Maternal selenium status is profoundly involved in metabolic fetal programming by modulating insulin resistance, oxidative balance and energy homeostasis



High and low levels of selenium (Se) have been related to metabolic disorders in dams and in their offspring. Their relationship to oxidative balance and to AMP-activated protein kinase (AMPK) is some of the mechanisms proposed. The aim of this study is to acquire information about how Se is involved in metabolic programming.


Three experimental groups of dam rats were used: control (Se: 0.1 ppm), Se supplemented (Se: 0.5 ppm) and Se deficient (Se: 0.01 ppm). At the end of lactation, the pups’ metabolic profile, oxidative balance, Se levels, selenoproteins and IRS-1 hepatic expression, as well as hepatic AMPK activation were measured.


The experimental groups present deep changes in Se homeostasis, selenoproteins and IRS-1 hepatic expression, oxidative balance, AMPK activation ratio and insulin levels. They do, however, have different metabolic profiles.


High- and low-Se diets are linked to insulin resistance, yet the mechanisms involved are completely opposite.

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  1. 1.

    Wiernsperger N, Rapin J (2010) Trace elements in glucometabolic disorders: an update. Diabetol Metab Syndr 2:70

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Carreras O, Ojeda ML, Nogales F (2016) Selenium dietary supplementation and oxidative balance in alcoholism. In: Patel V (ed) Molecular aspects of alcohol and nutrition, 1 edn. Elsevier, London, pp 133–142

    Google Scholar 

  3. 3.

    Day C (2007) Metabolic syndrome, or What you will: definitions and epidemiology. Diab Vasc Dis Res 4:32

    PubMed  Google Scholar 

  4. 4.

    Zou M, Arentson EJ, Teegarden D et al (2012) Fructose consumption during pregnancy and lactation induces fatty liver and glucose intolerance in rats. Nutr Res 32:588–598

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Fowden AL, Forhead AJ (2004) Endocrine mechanisms of intrauterine programming. Reproduction 127:515–526

    CAS  PubMed  Google Scholar 

  6. 6.

    Nogales F, Ojeda ML, Muñoz del Valle P, Serrano A, Murillo ML, Carreras O (2017) Metabolic syndrome and selenium during gestation and lactation. Eur J Nutr 56:819–830

    CAS  PubMed  Google Scholar 

  7. 7.

    Ojeda ML, Nogales F, Muñoz Del Valle P, Díaz-Castro j, Murillo ML, Carreras O (2016) Metabolic syndrome and selenium in fetal programming: gender differences. Food Funct 7:3031–3038

    CAS  PubMed  Google Scholar 

  8. 8.

    Serrano A, Nogales F, Sobrino P, Murillo ML, Carreras O, Ojeda ML (2016) Heart selenoproteins status of metabolic syndrome-exposed pups: a potential target for attenuating cardiac damage. Mol Nutr Food Res 60:2633–2641

    CAS  PubMed  Google Scholar 

  9. 9.

    Zhou J, Huang K, Lei XG (2013) Selenium and diabetes—evidence from animal studies. Free Radic Biol Med 65:1548–1556

    CAS  PubMed  Google Scholar 

  10. 10.

    Labunskyy VM, Lee BC, Handy DE et al (2011) Both maximal expression of selenoproteins and selenoprotein deficiency can promote development of type 2 diabetes-like phenotype in mice. Antioxid Redox Signal 14:2327–2336

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Wang X, Zhang W, Chen H et al (2014) High selenium impairs hepatic insulin sensitivity through opposite regulation of ROS. Toxicol Lett 224:16–23

    CAS  PubMed  Google Scholar 

  12. 12.

    Seale LA, Hashimoto AC, Kurokawa S et al (2012) Disruption of the selenocysteine lyase-mediated selenium recycling pathway leads to metabolic syndrome in mice. Mol Cell Biol 32:4141–4154

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Reddi AS, Bollineni JS (2001) Selenium-deficient diet induces renal oxidative stress and injury via TGF-β1 in normal and diabetic rats. Kidney Int 59:1342–1353

    CAS  PubMed  Google Scholar 

  14. 14.

    Ozkaya M, Sahin M, Cakal E et al (2009) Selenium levels in first-degree relatives of diabetic patients. Biol Trace Elem Res 128:144–151

    CAS  PubMed  Google Scholar 

  15. 15.

    Stranges S, Marshall JR, Natarajan R (2007) Effects of long-term selenium supplementation on the incidence of type 2 diabetes: a randomized trial. Ann Intern Med 147:217–223

    PubMed  Google Scholar 

  16. 16.

    Houstis N, Rosen ED, Lander ES (2006) Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nat 440:944–948

    CAS  Google Scholar 

  17. 17.

    Steinbrenner H (2013) Interference of selenium and selenoproteins with the insulin-regulated carbohydrate and lipid metabolism. Free Radic Biol Med 65:1538–1547

    CAS  PubMed  Google Scholar 

  18. 18.

    Hardie DG (2015) AMPK: positive and negative regulation, and its role in whole-body energy homeostasis. Curr Opin Cell Biol 33:1–7

    CAS  PubMed  Google Scholar 

  19. 19.

    Pinto A, Juniper DT, Sanil M (2012) Supranutritional selenium induces alterations in molecular targets related to energy metabolism in skeletal muscle and visceral adipose tissue of pigs. J Inorg Biochem 114:47–54

    CAS  PubMed  Google Scholar 

  20. 20.

    Tajima-Shirasaki N, Ishii KA, Takayama H et al (2017) Eicosapentaenoic acid down-regulates expression of the selenoprotein P gene by inhibiting SREBP-1c protein independently of the AMP-activated protein kinase pathway in H4IIEC3 hepatocytes. J Biol Chem 292:10791–10800

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Zhou X, Wang F, Yang H et al (2014) Selenium-enriched exopolysaccharides produced by Enterobacter cloacae Z0206 alleviate adipose inflammation in diabetic KKAy mice through the AMPK/SirT1 pathway. Mol Med Rep 9:683–688

    CAS  PubMed  Google Scholar 

  22. 22.

    Pepper MP, Vatamaniuk MZ, Yan X et al (2011) Impacts of dietary selenium deficiency on Me tabolic phenotypes of diet-restricted GPX1-overexpressing mice. Antioxid Redox Signal 14:383–390

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Addinsall AB, Wright CR, Andrikopoulos S, van der Poel C, Stupka N (2018) Emerging roles of endoplasmic reticulum-resident selenoproteins in the regulation of cellular stress responses and the implications for metabolic disease. Biochem J 475:1037–1057

    CAS  PubMed  Google Scholar 

  24. 24.

    Ojeda ML, Nogales F, Vázquez B et al (2009) Alcohol, gestation and breastfeeding: selenium as an antioxidant therapy. Alcohol Alcohol 44:272–277

    CAS  PubMed  Google Scholar 

  25. 25.

    Nogales F, Ojeda ML, Fenutría M et al (2013) Role of selenium and glutathione peroxidase on development, growth, and oxidative balance in rat offspring. Reproduction 146: 659–667

    CAS  PubMed  Google Scholar 

  26. 26.

    Zhao H, Li K, Tang JY et al (2015) Expression of selenoprotein genes is affected by obesity of pigs fed a high-fat diet. J Nutr 145:1394–1401

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Metzger BE, Buchanan TA, Coustan DR et al (2007) Summary and recommendations of the fifth international workshop-conference on gestational diabetes mellitus. Diabetes Care 30:S251–S260

    CAS  PubMed  Google Scholar 

  28. 28.

    Ojeda ML, Jotty K, Nogales F et al (2010) Selenium or selenium plus folic acid intake improves the detrimental effects of ethanol on pups’ Selenium balance. Food Chem Toxicol 48:3486–3491

    CAS  PubMed  Google Scholar 

  29. 29.

    Feoli AM, Macagnan FE, Piovesan CH (2014) Xanthine oxidase activity is associated with risk factors for cardiovascular disease and inflammatory and oxidative status markers in metabolic syndrome: effects of a single exercise session. Oxid Med Cell Longev 2014:587083

    PubMed  PubMed Central  Google Scholar 

  30. 30.

    Misu H, Takamura T, Takayama H et al (2010) A liver-derived secretory protein, selenoprotein P, causes insulin resistance. Cell Metab 12:483–495

    CAS  PubMed  Google Scholar 

  31. 31.

    Tanti JF, Jager J (2009) Cellular mechanisms of insulin resistance: role of stress-regulated serine kinases and insulin receptor substrates (IRS) serine phosphorylation. Curr Opin Pharmacol 9:753–762

    CAS  PubMed  Google Scholar 

  32. 32.

    Sonntag AG, Dalle Pezze P, Shanley DP, Thedieck K (2012) A modelling-experimental approach reveals insulin receptor substrate (IRS)-dependent regulation of adenosine monosphosphate-dependent kinase (AMPK) by insulin. FEBS J 279:3314–3328

    CAS  PubMed  Google Scholar 

  33. 33.

    Bijland S, Mancini SJ, Salt IP (2013) Role of AMP-activated protein kinase in adipose tissue metabolism and inflammation. Clin Sci 124:491–507

    CAS  PubMed  Google Scholar 

  34. 34.

    Ruderman NB, Carling D, Prentki M, Cacicedo JM (2013) AMPK, insulin resistance, and the metabolic syndrome. J Clin Invest 123:2764–2772

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Mistry HD, Broughton Pipkin F et al (2012) Selenium in reproductive health. Am J Obstet Gynecol 206:21–30

    CAS  PubMed  Google Scholar 

  36. 36.

    Hamieh A, Cartier D, Abid H et al (2017) Selenoprotein T is a novel OST subunit that regulates UPR signaling and hormone secretion. EMBO Rep 18:1935–1946

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Imai H, Hirao F, Sakamoto T et al (2003) Early embryonic lethality caused by targeted disruption of the mouse PHGPx gene. Biochem Biophys Res Commun 305:278–286

    CAS  PubMed  Google Scholar 

  38. 38.

    Shi D, Guo S, Liao S et al (2012) Influence of selenium on hepatic mitochondrial antioxidant capacity in ducklings intoxicated with aflatoxin B1. Biol Trace Elem Res 145:325–329

    CAS  PubMed  Google Scholar 

  39. 39.

    He S, Guo X, Tan W et al (2016) Effect of selenium deficiency on phosphorylation of the AMPK pathway in rats. Biol Trace Elem Res 169:254–260

    CAS  PubMed  Google Scholar 

  40. 40.

    Yoon MS (2017) mTOR as a key regulator in maintaining skeletal muscle mass. Front Physiol 8:788

    PubMed  PubMed Central  Google Scholar 

  41. 41.

    Gong T, Torres DJ, Berry MJ, Pitts MW (2018) Hypothalamic redox balance and leptin signaling—emerging role of selenoproteins. Free Radic Biol Med S0891–5849:30103–30105

    Google Scholar 

  42. 42.

    Yang J, Hamid S, Cai J et al (2017) Selenium deficiency-induced thioredoxin suppression and thioredoxin knock down disbalanced insulin responsiveness in chicken cardiomyocytes through PI3K/Akt pathway inhibition. Cell Signal 38:192–200

    PubMed  Google Scholar 

  43. 43.

    Xu J, Wang L, Tang J et al (2017) Pancreatic atrophy caused by dietary selenium deficiency induces hypoinsulinemic hyperglycemia via global down-regulation of selenoprotein encoding genes in broilers. PLoS One 12:e0182079

    PubMed  PubMed Central  Google Scholar 

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Grants from Andalusian Regional Government for its support to CTS-193 research group.

Author information




MLO and FN were responsible for the study concept and design. AM and FN were responsible for acquisition of animal data. MLO was responsible for data analysis and interpretation of findings. MLO drafted the manuscript. FN and OC provided critical revision of the manuscript. All authors critically reviewed content and approved final version for publication. OC was responsible to find financing for the study.

Corresponding author

Correspondence to Fátima Nogales.

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On behalf of all authors, the corresponding author states that there is no conflict of interest.

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Ojeda, M.L., Nogales, F., Membrilla, A. et al. Maternal selenium status is profoundly involved in metabolic fetal programming by modulating insulin resistance, oxidative balance and energy homeostasis. Eur J Nutr 58, 3171–3181 (2019).

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  • Dietary selenium
  • Metabolic programming
  • Insulin resistance
  • Oxidative balance
  • Energy homeostasis