Folic acid oversupplementation during pregnancy disorders lipid metabolism in male offspring via regulating arginase 1-associated NOS3-AMPKα pathway

  • Zhipeng Liu
    Affiliations
    National Key Discipline Laboratory, Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, Harbin, PR China
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  • Yuntao Zhang
    Affiliations
    National Key Discipline Laboratory, Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, Harbin, PR China
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  • Zengjiao Liu
    Affiliations
    National Key Discipline Laboratory, Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, Harbin, PR China
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  • Zhen Tian
    Affiliations
    National Key Discipline Laboratory, Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, Harbin, PR China
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  • Xinyi Pei
    Affiliations
    National Key Discipline Laboratory, Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, Harbin, PR China
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  • Liyan Liu
    Correspondence
    Corresponding author. Department of Nutrition and Food Hygiene, Public Health College, Harbin Medical University, 157 Baojian Road, Nangang District, Harbin, PR China.
    Affiliations
    National Key Discipline Laboratory, Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, Harbin, PR China
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  • Ying Li
    Correspondence
    Corresponding author. Department of Nutrition and Food Hygiene, Public Health College, Harbin Medical University, 157 Baojian Road, Nangang District, Harbin, 150086, PR China. Fax: +86 0451 87502885.
    Affiliations
    National Key Discipline Laboratory, Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, Harbin, PR China
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Published:November 09, 2021DOI:https://doi.org/10.1016/j.clnu.2021.11.004

      Summary

      Background & aims

      Folic acid supplementation is widely accepted during pregnancy, as it exerts a protective effect on neural tube defects. However, the long-term underlying effects of folic acid supplementation during pregnancy (FASDP) on offspring remain unclear.

      Methods

      Thirty pregnant female rats were randomly divided into normal control group, folic acid appropriate supplementation group (2.5 × FA group) and folic acid oversupplementation group (5 × FA group) and fed with corresponding folic acid concentration AIN93G diet. UPLC-Q-TOF-MS, UPLC-TQ-MS and GC–MS were performed to detect the serum metabolites profiles in adult male offspring and explore the effects of FASDP. Moreover, molecular biology technologies were used to clarify the underlying mechanism.

      Results

      We demonstrate that 2.5-folds folic acid leads to dyslipidemic-diabetic slightly in male offspring, while 5-folds folic acid aggravates the disorder and prominent hepatic lipid accumulations. Using untargeted and targeted metabolomics, total 63 differential metabolites and 12 significantly differential KEGG pathways are identified. Of note, arginine biosynthesis, arginine and proline metabolism are the two most significant pathways. Mechanistic investigations reveal that the increased levels of arginase-1 (Arg1) causes the lipid metabolism disorder by regulating nitric oxide synthase-3 (NOS3)-adenosine monophosphate activated protein kinase-α (AMPKα) pathway, resulting in lipid accumulation in hepatocytes.

      Conclusions

      Our data suggest that maternal folic acid oversupplementation during pregnancy contributes to lipid metabolism disorder in male offspring by regulating Arg1-NOS3-AMPKα pathway.

      Keywords

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