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.

  • Article
  • Published:

Physiology and Biochemistry

Fetal macrosomia in a Hispanic/Latinx predominant cohort and altered expressions of genes related to placental lipid transport and metabolism

International Journal of Obesity volume 44, pages 1743–1752 (2020)Cite this article

Subjects

Abstract

Introduction

Fetal overgrowth, termed fetal macrosomia when birth weight is >4000 g, is the major concern in the treatment of gestational diabetes mellitus (GDM). However, to date, the underlying mechanisms of fetal macrosomia have not been understood completely. Placental lipid metabolism is emerging as a critical player in fetal growth. In this study, we hypothesized that fatty-acid transport and metabolism in the placental tissue is impaired in GDM women, dependent on fetal sex.

Methods

To test this hypothesis, we analyzed the incidence of GDM, fetal macrosomia, and obesity in a large cohort consisting of 17,995 pregnant subjects and majority of subjects being Hispanic/Latinx, and investigated expression of genes related to lipid transport and metabolism in placentas from obese women with or without GDM, and with or without fetal macrosomia.

Results

The main findings include: (1) there was a higher incidence of GDM and obesity in Hispanic subjects compared with non-Hispanic subjects, but not fetal macrosomia; (2) expressions of most of genes related to placental lipid transport and metabolism were not altered by the presence of GDM, fetal macrosomia, or fetal sex; (3) expression of FABP4 was increased in obese women with GDM and fetal macrosomia, and this occurred in male placentas; (4) expression of LPL was decreased in obese women with GDM despite fetal macrosomia, and this occurred in male placentas; (5) expression of ANGPTL3 was decreased in obese women with GDM and fetal macrosomia, but was not altered when fetal sex was included in the analysis.

Conclusions

This study indicates that there is race disparity in GDM with higher incidence of GDM in obese Hispanic women, although fetal macrosomia disparity is not present. Moreover, altered placental lipid transport may contribute to fetal overgrowth in obese women with GDM.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Fig. 1: Quantitative real-time PCR analysis of FABP4 in placental tissues from obese women with or without gestational diabetes mellitus (GDM) and with or without fetal macrosomia.
Fig. 2: Quantitative real-time PCR analysis of LPL in placental tissues from obese women with or without gestational diabetes mellitus (GDM) and with or without fetal macrosomia.
Fig. 3: Quantitative real-time PCR analysis of ANGPTAL3 in placental tissues from obese women with or without gestational diabetes mellitus (GDM) and with or without fetal macrosomia.

Similar content being viewed by others

References

  1. Coustan DR, Lowe LP, Metzger BE. The hyperglycemia and adverse pregnancy outcome (HAPO) study: can we use the results as a basis for change? J Matern Fetal Neonatal Med. 2010;23:204–9.

    Article  PubMed  Google Scholar 

  2. Kjos SL, Buchanan TA. Gestational diabetes mellitus. N Engl J Med. 1999;341:1749–56.

    Article  CAS  PubMed  Google Scholar 

  3. Munda A, Starcic Erjavec M, Molan K, Ambrozic Avgustin J, Zgur-Bertok D, Pongrac Barlovic D. Association between pre-pregnancy body weight and dietary pattern with large-for-gestational-age infants in gestational diabetes. Diabetol Metab Syndr. 2019;11:68.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Blondeau B, Joly B, Perret C, Prince S, Bruneval P, Lelievre-Pegorier M, et al. Exposure in utero to maternal diabetes leads to glucose intolerance and high blood pressure with no major effects on lipid metabolism. Diabetes Metab. 2011;37:245–51.

    Article  CAS  PubMed  Google Scholar 

  5. West NA, Crume TL, Maligie MA, Dabelea D. Cardiovascular risk factors in children exposed to maternal diabetes in utero. Diabetologia. 2011;54:504–7.

    Article  CAS  PubMed  Google Scholar 

  6. Bellamy L, Casas JP, Hingorani AD, Williams D. Type 2 diabetes mellitus after gestational diabetes: a systematic review and meta-analysis. Lancet. 2009;373:1773–9.

    Article  CAS  PubMed  Google Scholar 

  7. Li LJ, Aris IM, Su LL, Chong YS, Wong TY, Tan KH, et al. Effect of gestational diabetes and hypertensive disorders of pregnancy on postpartum cardiometabolic risk. Endocr Connect. 2018;7:433–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Barbour LA, Hernandez TL. Maternal non-glycemic contributors to fetal growth in obesity and gestational diabetes: spotlight on lipids. Curr Diab Rep. 2018;18:37.

    Article  PubMed  CAS  Google Scholar 

  9. Nicholas LM, Morrison JL, Rattanatray L, Zhang S, Ozanne SE, McMillen IC. The early origins of obesity and insulin resistance: timing, programming and mechanisms. Int J Obes. 2016;40:229–38.

    Article  CAS  Google Scholar 

  10. Herrera E, Ortega-Senovilla H. Implications of lipids in neonatal body weight and fat mass in gestational diabetic mothers and non-diabetic controls. Curr Diab Rep. 2018;18:7.

    Article  PubMed  CAS  Google Scholar 

  11. Hill DJ. Placental control of metabolic adaptations in the mother for an optimal pregnancy outcome. What goes wrong in gestational diabetes? Placenta. 2018;69:162–8.

    Article  CAS  PubMed  Google Scholar 

  12. Jayabalan N, Lai A, Ormazabal V, Adam S, Guanzon D, Palma C, et al. Adipose tissue exosomal proteomic profile reveals a role on placenta glucose metabolism in gestational diabetes mellitus. J Clin Endocrinol Metab. 2019;104:1735–52.

    Article  PubMed  Google Scholar 

  13. Jarmuzek P, Wielgos M, Bomba-Opon D. Placental pathologic changes in gestational diabetes mellitus. Neuro Endocrinol Lett. 2015;36:101–5.

    CAS  PubMed  Google Scholar 

  14. Muralimanoharan S, Maloyan A, Myatt L. Mitochondrial function and glucose metabolism in the placenta with gestational diabetes mellitus: role of miR-143. Clin Sci. 2016;130:931–41.

    Article  CAS  Google Scholar 

  15. Barbour LA, Hernandez TL. Maternal lipids and fetal overgrowth: making fat from fat. Clin Ther. 2018;40:1638–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Barrett HL, Dekker Nitert M, McIntyre HD, Callaway LK. Normalizing metabolism in diabetic pregnancy: is it time to target lipids? Diabetes Care. 2014;37:1484–93.

    Article  CAS  PubMed  Google Scholar 

  17. National Center for Health Statistics. Health, United States, 2016: With Chartbook on Long-term Trends in Health. Hyattsville, MD. 2017;11–5.

  18. Hedderson MM, Darbinian JA, Ferrara A. Disparities in the risk of gestational diabetes by race-ethnicity and country of birth. Paediatr Perinat Epidemiol. 2010;24:441–8.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Xiang AH, Li BH, Black MH, Sacks DA, Buchanan TA, Jacobsen SJ, et al. Racial and ethnic disparities in diabetes risk after gestational diabetes mellitus. Diabetologia. 2011;54:3016–21.

    Article  CAS  PubMed  Google Scholar 

  20. Hedderson M, Ehrlich S, Sridhar S, Darbinian J, Moore S, Ferrara A. Racial/ethnic disparities in the prevalence of gestational diabetes mellitus by BMI. Diabetes Care. 2012;35:1492–8.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Jaskolka D, Retnakaran R, Zinman B, Kramer CK. Sex of the baby and risk of gestational diabetes mellitus in the mother: a systematic review and meta-analysis. Diabetologia. 2015;58:2469–75.

    Article  PubMed  Google Scholar 

  22. Retnakaran R, Kramer CK, Ye C, Kew S, Hanley AJ, Connelly PW, et al. Fetal sex and maternal risk of gestational diabetes mellitus: the impact of having a boy. Diabetes Care. 2015;38:844–51.

    Article  CAS  PubMed  Google Scholar 

  23. Hou L, Wang X, Li G, Zou L, Chen Y, Zhang W. Cross sectional study in China: fetal gender has adverse perinatal outcomes in mainland China. BMC Pregnancy Childbirth. 2014;14:372.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Li G, Kong L, Li Z, Zhang L, Fan L, Zou L, et al. Prevalence of macrosomia and its risk factors in china: a multicentre survey based on birth data involving 101,723 singleton term infants. Paediatr Perinat Epidemiol. 2014;28:345–50.

    Article  PubMed  Google Scholar 

  25. Antony KM, Hemarajata P, Chen J, Morris J, Cook C, Masalas D, et al. Generation and validation of a universal perinatal database and biospecimen repository: PeriBank. J Perinatol. 2016;36:921–9.

    Article  CAS  PubMed  Google Scholar 

  26. Wexler DJ, Powe CE, Barbour LA, Buchanan T, Coustan DR, Corcoy R, et al. Research gaps in gestational diabetes mellitus: executive summary of a National Institute of Diabetes and Digestive and Kidney Diseases Workshop. Obstet Gynecol. 2018;132:496–505.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Barbour LA, Scifres C, Valent AM, Friedman JE, Buchanan TA, Coustan D, et al. A cautionary response to SMFM statement: pharmacological treatment of gestational diabetes. Am J Obstet Gynecol. 2018;219:367 e1–7.

    Article  Google Scholar 

  28. Pedersen J. Diabetes and pregnancy; blood sugar of newborn infants during fasting and glucose administration. Nord Med. 1952;47:1049.

    CAS  PubMed  Google Scholar 

  29. Martin JA, Hamilton BE, Osterman MJK. Births in the United States, 2018. NCHS Data Brief. 2019;346:1–8.

  30. Pu J, Zhao B, Wang EJ, Nimbal V, Osmundson S, Kunz L, et al. Racial/Ethnic differences in gestational diabetes prevalence and contribution of common risk factors. Paediatr Perinat Epidemiol. 2015;29:436–43.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Cavicchia PP, Liu J, Adams SA, Steck SE, Hussey JR, Daguise VG, et al. Proportion of gestational diabetes mellitus attributable to overweight and obesity among non-Hispanic black, non-Hispanic white, and Hispanic women in South Carolina. Matern Child Health J. 2014;18:1919–26.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Martin JA, Hamilton BE, Osterman MJ, Driscoll AK, Mathews TJ. Births: final data for 2015. Natl Vital Stat Rep. 2017;66:1.

    PubMed  Google Scholar 

  33. Yuen L, Wong VW. Gestational diabetes mellitus: challenges for different ethnic groups. World J Diabetes. 2015;6:1024–32.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Alur P. Sex differences in nutrition, growth, and metabolism in preterm infants. Front Pediatr. 2019;7:22.

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Steier JA, Ulstein M, Myking OL. Human chorionic gonadotropin and testosterone in normal and preeclamptic pregnancies in relation to fetal sex. Obstet Gynecol. 2002;100:552–6.

    CAS  PubMed  Google Scholar 

  37. Evans L, Myatt L. Sexual dimorphism in the effect of maternal obesity on antioxidant defense mechanisms in the human placenta. Placenta. 2017;51:64–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Wang Y, Bucher M, Myatt L. Use of glucose, glutamine and fatty acids for trophoblast respiration in lean, obese and gestational diabetic women. J Clin Endocrinol Metab. 2019;104:4178–87.

    Article  PubMed Central  Google Scholar 

  39. Myatt L, Maloyan A. Obesity and placental function. Semin Reprod Med. 2016;34:42–9.

    Article  CAS  PubMed  Google Scholar 

  40. Rosenfeld CS. Sex-specific placental responses in fetal development. Endocrinology. 2015;156:3422–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Furuhashi M, Hotamisligil GS. Fatty acid-binding proteins: role in metabolic diseases and potential as drug targets. Nat Rev Drug Discov. 2008;7:489–503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Furuhashi M, Saitoh S, Shimamoto K, Miura T. Fatty acid-binding protein 4 (FABP4): pathophysiological insights and potent clinical biomarker of metabolic and cardiovascular diseases. Clin Med Insights Cardiol. 2014;8(Suppl 3):23–33.

    PubMed  Google Scholar 

  43. Furuhashi M. Fatty acid-binding protein 4 in cardiovascular and metabolic diseases. J Atheroscler Thromb. 2019;26:216–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Yang R, Castriota G, Chen Y, Cleary MA, Ellsworth K, Shin MK, et al. RNAi-mediated germline knockdown of FABP4 increases body weight but does not improve the deranged nutrient metabolism of diet-induced obese mice. Int J Obes. 2011;35:217–25.

    Article  CAS  Google Scholar 

  45. Zhang Y, Zhang HH, Lu JH, Zheng SY, Long T, Li YT, et al. Changes in serum adipocyte fatty acid-binding protein in women with gestational diabetes mellitus and normal pregnant women during mid- and late pregnancy. J Diabetes Investig. 2016;7:797–804.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Patro-Malysza J, Trojnar M, Kimber-Trojnar Z, Mierzynski R, Bartosiewicz J, Oleszczuk J, et al. FABP4 in gestational diabetes-association between mothers and offspring. J Clin Med. 2019;8:285–96.

    Article  CAS  PubMed Central  Google Scholar 

  47. Yang X, Glazebrook P, Ranasinghe GC, Haghiac M, Calabuig-Navarro V, Minium J, et al. Fatty acid transporter expression and regulation is impaired in placental macrovascular endothelial cells in obese women. J Matern Fetal Neonatal Med. 2019;32:971–8.

    Article  CAS  PubMed  Google Scholar 

  48. Yan Y, Peng H, Wang P, Wang H, Dong M. Increased expression of fatty acid binding protein 4 in preeclamptic placenta and its relevance to preeclampsia. Placenta. 2016;39:94–100.

    Article  CAS  PubMed  Google Scholar 

  49. Daskalakis G, Marinopoulos S, Krielesi V, Papapanagiotou A, Papantoniou N, Mesogitis S, et al. Placental pathology in women with gestational diabetes. Acta Obstet Gynecol Scand. 2008;87:403–7.

    Article  PubMed  Google Scholar 

  50. Smith AJ, Sanders MA, Juhlmann BE, Hertzel AV, Bernlohr DA. Mapping of the hormone-sensitive lipase binding site on the adipocyte fatty acid-binding protein (AFABP). Identification of the charge quartet on the AFABP/aP2 helix-turn-helix domain. J Biol Chem. 2008;283:33536–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Shen WJ, Sridhar K, Bernlohr DA, Kraemer FB. Interaction of rat hormone-sensitive lipase with adipocyte lipid-binding protein. Proc Natl Acad Sci U S A. 1999;96:5528–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Dube E, Gravel A, Martin C, Desparois G, Moussa I, Ethier-Chiasson M. et al. Modulation of fatty acid transport and metabolism by maternal obesity in the human full-term placenta. Biol Reprod. 2012;87:14.

    Article  PubMed  CAS  Google Scholar 

  53. Magnusson-Olsson AL, Hamark B, Ericsson A, Wennergren M, Jansson T, Powell TL. Gestational and hormonal regulation of human placental lipoprotein lipase. J Lipid Res. 2006;47:2551–61.

    Article  CAS  PubMed  Google Scholar 

  54. Dube E, Ethier-Chiasson M, Lafond J. Modulation of cholesterol transport by insulin-treated gestational diabetes mellitus in human full-term placenta. Biol Reprod. 2013;88:16.

    Article  PubMed  CAS  Google Scholar 

  55. Heerwagen MJR, Gumina DL, Hernandez TL, Van Pelt RE, Kramer AW, Janssen RC, et al. Placental lipoprotein lipase activity is positively associated with newborn adiposity. Placenta. 2018;64:53–60.

    Article  CAS  PubMed  Google Scholar 

  56. Zhang R. The ANGPTL3-4-8 model, a molecular mechanism for triglyceride trafficking. Open Biol. 2016;6:150272.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Arca M, Minicocci I, Maranghi M. The angiopoietin-like protein 3: a hepatokine with expanding role in metabolism. Curr Opin Lipidol. 2013;24:313–20.

    Article  CAS  PubMed  Google Scholar 

  58. Kolahi KS, Valent AM, Thornburg KL. Real-time microscopic assessment of fatty acid uptake kinetics in the human term placenta. Placenta. 2018;72-73:1–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Conings S, Amant F, Annaert P, Van Calsteren K. Integration and validation of the ex vivo human placenta perfusion model. J Pharmacol Toxicol Methods. 2017;88:25–31.

    Article  CAS  PubMed  Google Scholar 

  60. Bowers K, Laughon SK, Kiely M, Brite J, Chen Z, Zhang C. Gestational diabetes, pre-pregnancy obesity and pregnancy weight gain in relation to excess fetal growth: variations by race/ethnicity. Diabetologia. 2013;56:1263–71.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This research was partially supported by National Institutes of Health grants R03HD095417, U54MD007597, and R01HL102866. The authors thank PeriBank Repository, Baylor College of Medicine for tissue and data collection, storage, and sharing and Ms Jia Chen for clinical data analysis. The authors also thank Drs Fatimah Jackson and Robert Jackson for constructive discussions in manuscript preparation and the Summer Academy Creative Writing Program, Office of Provost, Howard University for administrative and mentoring support.

Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, 100020, China

    Heqin Yang

  2. Reproductive Physiology Laboratory, National Research Institute for Family Planning, Beijing, 100081, China

    Bin He

  3. Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX, 77030, USA

    Chandra Yallampalli

  4. Department of Obstetrics and Gynecology, Howard University College of Medicine, Washington, DC, 20059, USA

    Haijun Gao

Authors
  1. Heqin Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bin He
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chandra Yallampalli
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Haijun Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Haijun Gao.

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.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yang, H., He, B., Yallampalli, C. et al. Fetal macrosomia in a Hispanic/Latinx predominant cohort and altered expressions of genes related to placental lipid transport and metabolism. Int J Obes 44, 1743–1752 (2020). https://doi.org/10.1038/s41366-020-0610-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41366-020-0610-y

This article is cited by

Search

Advanced search

Quick links