Leptin in the canine uterus and placenta: possible implications in pregnancy

Reproductive Biology and Endocrinology

Iris M Reichler¹  Mariusz P Kowalewski²  Alois Boos²  Aykut Gram²  Livia P Staub¹  Orsolya Balogh¹ 

[1] Clinic of Reproductive Medicine, Vetsuisse-Faculty, University of Zurich, Winterthurerstrasse 260, Zurich, 8057, Switzerland;Institute of Veterinary Anatomy, Vetsuisse-Faculty, University of Zurich, Winterthurerstrasse 260, Zurich, 8057, Switzerland

关键词: In situ hybridization;    Immunohistochemistry;    Placenta;    Uterus;    Gestation;    Dog;    Leptin receptor;    Leptin;   

Others  :  1139684
DOI  :  10.1186/s12958-015-0003-6

 received in 2014-10-06, accepted in 2015-02-06,  发布年份 2015

【 摘 要 】

Background

Leptin (Lep) is known for its involvement in the regulation of reproductive functions. It is important for uterine receptivity, implantation, placental growth and maternal energy homeostasis in several species, but Lep’s function in the pregnant dog has not been investigated.

Methods

Pregnant bitches were ovariohysterectomized at pre-implantation, post-implantation, mid-gestation and prepartum luteolysis. Two additional groups were treated with aglepristone in mid-gestation, and ovariohysterectomized 24 or 72 h later. Lep and leptin receptor (LepR) gene expression was detected by semi-quantitative real-time PCR in pre-implantation and inter-placental uterine sections (Ut) and in utero-placental compartments (Ut/Pl). Immunohistochemistry and in situ hybridization (ISH) were performed for Lep and LepR protein and mRNA localization. Parametric one-way ANOVA, paired t-test and Wilcoxon signed-rank test were used for statistical analysis.

Results

In the Ut/Pl, Lep expression was higher at post-implantation and prepartum luteolysis than at mid-gestation, while in the Ut, Lep mRNA levels did not change during pregnancy. LepR expression in the Ut/Pl was up-regulated at prepartum luteolysis compared to the earlier stages. In the Ut, highest LepR mRNA was found at pre- and post-implantation. LepR expression was down-regulated in the Ut/Pl compared to the Ut at post-implantation and at mid-gestation. Aglepristone treatment resulted in a decrease of Lep mRNA levels from 24 to 72 h in the Ut without concomitant changes in the Ut/Pl or in LepR levels. Lep and LepR immunoreactivities were strong in the luminal and glandular epithelium in the Ut with abundant LepR signals in the subepithelial stroma. In the Ut/Pl, fetal trophoblasts stained stronger for Lep and LepR than decidual cells, and signals for both proteins were also detected in the glandular chambers. The myometrium, blood vessel media, and sporadically also the endothelium stained for Lep and LepR. ISH showed similar signal distribution in the Ut and Ut/Pl.

Conclusions

Lep and LepR are differentially expressed in the canine uterus and placenta during pregnancy, and their presence in various cell types indicates paracrine/autocrine roles. The Lep signaling system may be one of the pathways involved in feto-maternal cross-talk, implantation and maintenance of pregnancy, and may have a regulatory role around parturition.

【 授权许可】

   
2015 Balogh et al.; licensee BioMed Central.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

Figure 7.

【 参考文献 】

• [1]Kielar D, Clark JS, Ciechanowicz A, Kurzawski G, Sulikowski T, Naruszewicz M: Leptin receptor isoforms expressed in human adipose tissue. Metabolism 1998, 47:844-7.
• [2]Jin L, Burguera BG, Couce ME, Scheithauer BW, Lamsan J, Eberhardt NL, et al.: Leptin and leptin receptor expression in normal and neoplastic human pituitary: evidence of a regulatory role for leptin on pituitary cell proliferation. J Clin Endocrinol Metab 1999, 84:2903-11.
• [3]González RR, Caballero-Campo P, Jasper M, Mercader A, Devoto L, Pellicer A, et al.: Leptin and leptin receptor are expressed in the human endometrium and endometrial leptin secretion is regulated by the human blastocyst. J Clin Endocrinol Metab 2000, 85:4883-8.
• [4]Ryan NK, Woodhouse CM, Van der Hoek KH, Gilchrist RB, Armstrong DT, Norman RJ: Expression of leptin and its receptor in the murine ovary: possible role in the regulation of oocyte maturation. Biol Reprod 2002, 66:1548-54.
• [5]Cervero A, Horcajadas JA, Martín J, Pellicer A, Simón C: The leptin system during human endometrial receptivity and preimplantation development. J Clin Endocrinol Metab 2004, 8:2442-51.
• [6]Martos-Moreno GA, Chowen JA, Argente J: Metabolic signals in human puberty: effects of over and undernutrition. Mol Cell Endocrinol 2010, 324:70-81.
• [7]Herrid M, Palanisamy SK, Ciller UA, Fan R, Moens P, Smart NA, et al.: An updated view of leptin on implantation and pregnancy: a review. Physiol Res 2014, 63:543-57.
• [8]Hardie L, Trayhurn P, Abramovich D, Fowler P: Circulating leptin in women: a longitudinal study in the menstrual cycle and during pregnancy. Clin Endocrinol (Oxf) 1997, 47:101-6.
• [9]Gavrilova O, Barr V, Marcus-Samuels B, Reitman M: Hyperleptinemia of pregnancy associated with the appearance of a circulating form of the leptin receptor. J Biol Chem 1997, 272:30546-51.
• [10]Amico JA, Thomas A, Crowley RS, Burmeister LA: Concentrations of leptin in the serum of pregnant, lactating, and cycling rats and of leptin messenger ribonucleic acid in rat placental tissue. Life Sci 1998, 63:1387-95.
• [11]Berg EL, McNamara DL, Keisler DH: Endocrine profiles of periparturient mares and their foals. J Anim Sci 2007, 85:1660-8.
• [12]Tessier DR, Ferraro ZM, Gruslin A: Role of leptin in pregnancy: consequences of maternal obesity. Placenta 2013, 34:205-11.
• [13]Hoggard N, Hunter L, Duncan JS, Williams LM, Trayhurn P, Mercer JG: Leptin and leptin receptor mRNA and protein expression in the murine fetus and placenta. Proc Natl Acad Sci U S A 1997, 94:11073-8.
• [14]Masuzaki H, Ogawa Y, Sagawa N, Hosoda K, Matsumoto T, Mise H, et al.: Nonadipose tissue production of leptin: leptin as a novel placenta-derived hormone in humans. Nat Med 1997, 3:1029-33.
• [15]Jansson N, Greenwood SL, Johansson BR, Powell TL, Jansson T: Leptin stimulates the activity of the system A amino acid transporter in human placental villous fragments. J Clin Endocrinol Metab 2003, 88:1205-11.
• [16]Mousiolis AV, Kollia P, Skentou C, Messinis IE: Effects of leptin on the expression of fatty acid-binding proteins in human placental cell cultures. Mol Med Rep 2012, 5:497-502.
• [17]Cao R, Brakenhielm E, Wahlestedt C, Thyberg J, Cao Y: Leptin induces vascular permeability and synergistically stimulates angiogenesis with FGF-2 and VEGF. Proc Natl Acad Sci U S A 2001, 98:6390-5.
• [18]Anagnostoulis S, Karayiannakis AJ, Lambropoulou M, Efthimiadou A, Polychronidis A, Simopoulos C: Human leptin induces angiogenesis in vivo. Cytokine 2008, 42:353-7.
• [19]Leiser R, Kaufmann P: Placental structure: in a comparative aspect. Exp Clin Endocrinol 1994, 102:122-34.
• [20]Staun-Ram E, Shalev E: Human trophoblast function during the implantation process. Reprod Biol Endocrinol 2005, 3:56. BioMed Central Full Text
• [21]Staun-Ram E, Goldman S, Gabarin D, Shalev E: Expression and importance of matrix metalloproteinase 2 and 9 (MMP-2 and −9) in human trophoblast invasion. Reprod Biol Endocrinol 2004, 2:59. BioMed Central Full Text
• [22]Castelucci M, De Matteis R, Meisser A, Cancello R, Monsurrò V, Islami D, et al.: Leptin modulates extracellular matrix molecules and metalloproteinases: possible implications for trophoblast invasion. Mol Hum Reprod 2000, 6:951-8.
• [23]Gonzalez RR, Devoto L, Campana A, Bischof P: Effects of leptin, interleukin-1α, interleukin-6, and transforming growth factor-β on markers of trophoblast invasive phenotype: integrins and metalloproteinases. Endocrine 2001, 15:157-64.
• [24]Schulz LC, Widmaier EP: The effect of leptin on mouse trophoblast cell invasion. Biol Reprod 2004, 71:1963-7.
• [25]Gonzalez RR, Leavis P: Leptin upregulates beta3-integrin expression and interleukin-1beta, upregulates leptin and leptin receptor expression in human endometrial epithelial cell cultures. Endocrine 2001, 16:21-8.
• [26]Gonzalez RR, Rueda BR, Ramos MP, Littell RD, Glasser S, Leavis PC: Leptin-induced increase in leukemia inhibitory factor and its receptor by human endometrium is partially mediated by interleukin 1 receptor signaling. Endocrinology 2004, 145:3850-7.
• [27]Kawamura K, Sato N, Fukuda J, Kodama H, Kumagai J, Tanikawa H, et al.: Leptin promotes the development of mouse preimplantation embryos in vitro. Endocrinology 2002, 143:1922-31.
• [28]Herrid M, Nguyen VL, Hinch G, McFarlane JR: Leptin has concentration and stage-dependent effects on embryonic development in vitro. Reproduction 2006, 132:247-56.
• [29]Lange Consiglio A, Dell’Aquila ME, Fiandanese N, Ambruosi B, Cho YS, Bosi G, et al.: Effects of leptin on in vitro maturation, fertilization and embryonic cleavage after ICSI and early developmental expression of leptin (Ob) and leptin receptor (ObR) proteins in the horse. Reprod Biol Endocrinol 2009, 7:113. BioMed Central Full Text
• [30]Ramos MP, Rueda BR, Leavis PC, Gonzalez RR: Leptin serves as an upstream activator of an obligatory signaling cascade in the embryo-implantation process. Endocrinology 2005, 146:694-701.
• [31]Sokolowski JH: The effects of ovariectomy on pregnancy maintenance in the bitch. Lab Anim Sci 1971, 21:696-9.
• [32]Concannon PW, Hansel W, Visek WJ: The ovarian cycle of the bitch: plasma estrogen, LH and progesterone. Biol Reprod 1975, 13:112-21.
• [33]Hoffmann B, Höveler R, Nohr B, Hasan SH: Investigations on hormonal changes around parturition in the dog and the occurrence of pregnancy-specific non conjugated oestrogens. Exp Clin Endocrinol 1994, 102:185-9.
• [34]Steinetz BG, Goldsmith LT, Lust G: Plasma relaxin in pregnant and lactating dogs. Biol Reprod 1987, 37:719-25.
• [35]Jöchle W: Prolactin in canine and feline reproduction. Reprod Domest Anim 1997, 32:183-93.
• [36]Onclin K, Murphy B, Verstegen JP: Comparisons of estradiol, LH and FSH patterns in pregnant and nonpregnant beagle bitches. Theriogenology 2002, 57:1957-72.
• [37]Schäfer-Somi S, Beceriklisoy HB, Budik S, Kanca H, Aksoy OA, Polat B, et al.: Expression of genes in the canine pre-implantation uterus and embryo: implications for an active role of the embryo before and during invasion. Reprod Domest Anim 2008, 43:656-63.
• [38]Schäfer-Somi S, Klein D, Beceriklisoy HB, Sabitzer S, Ay SS, Agaoglu AR, et al.: Uterine progesterone receptor and leukaemia inhibitory factor mRNA expression in canine pregnancy. Reprod Domest Anim 2009, 44(Suppl 2):109-14.
• [39]Beceriklisoy HB, Schäfer-Somi S, Kücükaslan I, Agaoglu R, Gültiken N, Ay SS, et al.: Cytokines, growth factors and prostaglandin synthesis in the uterus of pregnant and non-pregnant bitches: the features of placental sites. Reprod Domest Anim 2009, 44(Suppl 2):115-9.
• [40]Kautz E, Gram A, Aslan S, Ay SS, Selçuk M, Kanca H, et al.: Expression of genes involved in the embryo-maternal interaction in the early-pregnant canine uterus. Reproduction 2014, 147:703-17.
• [41]Kowalewski MP, Beceriklisoy HB, Pfarrer C, Aslan S, Kindahl H, Kücükaslan I, et al.: Canine placenta: a source of prepartal prostaglandins during normal and antiprogestin-induced parturition. Reproduction 2010, 139:655-64.
• [42]Kowalewski MP, Michel E, Gram A, Boos A, Guscetti F, Hoffmann B, et al.: Luteal and placental function in the bitch: spatio-temporal changes in prolactin receptor (PRLr) expression at dioestrus, pregnancy and normal and induced parturition. Reprod Biol Endocrinol 2011, 9:109. BioMed Central Full Text
• [43]Gram A, Büchler U, Boos A, Hoffmann B, Kowalewski MP: Biosynthesis and degradation of canine placental prostaglandins: prepartum changes in expression and function of prostaglandin F2α-synthase (PGFS, AKR1C3) and 15-hydroxyprostaglandin dehydrogenase (HPGD). Biol Reprod 2013, 89:2.
• [44]Jeusette IC, Detilleux J, Shibata H, Saito M, Honjoh T, Delobel A, et al.: Effects of chronic obesity and weight loss on plasma ghrelin and leptin concentrations in dogs. Res Vet Sci 2005, 79:169-75.
• [45]Nishii N, Takasu M, Ohba Y, Maeda S, Kitoh K, Ohtsuka Y, et al.: Effects of administration of glucocorticoids and feeding status on plasma leptin concentrations in dogs. Am J Vet Res 2006, 67:266-70.
• [46]Ishioka K, Hosoya K, Kitagawa H, Shibata H, Honjoh T, Kimura K, et al.: Plasma leptin concentration in dogs: effects of body condition score, age, gender and breeds. Res Vet Sci 2007, 82(1):11-5.
• [47]Saleri R, Tirelli M, Grasselli F, Dondi M, Arisi M: Sexual dimorphism in leptin blood levels in the dog. Veterinaria 2003, 17:47-51.
• [48]Balogh O, Kowalewski MP, Reichler IM: Leptin and leptin receptor gene expression in the canine corpus luteum during diestrus, pregnancy and after aglepristone-induced luteolysis. Reprod Domest Anim 2012, 47(Suppl 6):40-2.
• [49]Sorace M, Tripodi L, Tripodi A, Groppetti D, Cremonesi F: Leptin: pharmacological aspects in gynecology. Clin Exp Obstet Gynecol 2006, 33:113-6.
• [50]Bartel C, Tichy A, Walter I: Characterization of foamy epithelial surface cells in the canine endometrium. Anat Histol Embryol 2014, 43:165-81.
• [51]Kowalewski MP, Beceriklisoy HB, Aslan S, Agaoglu AR, Hoffmann B: Time related changes in luteal prostaglandin synthesis and steroidogenic capacity during pregnancy, normal and antiprogestin induced luteolysis in the bitch. Anim Reprod Sci 2009, 116:129-38.
• [52]Bouchard GF, Solorzano N, Concannon PW, Youngquist RS, Bierschwal CJ: Determination of ovulation time in bitches based on teasing, vaginal cytology, and elisa for progesterone. Theriogenology 1991, 35:603-11.
• [53]Link KRJ, Allio I, Rand JS, Eppler E: The effect of experimentally induced chronic hyperglycaemia on serum and pancreatic insulin, pancreatic islet IGF-I and plasma and urinary ketones in the domestic cat (Felis felis). Gen Comp Endocrinol 2013, 188:269-81.
• [54]Kowalewski MP, Schuler G, Taubert A, Engel E, Hoffmann B: Expression of cyclooxygenase 1 and 2 in the canine corpus luteum during diestrus. Theriogenology 2006, 66:1423-30.
• [55]Kowalewski MP, Mason JI, Howie AF, Morley SD, Schuler G, Hoffmann B: Characterization of the canine 3β-hydroxysteroid dehydrogenase and its expression in the corpus luteum during diestrus. J Steroid Biochem Mol Biol 2006, 101:254-62.
• [56]Kowalewski MP, Meyer A, Hoffmann B, Aslan S, Boos A: Expression and functional implications of peroxisome proliferator-activated receptor gamma (PPARγ) in canine reproductive tissues during normal pregnancy and parturition and at antiprogestin induced abortion. Theriogenology 2011, 75:877-86.
• [57]Kitawaki J, Koshiba H, Ishihara H, Kusuki I, Tsukamoto K, Honjo H: Expression of leptin receptor in human endometrium and fluctuation during the menstrual cycle. J Clin Endocrinol Metab 2000, 85:1946-50.
• [58]Bukowska D, Kempisty B, Jackowska M, Woźna M, Antosik P, Piotrowska H, et al.: Analysis of integrins and vascular endothelial growth factor isoforms mRNA expression in the canine uterus during perimplantation period. Pol J Vet Sci 2011, 14:253-8.
• [59]Reese J, Das SK, Paria BC, Lim H, Song H, Matsumoto H, et al.: Global gene expression analysis to identify molecular markers of uterine receptivity and embryo implantation. J Biol Chem 2001, 276:44137-45.
• [60]Yoon SJ, Cha KY, Lee KA: Leptin receptors are down-regulated in uterine implantation sites compared to interimplantation sites. Mol Cell Endocrinol 2005, 232:27-35.
• [61]Dos Santos E, Serazin V, Morvan C, Torre A, Wainer R, de Mazancourt P, et al.: Adiponectin and leptin systems in human endometrium during window of implantation. Fertil Steril 2012, 97:771-8. e1
• [62]Ashworth CJ, Hoggard N, Thomas L, Mercer JG, Wallace JM, Lea RG: Placental leptin. Rev Reprod 2000, 5:18-24.
• [63]Challier J, Galtier M, Bintein T, Cortez A, Lepercq J, Hauguel-de Mouzon S: Placental leptin receptor isoforms in normal and pathological pregnancies. Placenta 2003, 24:92-9.
• [64]Toth B, Fischl A, Scholz C, Kuhn C, Friese K, Karamouti M, et al.: Insulin and leptin receptors as possible new candidates for endocrine control in normal and disturbed human pregnancy. Mol Hum Reprod 2009, 15:231-9.
• [65]Smolinska N, Siawrys G, Kaminski T, Przala J: Leptin gene and protein expression in the trophoblast and uterine tissues during early pregnancy and the oestrous cycle of pigs. J Physiol Pharmacol 2007, 58:563-81.
• [66]Smolinska N, Kaminski T, Siawrys G, Przala J: Long form of leptin receptor gene and protein expression in the porcine trophoblast and uterine tissues during early pregnancy and the oestrous cycle. Anim Reprod Sci 2009, 113:125-36.
• [67]Dall’Aglio C, Polisca A, Boiti C, Ceccarelli P: Immunolocalization of leptin and its receptor in the placenta of cats. Acta Histochem 2012, 114:719-22.
• [68]Magariños MP, Sánchez-Margalet V, Kotler M, Calvo JC, Varone CL: Leptin promotes cell proliferation and survival of trophoblastic cells. Biol Reprod 2007, 76:203-10.
• [69]Pérez-Pérez A, Maymó J, Gambino Y, Dueñas JL, Goberna R, Varone C, et al.: Leptin stimulates protein synthesis-activating translation machinery in human trophoblastic cells. Biol Reprod 2009, 81:826-32.
• [70]Madej T, Boguski MS, Bryant SH: Threading analysis suggests that the obese gene product may be a helical cytokine. FEBS Lett 1995, 373:13-8.
• [71]Molvarec A, Szarka A, Walentin S, Bekő G, Karádi I, Prohászka Z, et al.: Serum leptin levels in relation to circulating cytokines, chemokines, adhesion molecules and angiogenic factors in normal pregnancy and preeclampsia. Reprod Biol Endocrinol 2011, 9:124. BioMed Central Full Text
• [72]Nuamah MA, Yura S, Sagawa N, Itoh H, Mise H, Korita D, et al.: Significant increase in maternal plasma leptin concentration in induced delivery: a possible contribution of pro-inflammaotry cytokines to placental leptin secretion. Endocr J 2004, 51:177-87.
• [73]Lappas M, Permezel M, Rice GE: Leptin and adiponectin stimulate the release of proinflammatory cytokines and prostaglandins from human placenta and maternal adipose tissue via nuclear factor-kappaB, peroxisomal proliferator-activated receptor-gamma and extracellularly regulated kinase 1/2. Endocrinology 2005, 146:3334-42.
• [74]Frühbeck G: Intracellular signalling pathways activated by leptin. Biochem J 2006, 393:7-20.
• [75]Schulz LC, Widmaier EP: Leptin receptors. In Leptin. Edited by Castracane VD, Henson MC. Springer Science + Business Media LLC, New York; 2006:11-31.