Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Maternal and pediatric nutrition

Placental expression of leptin: fetal sex-independent relation with human placental growth

Abstract

Objectives

Leptin (LEP) is a vital placental hormone that is known to affect different aspects of placental function and fetal development. The present study aimed to determine the association of placental LEP transcript abundance with maternal, placental, and newborn parameters.

Subjects/methods

In this retrospective case-control study, placental samples (n = 105) were collected from small (SGA) and appropriate (AGA) for gestational age full-term singleton pregnancies (n = 44 SGA and n = 61 AGA). Placental transcript abundance of LEP was assessed by real-time quantitative PCR after normalization to a reference gene panel. LEP methylation was measured using a quantitative MethyLight assay in a subset of samples (n = 54).

Results

Placental LEP transcript abundance was negatively and significantly associated with placental weight (β = −3.883, P = 0.015). This association continued to be significant in the SGA group (β = −10.332, P = 0.001), both in female (β = −15.423, P = 0.021) and male births (β = −10.029, P = 0.007). LEP transcript abundance was not associated with LEP methylation levels (Spearman’s ρ = 0.148, P = 0.287).

Conclusion

We conclude that placental upregulation of LEP is an integral and fetal sex-independent component of placental growth restriction, which can be potentially targeted through maternal dietary modifications to improve fetoplacental growth.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Scatter plots of correlations between birth weight or placental weight and placental LEP transcript abundance.
Fig. 2: Scatter plots of correlations between birth weight or placental weight and placental LEP transcript abundance within SGA and AGA births categorized by fetal sex.
Fig. 3: Correlation of placental LEP transcript abundance and methylation.

Similar content being viewed by others

References

  1. 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.

    CAS  Google Scholar 

  2. Señarís R, Garcia-Caballero T, Casabiell X, Gallego R, Castro R, Considine RV, et al. Synthesis of leptin in human placenta. Endocrinology. 1997;138:4501–4.

    Google Scholar 

  3. Rubio-Jurado B, Balderas-Peña LMA, García-Luna EE, Zavala-Cerna MG, Riebeling-Navarro C, Reyes PA, et al. Obesity, thrombotic risk, and inflammation in cancer. Adv Clin Chem. 2018;85:71–89.

    CAS  Google Scholar 

  4. Christou H, Serdy S, Mantzoros CS. Leptin in relation to growth and developmental processes in the fetus. Semin Reprod Med. 2002;20:123–9.

    CAS  Google Scholar 

  5. Henson MC, Swan KF, O’Neil JS. Expression of placental leptin and leptin receptor transcripts in early pregnancy and at term. Obstet Gynecol. 1998;92:1020–8.

    CAS  Google Scholar 

  6. Hoogard 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 USA. 1997;94:11073–8.

    Google Scholar 

  7. Bi S, Gavrilova O, Gong DW, Mason MM, Reitman M. Identification of a placental enhancer for the human leptin gene. J Biol Chem. 1997;272:30583–8.

    CAS  Google Scholar 

  8. Pérez-Pérez A, Toro A, Vilariño-García T, Maymó J, Guadix P, Dueñas JL, et al. Leptin action in normal and pathological pregnancies. J Cell Mol Med. 2018;22:716–27.

    Google Scholar 

  9. Bajoria R, Sooranna SR, Ward BSCR. Prospective function of placental leptin at maternal–fetal interface. Placenta. 2002;23:103–15.

    CAS  Google Scholar 

  10. Michael C, Henson VDC. Leptin in pregnancy: an update. Biol Reprod. 2006;74:218–29.

    Google Scholar 

  11. Lin KC. Increase of maternal plasma leptin concentrations during pregnancy: comparison with nonpregnant women. Kaohsiung J Med Sci. 1999;15:640–5.

    CAS  Google Scholar 

  12. Gambino YP, Pérez Pérez A, Dueñas JL, Calvo JC, Sánchez-Margalet V, Varone CL. Regulation of leptin expression by 17beta-estradiol in human placental cells involves membrane associated estrogen receptor alpha. Biochim Biophys Acta. 2012;1823:900–10.

    CAS  Google Scholar 

  13. Hauguel-de Mouzon S, Lepercq J. Placental leptin and pregnancy pathologies. Gynecol Obstet Fertil. 2001;29:534–7.

    CAS  Google Scholar 

  14. WHO. Physical status: the use of and interpretation of anthropometry. Report of a WHO Expert Committee, World Health Organization technical report series No. 854. World Health Organization, Geneva, Switzerland; 1995 p. 1–452.

  15. Mukhopadhyay A, Ravikumar G, Dwarkanath P, Meraaj H, Thomas A, Crasta J, et al. Placental expression of the insulin receptor binding protein GRB10: Relation to human fetoplacental growth and fetal gender. Placenta.2015;36:1225–30.

    CAS  Google Scholar 

  16. Mukhopadhyay A, Ravikumar G, Meraaj H, Dwarkanath P, Thomas A, Crasta J, et al. Placental expression of DNA methyltransferase 1 (DNMT1): gender-specific relation with human placental growth. Placenta. 2016;48:119–25.

    CAS  Google Scholar 

  17. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2-ΔΔCT method. Methods. 2001;25:402–8.

    CAS  Google Scholar 

  18. Hou L, Zhu ZZ, Zhang X, Nordio F, Bonzini M, Schwartz J, et al. Airborne particulate matter and mitochondrial damage: a cross-sectional study. Environ Health. 2010;9:48.

    Google Scholar 

  19. Aggerholm A, Guldberg P, Hokland M, Hokland P. Extensive intra- and interindividual heterogeneity of p15 INK4B methylation in acute myeloid leukemia. Cancer Res. 1999;59:436–41.

    CAS  Google Scholar 

  20. Weisenberger DJ, Campan M, Long TI, Kim M, Woods C, Fiala E, et al. Analysis of repetitive element DNA methylation by MethyLight. Nucleic Acids Res. 2005;33:6823–36.

    CAS  Google Scholar 

  21. Hoque MO, Rosenbaum E, Westra WH, Xing M, Ladenson P, Zeiger MA, et al. Quantitative assessment of promoter methylation profiles in thyroid neoplasms. J Clin Endocrinol Metab. 2005;90:4011–8.

    CAS  Google Scholar 

  22. Lea RG, Howe D, Hannah LT, Bonneau O, Hunter L, Hoggard N. Placental leptin in normal, diabetic and fetal growth-retarded pregnancies. Mol Hum Reprod. 2000;6:763–9.

    CAS  Google Scholar 

  23. Linnemann K, Malek A, Sager R, Blum WF, Schneider H, Fusch C. Leptin production and release in the dually in vitro perfused human placenta. J Clin Endocrinol Metab. 2000;85:4298–301.

    CAS  Google Scholar 

  24. Struwe E, Berzl GM, Schild RL, Dötsch J. Gene expression of placental hormones regulating energy balance in small for gestational age neonates. Eur J Obstet Gynecol Reprod Biol. 2009;142:38–42.

    CAS  Google Scholar 

  25. Lazo-De-La-Vega-Monroy ML, González-Domínguez MI, Zaina S, Sabanero M, Daza-Benítez L, Malacara JM, et al. Leptin and its receptors in human placenta of small, adequate, and large for gestational age newborns. Horm Metab Res. 2017;49:350–8.

    CAS  Google Scholar 

  26. Sõber S, Reiman M, Kikas T, Rull K, Inno R, Vaas P, et al. Extensive shift in placental transcriptome profile in preeclampsia and placental origin of adverse pregnancy outcomes. Sci Rep. 2015;5:13336.

    Google Scholar 

  27. Mukhopadhyay A, Thomas T, Bosch RJ, Dwarkanath P, Thomas A, Duggan CP, et al. Fetal sex modifies the effect of maternal macronutrient intake on the incidence of small-for-gestational-age births: a prospective observational cohort study. Am J Clin Nutr. 2018;108:814–20.

    CAS  Google Scholar 

  28. Mani I, Dwarkanath P, Thomas T, Thomas A, Kurpad AV. Maternal fat and fatty acid intake and birth outcomes in a South Indian population. Int J Epidemiol. 2016;45:523–31.

    Google Scholar 

  29. Muthayya S, Dwarkanath P, Thomas T, Vaz M, Mhaskar A, Mhaskar R, et al. Anthropometry and body composition of south Indian babies at birth. Public Health Nutr. 2006;9:896–903.

    CAS  Google Scholar 

  30. Bouloumié A, Drexler HCA, Lafontan M, Busse R. Leptin, the product of Ob gene, promotes angiogenesis. Circ Res. 1998;83:1059–66.

    Google Scholar 

  31. Park HY, Kwon HM, Lim HJ, Hong BK, Lee JY, Park BE, et al. Potential role of leptin in angiogenesis: leptin induces endothelial cell proliferation and expression of matrix metalloproteinases in vivo and in vitro. Exp Mol Med. 2001;33:95–102.

    CAS  Google Scholar 

  32. Sierra-Honigmann MR, Nath AK, Murakami C, García-Cardeña G, Papapetropoulos A, Sessa WC, et al. Biological action of leptin as an angiogenic factor. Science. 1998;281:1683–6.

    CAS  Google Scholar 

  33. 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 USA. 2001;98:6390–5.

    CAS  Google Scholar 

  34. McCarthy C, Cotter FE, McElwaine S, Twomey A, Mooney EE, Ryan F, et al. Altered gene expression patterns in intrauterine growth restriction: potential role of hypoxia. Am J Obstet Gynecol. 2007;196:70.e1–6.

    Google Scholar 

  35. Szentpéteri I, Rab A, Kornya L, Kovács P, Joó JG. Gene expression patterns of vascular endothelial growth factor (VEGF-A) in human placenta from pregnancies with intrauterine growth restriction. J Matern Neonatal Med. 2013;26:984–9.

    Google Scholar 

  36. Sood R, Zehnder JL, Druzin ML, Brown PO. Gene expression patterns in human placenta. Proc Natl Acad Sci USA. 2006;103:5478–83.

    CAS  Google Scholar 

  37. Brown ZA, Schalekamp-Timmermans S, Tiemeier HW, Hofman A, Jaddoe VWV, Steegers EAP. Fetal sex specific differences in human placentation: a prospective cohort study. Placenta. 2014;35:359–64.

    CAS  Google Scholar 

  38. Mouzaki A, Panagoulias I, Raptis G, Farri-Kostopoulou E. Cord blood leptin levels of healthy neonates are associated with IFN-γ production by cord blood T-cells. PLoS ONE. 2012;7:e40830.

    Google Scholar 

  39. Tung WK, Lin SJ, Hwang YS, Wu CM, Wang YH, Tsai WH. Association of cord plasma leptin with birth size in term newborns. Pediatr Neonatol. 2009;50:255–60.

    Google Scholar 

  40. Friis CM, Qvigstad E, Paasche Roland MC, Godang K, Voldner N, Bollerslev J, et al. Newborn body fat: associations with maternal metabolic state and placental size. PLoS One. 2013;8:e57467.

    CAS  Google Scholar 

  41. Melzner I, Scott V, Dorsch K, Fischer P, Wabitsch M, Brüderlein S, et al. Leptin gene expression in human preadipocytes is switched on by maturation-induced demethylation of distinct CpGs in its proximal promoter. J Biol Chem. 2002;277:45420–7.

    CAS  Google Scholar 

  42. Bouchard L, Thibault S, Guay S-P, Santure M, Monpetit A, St-Pierre J, et al. Leptin gene epigenetic adaptation to impaired glucose metabolism during pregnancy. Diabetes Care. 2010;33:2436–41.

    CAS  Google Scholar 

  43. Lesseur C, Armstrong DA, Paquette AG, Koestler DC, Padbury JF, Marsit CJ. Tissue-specific leptin promoter DNA methylation is associated with maternal and infant perinatal factors. Mol Cell Endocrinol. 2013;381:160–7.

    CAS  Google Scholar 

  44. Bekkering I, Leeuwerke M, Tanis JC, Schoots MH, Verkaik-Schakel RN, Plösch T, et al. Differential placental DNA methylation of VEGFA and LEP in small-for-gestational age fetuses with an abnormal cerebroplacental ratio. PLoS One. 2019;14:e0221972.

  45. Nogues P, Dos Santos E, Jammes H, Berveiller P, Arnould L, Vialard F, et al. Maternal obesity influences expression and DNA methylation of the adiponectin and leptin systems in human third-trimester placenta. Clin Epigenetics. 2019;11:20.

    Google Scholar 

  46. Lönnqvist F, Nordfors L, Jansson M, Thörne A, Schalling M, Arner P. Leptin secretion from adipose tissue in women: relationship to plasma levels and gene expression. J Clin Investig. 1997;99:2398–404.

    Google Scholar 

  47. Ranganathan S, Maffei M, Kern PA. Adipose tissue ob mRNA expression in humans: discordance with plasma leptin and relationship with adipose TNFα expression. J Lipid Res. 1998;39:724–30.

    CAS  Google Scholar 

  48. Nordfors L, Lönnqvist F, Heimbürger O, Danielsson A, Schalling M, Stenvinkel P. Low leptin gene expression and hyperleptinemia in chronic renal failure. Kidney Int. 1998;54:1267–75.

    CAS  Google Scholar 

  49. Schrey S, Kingdom J, Baczyk D, Fitzgerald B, Keating S, Ryan G, et al. Leptin is differentially expressed and epigenetically regulated across monochorionic twin placenta with discordant fetal growth. Mol Hum Reprod. 2013;19:764–72.

    CAS  Google Scholar 

  50. Mantzoros CS, Rifas-Shiman SL, Williams CJ, Fargnoli JL, Kelesidis T, Gillman MW. Cord blood leptin and adiponectin as predictors of adiposity in children at 3 years of age: a prospective cohort study. Pediatrics. 2009;123:682–9.

    Google Scholar 

Download references

Acknowledgements

We thank the pregnant women who participated in the study and doctors and nurses who made this study possible. The contribution of the research assistants Ms Nancy N, Ms Roopashree C, Ms Aruna BS, and Ms Arogya M who collected the samples and data is acknowledged. Histopath technician Ms Mahalakshmi S assisted the pathologists in placental grossing experiments. Research assistant Ms Hyfa Meeraj helped with the methylation experiments. We gratefully acknowledge the guiding role of Prof. TS Sridhar in initial establishment of human placental tissue related protocols. We thank Prof. Peter W. Laird for sharing leptin MethyLight primers and probe, which was used in this study.

Funding

This work was supported by the Department of Biotechnology, Government of India (Grant Sanction order 102/IFD/SAN/749/2014-2015 to AM, AVK, and PD).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to A. Mukhopadhyay.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kochhar, P., Manikandan, C., Ravikumar, G. et al. Placental expression of leptin: fetal sex-independent relation with human placental growth. Eur J Clin Nutr 74, 1603–1612 (2020). https://doi.org/10.1038/s41430-020-0649-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41430-020-0649-9

Search

Quick links