Molecular Medicine

, Volume 20, Issue 1, pp 332–340 | Cite as

Maternal Magnesium Deficiency in Mice Leads to Maternal Metabolic Dysfunction and Altered Lipid Metabolism with Fetal Growth Restriction

  • Madhu Gupta
  • Malvika H. Solanki
  • Prodyot K. Chatterjee
  • Xiangying Xue
  • Amanda Roman
  • Neeraj Desai
  • Burton Rochelson
  • Christine N. Metz
Research Article


Inadequate magnesium (Mg) intake is a widespread problem, with over 50% of women of reproductive age consuming less than the Recommended Dietary Allowance (RDA). Because pregnancy increases the requirement for Mg and the beneficial effects of magnesium sulfate for preeclampsia/eclampsia and fetal neuroprotection are well described, we examined the outcomes of Mg deficiency during pregnancy. Briefly, pregnant Swiss Webster mice were fed either control or Mg-deficient diets starting on gestational day (GD) 6 through euthanasia on GD17. Mg-deficient dams had significantly reduced weight gain and higher plasma adipokines, in the absence of inflammation. Livers of Mg-deficient dams had significantly higher saturated fatty acids (SFAs) and monounsaturated fatty acids (MUFAs) and lower polyunsaturated fatty acids (PUFAs), including docosahexaenoic acid (DHA) (P < 0.0001) and arachidonic acid (AA) (P < 0.0001). Mechanistically, Mg deficiency was accompanied by enhanced desaturase and elongase mRNA expression in maternal livers along with higher circulating insulin and glucose concentrations (P < 0.05) and increased mRNA expression of Srebf1 and Chrebp, regulators of fatty acid synthesis (P < 0.05). Fetal pups exposed to Mg deficiency were growth-restricted and exhibited reduced survival. Mg-deficient fetal livers showed lower MUFAs and higher PUFAs, with lower desaturase and elongase mRNA expression than controls. In addition, DHA concentrations were lower in Mg-deficient fetal brains (P < 0.05). These results indicate that Mg deficiency during pregnancy influences both maternal and fetal fatty acid metabolism, fetal growth and fetal survival, and support better understanding maternal Mg status before and during pregnancy.



We acknowledge Carla Harris at the Lipid Core Laboratory of Vanderbilt University’s Mouse Metabolic Phenotyping Center (grant DK59637) who extracted and quantified the liver and brain lipids. We thank Nina Kohn, MBA, MA, of the Biostatistics Unit of the Feinstein Institute for assistance with statistical analyses. This work was supported by The Feinstein Institute and the Oxenhorn Family Foundation.

Supplementary material

10020_2014_2001332_MOESM1_ESM.pdf (236 kb)
Supplementary material, approximately 235 KB.


  1. 1.
    Rosanoff A, Weaver CM, Rude RK. (2012) Suboptimal magnesium status in the United States: Are the health consequences underestimated? Nutr. Rev. 70:153–64.CrossRefPubMedGoogle Scholar
  2. 2.
    Ford ES, Mokdad AH. (2003) Dietary magnesium intake in a national sample of US adults. J. Nutr. 133:2879–82.CrossRefPubMedGoogle Scholar
  3. 3.
    Nadler JL, Rude RK. (1995) Disorders of magnesium metabolism. Endocrinol. Metab. Clin. North Am. 24:623–41.CrossRefPubMedGoogle Scholar
  4. 4.
    Swaminathan R. (2003) Magnesium metabolism and its disorders. Clin. Biochem. Rev. 24:47–66.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Burdge GC, Hunt AN, Postle AD. (1994) Mechanisms of hepatic phosphatidylcholine synthesis in adult rat: effects of pregnancy. Biochem. J. 303:941–7.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Larque E, et al. (2011) Placental transfer of fatty acids and fetal implications. Am. J. Clin. Nutr. 94:1908S–13S.CrossRefPubMedGoogle Scholar
  7. 7.
    Coti BP, O’Kusky JR, Innis SM. (2006) Maternal dietary (n-3) fatty acid deficiency alters neurogenesis in the embryonic rat brain. J. Nutr. 136:1570–5.CrossRefGoogle Scholar
  8. 8.
    Innis SM. (2003) Perinatal biochemistry and physiology of long-chain polyunsaturated fatty acids. J. Pediatr. 143:S1–8.CrossRefPubMedGoogle Scholar
  9. 9.
    Fung TT, et al. (2003) The association between magnesium intake and fasting insulin concentration in healthy middle-aged women. J. Am. Coll. Nutr. 22:533–8.CrossRefPubMedGoogle Scholar
  10. 10.
    Nadler JL, et al. (1993) Magnesium deficiency produces insulin resistance and increased thromboxane synthesis. Hypertension. 21:1024–9.CrossRefPubMedGoogle Scholar
  11. 11.
    Weglicki WB. (2012) Hypomagnesemia and inflammation: clinical and basic aspects. Annu. Rev. Nutr. 32:55–71.CrossRefPubMedGoogle Scholar
  12. 12.
    Ford ES, Li C, McGuire LC, Mokdad AH, Liu S. (2007) Intake of dietary magnesium and the prevalence of the metabolic syndrome among U.S. adults. Obesity (Silver Spring). 15:1139–46.CrossRefGoogle Scholar
  13. 13.
    Committee for the Update of the Guide for the Care and Use of Laboratory Animals, Institute for Laboratory Animal Research, Division on Earth and Life Studies, National Research Council of the National Academies. (2011) Guide for the Care and Use of Laboratory Animals. 8th edition. Washington (DC): National Academies Press.Google Scholar
  14. 14.
    Subcommittee on Laboratory Nutrition. (1995) Nutrient requirements of the mouse. In: Nutrient Requirements of Laboratory Animals. National Research Council, ed. Washington, DC: National Academy Press, p. 89.Google Scholar
  15. 15.
    Rude RK, et al. (2004) Bone loss induced by dietary magnesium reduction to 10% of the nutrient requirement in rats is associated with increased release of substance P and tumor necrosis factor-alpha. J. Nutr. 134:79–85.CrossRefPubMedGoogle Scholar
  16. 16.
    Roman A, et al. (2013) Maternal magnesium supplementation reduces intrauterine growth restriction and suppresses inflammation in a rat model. Am. J. Obstet. Gynecol. 208:383–7.PubMedGoogle Scholar
  17. 17.
    Folch J, Lees M, Sloane Stanley GH. (1957) A simple method for the isolation and purification of total lipides from animal tissues. J. Biol. Chem. 226:497–509.PubMedGoogle Scholar
  18. 18.
    Morrison WR, Smith LM. (1964) Preparation of fatty acid methyl esters and dimethylacetals from lipids with boron fluoride-methanol. J. Lipid Res. 5:600–8.PubMedGoogle Scholar
  19. 19.
    Dowling O, et al. (2012) Magnesium sulfate reduces bacterial LPS-induced inflammation at the maternal-fetal interface. Placenta. 33:392–8.CrossRefPubMedGoogle Scholar
  20. 20.
    Cikos S, Bukovska A, Koppel J. (2007) Relative quantification of mRNA: comparison of methods currently used for real-time PCR data analysis. BMC Mol. Biol. 8:113.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Green CD, Ozguden-Akkoc CG, Wang Y, Jump DB, Olson LK. (2010) Role of fatty acid elongases in determination of de novo synthesized monounsaturated fatty acid species. J. Lipid Res. 51:1871–7.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Alves SC, et al. (2013) Hypomagnesemia as a risk factor for the non-recovery of the renal function in critically ill patients with acute kidney injury. Nephrol. Dial. Transplant. 28:910–6.CrossRefPubMedGoogle Scholar
  23. 23.
    Noronha JL, Matuschak GM. (2002) Magnesium in critical illness: metabolism, assessment, and treatment. Intensive Care Med. 28:667–79.CrossRefPubMedGoogle Scholar
  24. 24.
    Standley CA, Whitty JE, Mason BA, Cotton DB. (1997) Serum ionized magnesium levels in normal and preeclamptic gestation. Obstet. Gynecol. 89:24–7.CrossRefPubMedGoogle Scholar
  25. 25.
    Lukacsi L, Lintner F, Zsolnai B, Somogyi J. (1991) Magnesium transport in human pregnancy (magnesium content of human gestation tissues and tissue fluids). Acta Chir. Hung. 32:263–8.PubMedGoogle Scholar
  26. 26.
    Arnaud MJ. (2008) Update on the assessment of magnesium status. Br. J. Nutr. 99 Suppl 3:S24–36.PubMedGoogle Scholar
  27. 27.
    Song Y, Li TY, van Dam RM, Manson JE, Hu FB. (2007) Magnesium intake and plasma concentrations of markers of systemic inflammation and endothelial dysfunction in women. Am. J. Clin. Nutr. 85:1068–74.CrossRefPubMedGoogle Scholar
  28. 28.
    Nishio A, Miyazaki A, Ishiguro S, Miyao N. (1986) Sex difference of pinnal hyperemia in magnesium-deficient rats: effects of castration and administration of sex hormone. Jpn. J. Pharmacol. 41:15–22.CrossRefPubMedGoogle Scholar
  29. 29.
    Du F, Higginbotham DA, White BD. (2000) Food intake, energy balance and serum leptin concentrations in rats fed low-protein diets. J. Nutr. 130:514–21.CrossRefPubMedGoogle Scholar
  30. 30.
    Seeber RM, Smith JT, Waddell BJ. (2002) Plasma leptin-binding activity and hypothalamic leptin receptor expression during pregnancy and lactation in the rat. Biol. Reprod. 66:1762–7.CrossRefPubMedGoogle Scholar
  31. 31.
    Baban RS, Ali NM, Al-Moayed HA. (2010) Serum leptin and insulin hormone level in recurrent pregnancy loss. Oman Med. J. 25:203–7.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Rosario FJ, et al. (2012) Chronic maternal infusion of full-length adiponectin in pregnant mice down-regulates placental amino acid transporter activity and expression and decreases fetal growth. J. Physiol. 590:1495–509.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Kadowaki T, Yamauchi T. (2005) Adiponectin and adiponectin receptors. Endocr. Rev. 26:439–51.CrossRefPubMedGoogle Scholar
  34. 34.
    Peleg D, Kennedy CM, Hunter SK. (1998) Intrauterine growth restriction: identification and management. Am. Fam. Physician. 58:453–7.PubMedGoogle Scholar
  35. 35.
    Takaya J, Yamato F, Higashino H, Kobayashi Y. (2004) Relationship of intracellular magnesium of cord blood platelets to birth weight. Metabolism. 53:1544–7.CrossRefPubMedGoogle Scholar
  36. 36.
    Huerta MG, et al. (2005) Magnesium deficiency is associated with insulin resistance in obese children. Diabetes Care. 28:1175–81.CrossRefPubMedGoogle Scholar
  37. 37.
    Stefikova K, Spustova V, Sebekova K, Dzurik R. (1992) Magnesium deficiency impairs rat soleus muscle glucose utilization and insulin sensitivity. Mater. Med. Pol. 24:215–6.PubMedGoogle Scholar
  38. 38.
    Takaya J, Higashino H, Kobayashi Y. (2004) Intra-cellular magnesium and insulin resistance. Magnes. Res. 17:126–36.PubMedGoogle Scholar
  39. 39.
    Paton CM, Ntambi JM. (2009) Biochemical and physiological function of stearoyl-CoA desaturase. Am. J. Physiol. Endocrinol. Metab. 297:E28–37.CrossRefPubMedGoogle Scholar
  40. 40.
    Xu X, So JS, Park JG, Lee AH. (2013) Transcriptional control of hepatic lipid metabolism by SREBP and ChREBP. Semin. Liver Dis. 33:301–11.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Raghow R, Yellaturu C, Deng X, Park EA, Elam MB. (2008) SREBPs: the crossroads of physiological and pathological lipid homeostasis. Trends Endocrinol. Metab. 19:65–73.CrossRefPubMedGoogle Scholar
  42. 42.
    Iizuka K, Horikawa Y. (2008) ChREBP: A glucose-activated transcription factor involved in the development of metabolic syndrome. Endocr. J. 55:617–24.CrossRefPubMedGoogle Scholar
  43. 43.
    Horton JD, Goldstein JL, Brown MS. (2002) SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J. Clin. Invest. 109:1125–31.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Shimomura I, Bashmakov Y, Horton JD. (1999) Increased levels of nuclear SREBP-1c associated with fatty livers in two mouse models of diabetes mellitus. J. Biol. Chem. 274:30028–32.CrossRefPubMedGoogle Scholar
  45. 45.
    Sekiya M, et al. (2003) Polyunsaturated fatty acids ameliorate hepatic steatosis in obese mice by SREBP-1 suppression. Hepatology. 38:1529–39.CrossRefPubMedGoogle Scholar
  46. 46.
    Yahagi N, et al. (1999) A crucial role of sterol regulatory element-binding protein-1 in the regulation of lipogenic gene expression by polyunsaturated fatty acids. J. Biol. Chem. 274:35840–4.CrossRefPubMedGoogle Scholar
  47. 47.
    Dentin R, et al. (2005) Polyunsaturated fatty acids suppress glycolytic and lipogenic genes through the inhibition of ChREBP nuclear protein translocation. J. Clin. Invest. 115:2843–54.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Postic C, Dentin R, Denechaud PD, Girard J. (2007) ChREBP, a transcriptional regulator of glucose and lipid metabolism. Annu. Rev. Nutr. 27:179–92.CrossRefPubMedGoogle Scholar
  49. 49.
    Liu X, Strable MS, Ntambi JM. (2011) Stearoyl CoA desaturase 1: Role in cellular inflammation and stress. Adv. Nutr. 2:15–22.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Ntambi JM, Miyazaki M. (2004) Regulation of stearoyl-CoA desaturases and role in metabolism. Prog. Lipid. Res. 43:91–104.CrossRefPubMedGoogle Scholar
  51. 51.
    Yamada M, et al. (2011) Early onset of fatty liver in growth-restricted rat fetuses and newborns. Congenit. Anom. (Kyoto). 51:167–73.CrossRefGoogle Scholar
  52. 52.
    van Eijsden M, Hornstra G, van der Wal MF, Vrijkotte TG, Bonsel GJ. (2008) Maternal n-3, n-6, and trans fatty acid profile early in pregnancy and term birth weight: a prospective cohort study. Am. J. Clin. Nutr. 87:887–95.CrossRefPubMedGoogle Scholar
  53. 53.
    Bernard JY, et al. (2013) The dietary n6:n3 fatty acid ratio during pregnancy is inversely associated with child neurodevelopment in the EDEN mother-child cohort. J. Nutr. 143:1481–8.CrossRefPubMedGoogle Scholar
  54. 54.
    Hanebutt FL, Demmelmair H, Schiessl B, Larque E, Koletzko B. (2008) Long-chain polyunsaturated fatty acid (LC-PUFA) transfer across the placenta. Clin. Nutr. 27:685–93.CrossRefPubMedGoogle Scholar
  55. 55.
    Green P, Yavin E. (1998) Mechanisms of docosa-hexaenoic acid accretion in the fetal brain. J. Neurosci. Res. 52:129–36.CrossRefPubMedGoogle Scholar
  56. 56.
    Chambaz J, et al. (1985) Essential fatty acids interconversion in the human fetal liver. Biol. Neonate. 47:136–40.CrossRefPubMedGoogle Scholar
  57. 57.
    Crupi R, Marino A, Cuzzocrea S. (2013) n-3 fatty acids: role in neurogenesis and neuroplasticity. Curr. Med. Chem. 20:2953–63.CrossRefPubMedGoogle Scholar
  58. 58.
    Martinez M. (1992) Tissue levels of polyunsatu-rated fatty acids during early human development. J. Pediatr. 120:S129–38.CrossRefPubMedGoogle Scholar
  59. 59.
    Ahmad A, Moriguchi T, Salem N. (2002) Decrease in neuron size in docosahexaenoic acid-deficient brain. Pediatr. Neurol. 26:210–8.CrossRefPubMedGoogle Scholar
  60. 60.
    Carlson SE, et al. (2013) DHA supplementation and pregnancy outcomes. Am. J. Clin. Nutr. 97:808–15.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© The Author(s) 2014

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, and provide a link to the Creative Commons license. You do not have permission under this license to share adapted material derived from this article or parts of it.

The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

To view a copy of this license, visit (

Authors and Affiliations

  • Madhu Gupta
    • 1
    • 2
  • Malvika H. Solanki
    • 1
    • 2
  • Prodyot K. Chatterjee
    • 2
  • Xiangying Xue
    • 2
  • Amanda Roman
    • 3
  • Neeraj Desai
    • 3
  • Burton Rochelson
    • 3
  • Christine N. Metz
    • 1
    • 2
    • 3
  1. 1.Elmezzi Graduate School of Molecular MedicineManhassetUSA
  2. 2.The Feinstein Institute for Medical ResearchThe Center for Immunology and InflammationManhassetUSA
  3. 3.Division of Maternal-Fetal MedicineHofstra North Shore-LIJ School of MedicineManhassetUSA

Personalised recommendations