Abstract
Purpose
The objective of this study was to test the hypothesis that ovarian kisspeptin (kiss1) and its receptor (kiss1r) expression are affected by age, obesity, and the age- and obesity-related chemokine monocyte chemoattractant protein-1 (MCP-1).
Methods
Ovaries from reproductive-aged and older C57BL/6J mice fed normal chow (NC) or high-fat (HF) diet, ovaries from age-matched young MCP-1 knockout and young control mice on NC, and finally, cumulus and mural granulosa cells (GCs) from women who underwent in vitro fertilization (IVF) were collected. Kiss1, kiss1r, anti-Mullerian hormone (AMH), and AMH receptor (AMHR-II) messenger RNA (mRNA) expression levels were quantified using real-time polymerase chain reaction (RT-PCR).
Results
In mouse ovaries, kiss1 and kiss1r mRNA levels were significantly higher in old compared to reproductive-aged mice, and diet-induced obesity did not alter kiss1 or kiss1r mRNA levels. Compared to young control mice, young MCP-1 knockout mice had significantly lower ovarian kiss1 mRNA but significantly higher AMH and AMHR-II mRNA levels. In human cumulus GCs, kiss1r mRNA levels were positively correlated with age but not with BMI. There was no expression of kiss1 mRNA in either cumulus or mural GCs.
Conclusion
These data suggest a possible age-related physiologic role for the kisspeptinergic system in ovarian physiology. Additionally, the inflammatory MCP-1 may be associated with kiss1 and AMH genes, which are important in ovulation and folliculogenesis, respectively.
Similar content being viewed by others
References
Tena-Sempere M. GPR54 and kisspeptin in reproduction. Hum Reprod Update. 2006;12:631–9.
Neal-Perry G, Lebesgue D, Lederman M, Shu J, Zeevalk GD, Etgen AM. The excitatory peptide kisspeptin restores the luteinizing hormone surge and modulates amino acid neurotransmission in the medial preoptic area of middle-aged rats. Endocrinology. 2009.
Gaytan F, Garcia-Galiano D, Dorfman MD, Manfredi-Lozano M, Castellano JM, Dissen GA, et al. Kisspeptin receptor haplo-insufficiency causes premature ovarian failure in spite of preserved gonadotropin secretion. Endocrinology. 2014;en20141110.
Ricu MA, Ramirez VD, Paredes AH, Lara HE. Evidence for a celiac ganglion-ovarian kisspeptin neural network in the rat: intraovarian anti-kisspeptin delays vaginal opening and alters estrous cyclicity. Endocrinology. 2012;153:4966–77.
Dorfman MD, Garcia-Rudaz C, Alderman Z, Kerr B, Lomniczi A, Dissen GA, et al. Loss of Ntrk2/Kiss1r signaling in oocytes causes premature ovarian failure. Endocrinology. 2014;en20141111.
Gaytan F, Gaytan M, Castellano JM, Romero M, Roa J, Aparicio B, et al. KiSS-1 in the mammalian ovary: distribution of kisspeptin in human and marmoset and alterations in KiSS-1 mRNA levels in a rat model of ovulatory dysfunction. Am J Physiol Endocrinol Metab. 2009;296:E520–31.
Neal-Perry G, Lebesgue D, Lederman M, Shu J, Zeevalk GD, Etgen AM. The excitatory peptide kisspeptin restores the luteinizing hormone surge and modulates amino acid neurotransmission in the medial preoptic area of middle-aged rats. Endocrinology. 2009;150:3699–708.
Lederman MA, Lebesgue D, Gonzalez VV, Shu J, Merhi ZO, Etgen AM, et al. Age-related LH surge dysfunction correlates with reduced responsiveness of hypothalamic anteroventral periventricular nucleus kisspeptin neurons to estradiol positive feedback in middle-aged rats. Neuropharmacology. 2010;58:314–20.
Heider U, Pedal I, Spanel-Borowski K. Increase in nerve fibers and loss of mast cells in polycystic and postmenopausal ovaries. Fertil Steril. 2001;75:1141–7.
Wahab F, Shahab M, Behr R. The involvement of gonadotropin inhibitory hormone and kisspeptin in the metabolic regulation of reproduction. J Endocrinol. 2015;225:R49–66.
Castellano JM, Navarro VM, Fernandez-Fernandez R, Nogueiras R, Tovar S, Roa J, et al. Changes in hypothalamic KiSS-1 system and restoration of pubertal activation of the reproductive axis by kisspeptin in undernutrition. Endocrinology. 2005;146:3917–25.
Matsuzaki T, Iwasa T, Kinouchi R, Yoshida S, Murakami M, Gereltsetseg G, et al. Fasting reduces the kiss1 mRNA levels in the caudal hypothalamus of gonadally intact adult female rats. Endocr J. 2011;58:1003–12.
Quennell JH, Howell CS, Roa J, Augustine RA, Grattan DR, Anderson GM. Leptin deficiency and diet-induced obesity reduce hypothalamic kisspeptin expression in mice. Endocrinology. 2011;152:1541–50.
Slimani H, Zhai Y, Yousif NG, Ao L, Zeng Q, Fullerton DA, et al. Enhanced monocyte chemoattractant protein-1 production in aging mice exaggerates cardiac depression during endotoxemia. Crit Care. 2014;18:527.
Wang M, Jiang L, Monticone RE, Lakatta EG. Proinflammation: the key to arterial aging. Trends Endocrinol Metab. 2014;25:72–9.
Sharma R, Kapila R, Haq MR, Salingati V, Kapasiya M, Kapila S. Age-associated aberrations in mouse cellular and humoral immune responses. Aging Clin Exp Res. 2014;26:353–62.
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.
Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R, et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest. 2006;116:1494–505.
Lim JP, Leung BP, Ding YY, Tay L, Ismail NH, Yeo A, et al. Monocyte chemoattractant protein-1: a proinflammatory cytokine elevated in sarcopenic obesity. Clin Interv Aging. 2015;10:605–9.
Dahm-Kahler P, Ghahremani M, Lind AK, Sundfeldt K, Brannstrom M. Monocyte chemotactic protein-1 (MCP-1), its receptor, and macrophages in the perifollicular stroma during the human ovulatory process. Fertil Steril. 2009;91:231–9.
Baggiolini M, Dewald B, Moser B. Interleukin-8 and related chemotactic cytokines—CXC and CC chemokines. Adv Immunol. 1994;55:97–179.
Deshmane SL, Kremlev S, Amini S, Sawaya BE. Monocyte chemoattractant protein-1 (MCP-1): an overview. J Interf Cytokine Res: Off J Int Soc Interf Cytokine Res. 2009;29:313–26.
Terasaka T, Otsuka F, Tsukamoto N, Nakamura E, Inagaki K, Toma K, et al. Mutual interaction of kisspeptin, estrogen and bone morphogenetic protein-4 activity in GnRH regulation by GT1-7 cells. Mol Cell Endocrinol. 2013;381:8–15.
Castano JP, Martinez-Fuentes AJ, Gutierrez-Pascual E, Vaudry H, Tena-Sempere M, Malagon MM. Intracellular signaling pathways activated by kisspeptins through GPR54: do multiple signals underlie function diversity? Peptides. 2009;30:10–5.
Yang CQ, Li W, Li SQ, Li J, Li YW, Kong SX, et al. MCP-1 stimulates MMP-9 expression via ERK 1/2 and p38 MAPK signaling pathways in human aortic smooth muscle cells. Cell Physiol Biochem: Int J Exp Cell Physiol Biochem Pharmacol. 2014;34:266–76.
Li Y, Zheng Y, Li T, Wang Q, Qian J, Lu Y, et al. Chemokines CCL2, 3, 14 stimulate macrophage bone marrow homing, proliferation, and polarization in multiple myeloma. Oncotarget. 2015;6:24218–29.
Merhi Z, Buyuk E, Berger DS, Zapantis A, Israel DD, Chua Jr S, et al. Leptin suppresses anti-Mullerian hormone gene expression through the JAK2/STAT3 pathway in luteinized granulosa cells of women undergoing IVF. Hum Reprod. 2013;28:1661–9.
Merhi Z, Doswell A, Krebs K, Cipolla M. Vitamin D alters genes involved in follicular development and steroidogenesis in human cumulus granulosa cells. J Clin Endocrinol Metab. 2014;jc20134161.
Merhi Z, Irani M, Doswell AD, Ambroggio J. Follicular fluid soluble receptor for advanced glycation end-products (sRAGE): a potential indicator of ovarian reserve. J Clin Endocrinol Metab. 2014;99:E226–33.
Catteau-Jonard S, Jamin SP, Leclerc A, Gonzales J, Dewailly D, di Clemente N. Anti-Mullerian hormone, its receptor, FSH receptor, and androgen receptor genes are overexpressed by granulosa cells from stimulated follicles in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2008;93:4456–61.
Pierre A, Peigne M, Grynberg M, Arouche N, Taieb J, Hesters L, et al. Loss of LH-induced down-regulation of anti-Mullerian hormone receptor expression may contribute to anovulation in women with polycystic ovary syndrome. Hum Reprod. 2013;28:762–9.
Franks S. Controversy in clinical endocrinology: diagnosis of polycystic ovarian syndrome: in defense of the Rotterdam criteria. J Clin Endocrinol Metab. 2006;91:786–9.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25:402–8.
Garcia-Ortega J, Pinto FM, Fernandez-Sanchez M, Prados N, Cejudo-Roman A, Almeida TA, et al. Expression of neurokinin B/NK3 receptor and kisspeptin/KISS1 receptor in human granulosa cells. Hum Reprod. 2014;29:2736–46.
Uyar A, Torrealday S, Seli E. Cumulus and granulosa cell markers of oocyte and embryo quality. Fertil Steril. 2013;99:979–97.
Dumesic DA, Meldrum DR, Katz-Jaffe MG, Krisher RL, Schoolcraft WB. Oocyte environment: follicular fluid and cumulus cells are critical for oocyte health. Fertil Steril. 2015;103:303–16.
Vanderhyden BC, Tonary AM. Differential regulation of progesterone and estradiol production by mouse cumulus and mural granulosa cells by A factor(s) secreted by the oocyte. Biol Reprod. 1995;53:1243–50.
Eppig JJ, Chesnel F, Hirao Y, O’Brien MJ, Pendola FL, Watanabe S, et al. Oocyte control of granulosa cell development: how and why. Hum Reprod. 1997;12:127–32.
Simerman AA, Hill DL, Grogan TR, Elashoff D, Clarke NJ, Goldstein EH, et al. Intrafollicular cortisol levels inversely correlate with cumulus cell lipid content as a possible energy source during oocyte meiotic resumption in women undergoing ovarian stimulation for in vitro fertilization. Fertil Steril. 2015;103:249–57.
Fernandois DD, Na EK, Cuevas FC, Cruz G, Lara H, Paredes AH. Kisspeptin is involved in ovarian follicular development during aging in rats. J Endocrinol. 2015.
Zhou Q, Chen H, Yang S, Li Y, Wang B, Chen Y, et al. High-fat diet decreases the expression of Kiss1 mRNA and kisspeptin in the ovary, and increases ovulatory dysfunction in postpubertal female rats. Reprod Biol Endocrinol. 2014;12:127.
Laoharatchatathanin T, Terashima R, Yonezawa T, Kurusu S, Kawaminami M. Augmentation of metastin/kisspeptin mRNA expression by the proestrous luteinizing hormone surge in granulosa cells of rats: implications for luteinization. Biol Reprod. 2015;93:15.
Zhang JJ, Feret M, Chang L, Yang M, Merhi Z. Obesity adversely impacts the number and maturity of oocytes in conventional IVF not in minimal stimulation IVF. Gynecolo Endocrinol: Off J Int Soc Gynecol Endocrinol. 2015;31:409–13.
Merhi ZO. Impact of bariatric surgery on female reproduction. Fertil Steril. 2009;92:1501–8.
Merhi ZO. Weight loss by bariatric surgery and subsequent fertility. Fertil Steril. 2007;87:430–2.
Merhi Z, Polotsky AJ, Bradford AP, Buyuk E, Chosich J, Phang T, et al. Adiposity alters genes important in inflammation and cell cycle division in human cumulus granulosa cell. Reprod Sci. 2015;22:1220–8.
Merhi Z, McGee EA, Buyuk E. Role of advanced glycation end-products in obesity-related ovarian dysfunction. Minerva Endocrinol. 2014;39:167–74.
Moy V, Jindal S, Lieman H, Buyuk E. Obesity adversely affects serum anti-mullerian hormone (AMH) levels in Caucasian women. J Assist Reprod Genet. 2015.
Kanasaki H, Purwana IN, Oride A, Mijiddorj T, Sukhbaatar U, Miyazaki K. Circulating kisspeptin and pituitary adenylate cyclase-activating polypeptide (PACAP) do not correlate with gonadotropin serum levels. Gynecolo Endocrinol: Off J Int Soc Gynecol Endocrinol. 2013;29:583–7.
Peng J, Xu H, Yang B, Hu J, Zhang BP, Zou L, et al. Plasma levels of kisspeptins in postmenopausal Chinese women do not show substantial elevation. Peptides. 2010;31:2255–8.
Abbara A, Jayasena CN, Christopoulos G, Narayanaswamy S, Izzi-Engbeaya C, Nijher GM, et al. Efficacy of kisspeptin-54 to trigger oocyte maturation in women at high risk of ovarian hyperstimulation syndrome (OHSS) during in vitro fertilization (IVF) therapy. J Clin Endocrinol Metab. 2015;100:3322–31.
Hsu MC, Wang JY, Lee YJ, Jong DS, Tsui KH, Chiu CH. Kisspeptin modulates fertilization capacity of mouse spermatozoa. Reproduction (Camb Engl). 2014;147:835–45.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Funding
Grant from Ferring Pharmaceuticals Inc. to Z.M. and the American Diabetes Association to M.J.C.
Conflict of interest
None
Additional information
Capsule
These data suggest a possible age-related physiologic role for the kisspeptinergic system in ovarian physiology.
Rights and permissions
About this article
Cite this article
Merhi, Z., Thornton, K., Bonney, E. et al. Ovarian kisspeptin expression is related to age and to monocyte chemoattractant protein-1. J Assist Reprod Genet 33, 535–543 (2016). https://doi.org/10.1007/s10815-016-0672-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10815-016-0672-x