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Diabetologia

, Volume 61, Issue 8, pp 1862–1876 | Cite as

Folate treatment of pregnant rat dams abolishes metabolic effects in female offspring induced by a paternal pre-conception unhealthy diet

  • Jian Li
  • Yong-Ping Lu
  • Oleg Tsuprykov
  • Ahmed A. Hasan
  • Christoph Reichetzeder
  • Mei Tian
  • Xiao Li Zhang
  • Qin Zhang
  • Guo-Ying Sun
  • Jingli Guo
  • Mohamed M. S. Gaballa
  • Xiao-Ning Peng
  • Ge Lin
  • Berthold Hocher
Article

Abstract

Aims/hypothesis

Paternal high-fat diet prior to mating programmes impaired glucose tolerance in female offspring. We examined whether the metabolic consequences in offspring could be abolished by folate treatment of either the male rats before mating or the corresponding female rats during pregnancy.

Methods

Male F0 rats were fed either control diet or high-fat, high-sucrose and high-salt diet (HFSSD), with or without folate, before mating. Male rats were mated with control-diet-fed dams. After mating, the F0 dams were fed control diet with or without folate during pregnancy.

Results

Male, but not female offspring of HFSSD-fed founders were heavier than those of control-diet-fed counterparts (p < 0.05 and p = 0.066 in males and females, respectively). Both male and female offspring of HFSSD-fed founders were longer compared with control (p < 0.01 for both sexes). Folate treatment of the pregnant dams abolished the effect of the paternal diet on the offspring’s body length (p ˂ 0.05). Female offspring of HFSSD-fed founders developed impaired glucose tolerance, which was restored by folate treatment of the dams during pregnancy. The beta cell density per pancreatic islet was decreased in offspring of HFSSD-fed rats (−20% in male and −15% in female F1 offspring, p ˂ 0.001 vs controls). Folate treatment significantly increased the beta cell density (4.3% and 3.3% after folate supplementation given to dams and founders, respectively, p ˂ 0.05 vs the offspring of HFSSD-fed male rats). Changes in liver connective tissue of female offspring of HFSSD-fed founders were ameliorated by treatment of dams with folate (p ˂ 0.01). Hepatic Ppara gene expression was upregulated in female offspring only (1.51-fold, p ˂ 0.05) and was restored in the female offspring by folate treatment (p ˂ 0.05). We observed an increase in hepatic Lcn2 and Tmcc2 expression in female offspring born to male rats exposed to an unhealthy diet during spermatogenesis before mating (p ˂ 0.05 vs controls). Folate treatment of the corresponding dams during pregnancy abolished this effect (p ˂ 0.05). Analysis of DNA methylation levels of CpG islands in the Ppara, Lcn2 and Tmcc2 promoter regions revealed that the paternal unhealthy diet induced alterations in the methylation pattern. These patterns were also affected by folate treatment. Total liver DNA methylation was increased by 1.52-fold in female offspring born to male rats on an unhealthy diet prior to mating (p ˂ 0.05). This effect was abolished by folate treatment during pregnancy (p ˂ 0.05 vs the offspring of HFSSD-fed male rats).

Conclusions/interpretation

Folate treatment of pregnant dams restores effects on female offspring’s glucose metabolism induced by pre-conception male founder HFSSD.

Keywords

Glucose tolerance High-fat-sucrose-salt diet Maternal folate treatment Paternal programming 

Abbreviations

5-MC%

Per cent 5-methylcytosine

HFSSD

High-fat, high-sucrose and high-salt diet

miRNA

microRNA

Notes

Contribution statement

BH designed the study. JL, MT, XLZ, QZ, OT, JG, MG, AH, CR, X-NP, G-YS, Y-PL and GL generated and analysed the data. JL, OT, BH, Y-PL, AH and CR interpreted the data and wrote the manuscript. All the authors revised the manuscript for intellectual content and approved its final version to be published. BH is the guarantor of this work.

Funding

This project has been funded in whole or in part with funds from the National Natural Science Foundation of China (Grant No. 81300557), Hunan Province Science and Technology Plan (grant no. 2014SK3003) and the Programme for Excellent Talents of Hunan Normal University (grant no. ET14106).

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Supplementary material

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Jian Li
    • 1
  • Yong-Ping Lu
    • 2
    • 3
  • Oleg Tsuprykov
    • 2
    • 4
  • Ahmed A. Hasan
    • 2
    • 5
  • Christoph Reichetzeder
    • 2
  • Mei Tian
    • 1
  • Xiao Li Zhang
    • 1
  • Qin Zhang
    • 1
  • Guo-Ying Sun
    • 1
  • Jingli Guo
    • 2
    • 6
  • Mohamed M. S. Gaballa
    • 2
    • 7
  • Xiao-Ning Peng
    • 1
  • Ge Lin
    • 8
    • 9
    • 10
  • Berthold Hocher
    • 1
    • 2
  1. 1.Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, School of MedicineHunan Normal UniversityChangshaChina
  2. 2.Institute of Nutritional ScienceUniversity of PotsdamNuthetalGermany
  3. 3.Department of Nephrology, Charité - Universitätsmedizin BerlinBerlinGermany
  4. 4.Institute for Laboratory Medicine, IFLBBerlinGermany
  5. 5.Department of Biochemistry, Faculty of PharmacyZagazig UniversityZagazigEgypt
  6. 6.Center for Cardiovascular Research, Charité - Universitätsmedizin BerlinBerlinGermany
  7. 7.Faculty of Veterinary MedicineBenha UniversityToukhEgypt
  8. 8.Institute of Reproductive and Stem Cell Engineering, College of Basic of MedicineCentral South UniversityChangshaChina
  9. 9.Reproductive and Genetic Hospital of CITIC-XiangyaChangshaChina
  10. 10.Key Laboratory of Reproductive and Stem Cell EngineeringNational Health and Family Planning CommissionChangshaChina

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