Maternal dietary imbalance between omega-6 and omega-3 polyunsaturated fatty acids impairs neocortical development via epoxy metabolites

Nobuyuki Sakayori, Takako Kikkawa, Hisanori Tokuda, Emiko Kiryu, Kaichi Yoshizaki, Hiroshi Kawashima, Tetsuya Yamada, Hiroyuki Arai, Jing X. Kang, Hideki Katagiri, Hiroshi Shibata, Sheila M. Innis, Makoto Arita, Noriko Osumi

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acids (PUFAs) are essential nutrients. Although several studies have suggested that a balanced dietary n-6:n-3 ratio is essential for brain development, the underlying cellular and molecular mechanism is poorly understood. Here, we found that feeding pregnant mice an n-6 excess/n-3 deficient diet, which reflects modern human diets, impairsed neocortical neurogenesis in the offspring. This impaired neurodevelopment occurs through a precocious fate transition of neural stem cells from the neurogenic to gliogenic lineage. A comprehensive mediator lipidomics screen revealed key mediators, epoxy metabolites, which were confirmed functionally using a neurosphere assay. Importantly, although the offspring were raised on a well-balanced n-6:n-3 diet, they exhibited increased anxiety-related behavior in adulthood. These findings provide compelling evidence that excess maternal consumption of n-6 PUFAs combined with insufficient intake of n-3 PUFAs causes abnormal brain development that can have long-lasting effects on the offspring's mental state. Stem Cells 2016;34:470-482 Omega-6 and omega-3 polyunsaturated fatty acids are essential nutrients. Although several studies have suggested that a balanced dietary omega-6:omega-3 ratio is essential for normal brain development, the underlying cellular and molecular mechanism is poorly understood. Here we shows that maternal consumption of an omega-6 rich/omega-3 poor diet impairs offspring's neocortical neuronal layer formation, and reveals its cellular and molecular mechanism; epoxy metabolites of omega-6 and omega-3 regulate the fate of neural stem cells (NSCs). We also show that these offspring demonstrate increased anxiety-related behavior. Our results raise important concerns regarding the increased consumption of such a modern diet, particularly during pregnancy.

Original languageEnglish
Pages (from-to)470-482
Number of pages13
JournalStem Cells
Volume34
Issue number2
DOIs
Publication statusPublished - 2016 Feb 1
Externally publishedYes

Keywords

  • Anxiety
  • Arachidonic acid
  • Docosahexaenoic acid
  • Epoxides
  • Metabolomics
  • Neural stem cells

ASJC Scopus subject areas

  • Molecular Medicine
  • Developmental Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Maternal dietary imbalance between omega-6 and omega-3 polyunsaturated fatty acids impairs neocortical development via epoxy metabolites'. Together they form a unique fingerprint.

  • Cite this

    Sakayori, N., Kikkawa, T., Tokuda, H., Kiryu, E., Yoshizaki, K., Kawashima, H., Yamada, T., Arai, H., Kang, J. X., Katagiri, H., Shibata, H., Innis, S. M., Arita, M., & Osumi, N. (2016). Maternal dietary imbalance between omega-6 and omega-3 polyunsaturated fatty acids impairs neocortical development via epoxy metabolites. Stem Cells, 34(2), 470-482. https://doi.org/10.1002/stem.2246