Skip to main content
SpringerLink
Log in

Activation of AMPK in Human Placental Explants Impairs Mitochondrial Function and Cellular Metabolism

  • Original Article
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

Objective

Adenosine monophosphate—activated protein kinase (AMPK) is a cellular energy sensor whose phosphorylation increases energy production. We sought to evaluate the placenta-specific effect of AMPK activation on the handling of nutrients required for fetal development.

Methods

Explants were isolated from term placenta of 29 women (pregravid body mass index: 29.1 ± 9.9 kg/m2) and incubated for 24 hours with 0 to 100 µmol/L resveratrol or 0 to 1 mmol/L of 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR). Following treatment, uptake and metabolism of radiolabeled fatty acids and glucose were measured. Phosphorylation of AMPK was measured by Western blotting. Adenosine diphosphate (ATP) production was assessed using the mitochondrial ToxGlo assay kit. P <.05 was considered statistically significant.

Results

Resveratrol and AICAR increased AMPK phosphorylation in human placental explants. Exposure to resveratrol decreased the uptake of polyunsaturated fatty acids, arachidonic acid, and docosahexaenoic acid at 100 µmol/L (P <.0001). Fatty acid oxidation was decreased by 100 µmol/L (P <.05) resveratrol, while esterification was unchanged. Resveratrol decreased glucose uptake at the 50 and 100 µmol/L doses (P <.05). Glycolysis was not significantly affected. AICAR had similar effects, decreasing fatty acid uptake and glycolysis (P <.05). Production of ATP declined at doses found to decrease nutrient metabolism (P <.05).

Conclusions

Activation of AMPK in the human placenta leads to global downregulation of metabolism, with mitotoxicity induced at the doses of resveratrol and AICAR used to activate AMPK. Although activation of this pathway has positive metabolic effects on other tissues, in the placenta there is potential for harm, as inadequate placental delivery of critical nutrients may compromise fetal development.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Calabuig-Navarro V, Haghiac M, Minium J, et al. Effect of maternal obesity on placental lipid metabolism. Endocrinology. 2017;158(8):2543–2555.

    Article  CAS  Google Scholar 

  2. Visiedo F, Bugatto F, Quintero-Prado R, Cozar-Castellano I, Bartha JL, Perdomo G. Glucose and fatty acid metabolism in placental explants from pregnancies complicated with gestational diabetes mellitus. Reprod Sci. 2015;22(7):798–801.

    Article  CAS  Google Scholar 

  3. Perazzolo S, Hirschmugl B, Wadsack C, Desoye G, Lewis RM, Sengers BG. The influence of placental metabolism on fatty acid transfer to the fetus. J Lipid Res. 2017;58(2):443–454.

    Article  CAS  Google Scholar 

  4. Jimenez-Gomez Y, Mattison JA, Pearson KJ, et al. Resveratrol improves adipose insulin signaling and reduces the inflammatory response in adipose tissue of rhesus monkeys on high-fat, high-sugar diet. Cell Metab. 2013;18(4):533–545.

    Article  CAS  Google Scholar 

  5. Um JH, Park SJ, Kang H, et al. AMP-activated protein kinase—deficient mice are resistant to the metabolic effects of resveratrol. Diabetes. 2010;59(3):554–563.

    Article  CAS  Google Scholar 

  6. Saben J, Lindsey F, Zhong Y, et al. Maternal obesity is associated with a lipotoxic placental environment. Placenta. 2014;35(3):171–177.

    Article  CAS  Google Scholar 

  7. Chen KH, Cheng ML, Jing YH, Chiu DT, Shiao MS, Chen JK. Resveratrol ameliorates metabolic disorders and muscle wasting in streptozotocin-induced diabetic rats. Am J Physiol Endocrinol Metab. 2011;301(5):E853–E863.

    Article  CAS  Google Scholar 

  8. Zhang BB, Zhou G, Li C. AMPK: an emerging drug target for diabetes and the metabolic syndrome. Cell Metab. 2009;9(5):407–416.

    Article  Google Scholar 

  9. Kulkarni SS, Canto C. The molecular targets of resveratrol. Biochim Biophys Acta. 2015;1852(6):1114–1123.

    Article  CAS  Google Scholar 

  10. Dasgupta B, Milbrandt J. Resveratrol stimulates AMP kinase activity in neurons. Proc Natl Acad Sci U S A. 2007;104(17):7217–7222.

    Article  CAS  Google Scholar 

  11. de Ligt M, Timmers S, Schrauwen P. Resveratrol and obesity: can resveratrol relieve metabolic disturbances? Biochim Biophys Acta. 2015;1852(6):1137–1144.

    Article  Google Scholar 

  12. Dolinsky VW, Chakrabarti S, Pereira TJ, et al. Resveratrol prevents hypertension and cardiac hypertrophy in hypertensive rats and mice. Biochim Biophys Acta. 2013;1832(10):1723–1733.

    Article  CAS  Google Scholar 

  13. Price NL, Gomes AP, Ling AJY, et al. SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Cell Metab. 2012;15(5):675–690.

    Article  CAS  Google Scholar 

  14. Rivera L, Moron R, Zarzuelo A, Galisteo M. Long-term resveratrol administration reduces metabolic disturbances and lowers blood pressure in obese Zucker rats. Biochem Pharmacol. 2009;77(6):1053–1063.

    Article  CAS  Google Scholar 

  15. Timmers S, Konings E, Bilet L, et al. Calorie restriction-like effects of 30 days of resveratrol (resVida™) supplementation on energy metabolism and metabolic profile in obese humans. Cell Metab. 2011;14(5): doi:https://doi.org/10.1016/j.cmet.2011.1010.1002.

  16. Roberts VH, Pound LD, Thorn SR, et al. Beneficial and cautionary outcomes of resveratrol supplementation in pregnant nonhuman primates. FASEB J. 2014;28(6):2466–2477.

    Article  CAS  Google Scholar 

  17. O’Tierney-Ginn P, Roberts V, Gillingham M, et al. Influence of high fat diet and resveratrol supplementation on placental fatty acid uptake in the Japanese macaque. Placenta. 2015;36(8):903–910.

    Article  Google Scholar 

  18. Bourque SL, Dolinsky VW, Dyck JR, Davidge ST. Maternal resveratrol treatment during pregnancy improves adverse fetal outcomes in a rat model of severe hypoxia. Placenta. 2012;33(5):449–452.

    Article  CAS  Google Scholar 

  19. Singh CK, Ndiaye MA, Ahmad N. Resveratrol and cancer: challenges for clinical translation. Biochim Biophys Acta. 2015;1852(6):1178–1185.

    Article  CAS  Google Scholar 

  20. Mullane K, Bullough D, Shapiro D. From academic vision to clinical reality: a case study of acadesine. Trends Cardiovasc Med. 1993;3(6):227–234.

    Article  CAS  Google Scholar 

  21. Liong S, Lappas M. Activation of AMPK improves inflammation and insulin resistance in adipose tissue and skeletal muscle from pregnant women. J Physiol Biochem. 2015;71(4):703–717.

    Article  CAS  Google Scholar 

  22. Lim R, Barker G, Lappas M. Activation of AMPK in human fetal membranes alleviates infection-induced expression of pro-inflammatory and pro-labour mediators. Placenta. 2015;36(4):454–462.

    Article  CAS  Google Scholar 

  23. Brass E, Hanson E, O’Tierney-Ginn PF. Placental oleic acid uptake is lower in male offspring of obese women. Placenta. 2013;34(6):503–509.

    Article  CAS  Google Scholar 

  24. Calabuig-Navarro V, Puchowicz M, Glazebrook P, et al. Effect of omega-3 supplementation on placental lipid metabolism in overweight and obese women. Am J Clin Nutr. 2016;103(4):1064–1072.

    Article  CAS  Google Scholar 

  25. Visiedo F, Bugatto F, Sanchez V, Cozar-Castellano I, Bartha JL, Perdomo G. High glucose levels reduce fatty acid oxidation and increase triglyceride accumulation in human placenta. Am J Physiol Endocrinol Metab. 2013;305(2):E205–E212.

    Article  CAS  Google Scholar 

  26. Poulsen MM, Vestergaard PF, Clasen BF, et al. High-dose resveratrol supplementation in obese men. An investigator-initiated, randomized, placebo-controlled clinical trial of substrate metabolism, insulin sensitivity, and body composition. Diabetes. 2013;62(4):1186–1195.

    Article  CAS  Google Scholar 

  27. Park EJ, Pezzuto JM. The pharmacology of resveratrol in animals and humans. Biochim Biophys Acta. 2015;1852(6):1071–1113.

    Article  CAS  Google Scholar 

  28. Gaidhu MP, Fediuc S, Ceddia RB. 5-Aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside-induced AMP-activated protein kinase phosphorylation inhibits basal and insulin-stimulated glucose uptake, lipid synthesis, and fatty acid oxidation in isolated rat adipocytes. J Biol Chem. 2006;281(36):25956–25964.

    Article  CAS  Google Scholar 

  29. Edwards JA, Beck M, Riegger C, Bausch J. Safety of resveratrol with examples for high purity, trans-resveratrol, resVida™. Anna N Y Acad Sci. 2011;1215(1):131–137.

    Article  CAS  Google Scholar 

  30. Patel KR, Brown VA, Jones DJ, et al. Clinical pharmacology of resveratrol and its metabolites in colorectal cancer patients. Cancer Res. 2010;70(19):7392–7399.

    Article  CAS  Google Scholar 

  31. Poulsen MM, Fjeldborg K, Ornstrup MJ, Kjær TN, Nøhr MK, Pedersen SB. Resveratrol and inflammation: challenges in translating pre-clinical findings to improved patient outcomes. Biochim Biophys Acta. 2015;1852(6):1124–1136.

    Article  CAS  Google Scholar 

  32. Bastianetto S, Ménard C, Quirion R. Neuroprotective action of resveratrol. Biochim Biophys Acta. 2015;1852(6):1195–1201.

    Article  CAS  Google Scholar 

  33. Pasinetti GM, Wang J, Ho L, Zhao W, Dubner L. Roles of resveratrol and other grape-derived polyphenols in Alzheimer’s disease prevention and treatment. Biochim Biophys Acta. 2015;1852(6):1202–1208.

    Article  CAS  Google Scholar 

  34. Zordoky BN, Robertson IM, Dyck JR. Preclinical and clinical evidence for the role of resveratrol in the treatment of cardiovascular diseases. Biochim Biophys Acta. 2015;1852(6):1155–1177.

    Article  CAS  Google Scholar 

  35. Wang B, Sun J, Li L, Zheng J, Shi Y, Le G. Regulatory effects of resveratrol on glucose metabolism and T-lymphocyte subsets in the development of high-fat diet-induced obesity in C57BL/6 mice. Food Funct. 2014;5(7):1452–1463.

    Article  CAS  Google Scholar 

  36. Cudmore MJ, Ramma W, Cai M, et al. Resveratrol inhibits the release of soluble fms-like tyrosine kinase (sFlt-1) from human placenta. Am J Obstet Gynecol. 2012;206(3):253 e210–253 e255.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Center for Reproductive Health, MetroHealth Medical Center, Cleveland, OH, USA

    Daphne Landau MD, Maricela Haghiac PhD, Judi Minium BSc, Yelenna Skomorovska-Prokvolit PhD & Perrie O’Tierney-Ginn PhD

  2. Department of Reproductive Biology, Case Western Reserve University, Cleveland, OH, USA

    Daphne Landau MD, Virtu Calabuig-Navarro PhD & Perrie O’Tierney-Ginn PhD

Authors
  1. Daphne Landau MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maricela Haghiac PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Judi Minium BSc
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yelenna Skomorovska-Prokvolit PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Virtu Calabuig-Navarro PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Perrie O’Tierney-Ginn PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Perrie O’Tierney-Ginn PhD.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Landau, D., Haghiac, M., Minium, J. et al. Activation of AMPK in Human Placental Explants Impairs Mitochondrial Function and Cellular Metabolism. Reprod. Sci. 26, 487–495 (2019). https://doi.org/10.1177/1933719118776803

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1177/1933719118776803

Keywords

Search

Navigation