  • 19 Su YQ, Sugiura K, Wigglesworth K, O’Brien MJ, Affourtit JP, Pangas SA, Matzuk MM, Eppig JJ. Oocyte regulation of metabolic cooperativity between mouse cumulus cells and oocytes: BMP15 and GDF9 control cholesterol biosynthesis in cumulus cells. Development 2008; 135: 111-121
  • 20 Tatemoto H, Sakurai N, Muto N. Protection of porcine oocytes against apoptotic cell death caused by oxidative stress during In vitro maturation: Role of cumulus cells. Biol Reprod 2000; 63: 805-810
  • 21 Jahromi BN, Mosallanezhad Z, Matloob N, Davari M, Ghobadifar MA. The potential role of granulosa cells in the maturation rate of immature human oocytes and embryo development: A co-culture study. Clin Exp Reprod Med 2015; 42: 111-117
  • 22 Polyzos NP, Sunkara SK. Sub-optimal responders following controlled ovarian stimulation: an overlooked group?. Hum Reprod 2015; 30: 2005-2008
  • 23 Steward RG, Lan L, Shah AA, Yeh JS, Price TM, Goldfarb JM, Muasher SJ. Oocyte number as a predictor for ovarian hyperstimulation syndrome and live birth: An analysis of 256,381 in vitro fertilization cycles. Fertil Steril 2014; 101: 967-973
  • 24 He RH, Sheng JZ, Luo Q, Jin F, Wang B, Qian YL, Zhou CY, Sheng X, Huang HF. Aquaporin-2 expression in human endometrium correlates with serum ovarian steroid hormones. Life Sci 2006; 79: 423-429
  • 25 Shi FT, Cheung AP, Leung PC. Growth differentiation factor 9 enhances activin a-induced inhibin B production in human granulosa cells. Endocrinology 2009; 150: 3540-3546
  • 26 Flegal KM, Kruszon-Moran D, Carroll MD, Fryar CD, Ogden CL. Trends in Obesity Among Adults in the United States, 2005 to 2014. JAMA 2016; 315: 2284-2291
  • 27 Lin XH, Wu DD, Gao L, Zhang JY, Pan HT, Wang H, Li C, Zhang P, Guo MX, Wu YT, Tan YJ, Jin L, Xiang YQ, Li JX, Sheng JZ, Huang HF. Altered DNA methylation in neonates born large-for-gestational-age is associated with cardiometabolic risk in children. Oncotarget 2016; 7: 86511-86521
  • 28 Van Royen E, Mangelschots K, De Neubourg D, Valkenburg M, Van de Meerssche M, Ryckaert G, Eestermans W, Gerris J. Characterization of a top quality embryo, a step towards single-embryo transfer. Hum Reprod 1999; 14: 2345-2349
  • 29 Zhu H, Liu L, Yang L, Xue Y, Tong X, Jiang L, Zhang S. The effect of progesterone level prior to oocyte retrieval on the numbers of oocytes retrieved and embryo quality in IVF treatment cycles: An analysis of 2,978 cycles. J Assist Reprod Genet 2014; 31: 1183-1187
  • 30 Mori T, Amano T, Shimizu H. Roles of gap junctional communication of cumulus cells in cytoplasmic maturation of porcine oocytes cultured in vitro. Biol Reprod 2000; 62: 913-919
  • 31 Araujo VR, Gastal MO, Figueiredo JR, Gastal EL. In vitro culture of bovine preantral follicles: A review. Reprod Biol Endocrinol 2014; 12: 78
  • 32 Ethics ETFo . Law I, Dondorp W, de Wert G, Pennings G, Shenfield F, Devroey P, Tarlatzis B, Barri P. Lifestyle-related factors and access to medically assisted reproduction. Hum Reprod 2010; 25: 578-583
  • 33 Chang HJ, Lee JH, Lee JR, Jee BC, Suh CS, Kim SH. Relationship between follicular fluid adipocytokines and the quality of the oocyte and corresponding embryo development from a single dominant follicle in in vitro fertilization/intracytoplasmic sperm injection cycles. Clin Exp Reprod Med 2014; 41: 21-28
  • 34 Tsai EM, Yang CH, Chen SC, Liu YH, Chen HS, Hsu SC, Lee JN. Leptin affects pregnancy outcome of in vitro fertilization and steroidogenesis of human granulosa cells. J Assist Reprod Genet 2002; 19: 169-176
  • 35 Anifandis G, Koutselini E, Stefanidis I, Liakopoulos V, Leivaditis C, Mantzavinos T, Vamvakopoulos N. Serum and follicular fluid leptin levels are correlated with human embryo quality. Reproduction 2005; 130: 917-921
  • 36 Zhao L, Yan X, Shi J, Ren F, Liu L, Sun S, Shan B. Ethanol extract of Forsythia suspensa root induces apoptosis of esophageal carcinoma cells via the mitochondrial apoptotic pathway. Mol Med Rep 2015; 11: 871-880
  • 37 Li HL, Huang XP, Zhou XH, Ji TH, Wu ZQ, Wang ZQ, Jiang HY, Liu FR, Zhao T. Correlation of seven biological factors (Hsp90a, p53, MDM2, Bcl-2, Bax, Cytochrome C, and Cleaved caspase3) with clinical outcomes of ALK+ anaplastic large-cell lymphoma. Biomed Environ Sci 2011; 24: 630-641
  • 38 Khan N, Afaq F, Mukhtar H. Apoptosis by dietary factors: the suicide solution for delaying cancer growth. Carcinogenesis 2007; 28: 233-239
  • 39 Tilly JL, Tilly KI, Kenton ML, Johnson AL. Expression of members of the bcl-2 gene family in the immature rat ovary: Equine chorionic gonadotropin-mediated inhibition of granulosa cell apoptosis is associated with decreased bax and constitutive bcl-2 and bcl-xlong messenger ribonucleic acid levels. Endocrinology 1995; 136: 232-241