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Downregulation of insulin receptor isoform A in the forebrain of fetal growth-restricted rats

Pediatric Research (2025)Cite this article

Abstract

Background

Children with asymmetrical fetal growth restriction (FGR), whose head size is relatively preserved, often have a poor neurodevelopmental prognosis. Insulin receptor isoform A (IR-A) is predominantly expressed in neurons and is important in neurodevelopment. This study investigated changes in brain IR-A expression in neonatal FGR model rats.

Methods

FGR model rats were generated by maternal caloric restriction (CR). Glucose uptake and the expression of glucose transporter (GLUT) genes in the brain and liver, and of the IR-A gene in the brain were compared between CR and control group neonates. Gene expression in the brain was examined by RNA sequencing. Brain IR-A localization was analyzed using immunohistochemistry.

Results

The brain-to-liver ratios for organ weight and glucose uptake were significantly higher in CR rats. GLUT gene expression was maintained in the CR brain. Whole brain IR-A expression was reduced in CR rats. Furthermore, IR-A expression was decreased in the forebrain of CR rats, but not changed in the hindbrain.

Conclusion

The regional differences in IR-A in the FGR rat brain indicate that an endocrinological mechanism regulates brain IR-A to maintain brain function under nutrient deficiency. However, a decrease in IR-A in the fetal period may cause postnatal brain impairment.

Impact

  • Insulin receptor isoform A (IR-A) expression is reduced in the neonatal brain of asymmetrical fetal growth restriction (FGR) model rats generated by maternal caloric restriction.

  • IR-A expression is decreased in the forebrain, which is important for cognitive brain functions, whereas IR-A expression is maintained in the hindbrain, which is important for basic vital activities.

  • The expression of genes related to forebrain development is significantly decreased, while the expression of genes related to hindbrain development is increased in neonatal FGR model rats. These results can explain why FGR infants have a poor neurodevelopmental prognosis despite their brain size being relatively protected.

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Fig. 1: Changes in fetal growth in the maternal caloric-restriction (CR) model.
Fig. 2: Altered glucose uptake in CR neonates.
Fig. 3: Changes in the levels of insulin receptor isoform mRNAs.
Fig. 4: Enrichment analyses by RNA-sequencing of neonatal CR brain.
Fig. 5: Brain-region-specific IR mRNA and protein expression levels.
Fig. 6: Images and quantitative analysis of immunohistochemistry.

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Data availability

The data sets generated during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors thank the Division of Histological Study, Center for Anatomical Studies, Graduate School of Medicine, Kyoto University, for preparing histological samples for microscopic examination. We also thank Jeremy Allen, PhD, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

Funding

This work was supported by JSPS KAKENHI, Grant Numbers JP22K17798, JP24K15678, and JP24K20703, the Mother and Child Health Foundation, Grant Number R05-K1-7, and Kawano Masanori Memorial Public Interest Incorporated Foundation for Promotion of Pediatrics, Grant Number 35-Waka1.

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Authors and Affiliations

  1. Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Yutaro Tomobe, Seiichi Tomotaki, Yukinori Yoshimura, Kouji Motokura & Junko Takita

  2. Department of Neonatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Ryosuke Araki & Masahiko Kawai

Authors
  1. Yutaro Tomobe
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  2. Seiichi Tomotaki
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  3. Yukinori Yoshimura
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  7. Masahiko Kawai
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Contributions

Conceptualization: Y.T., S.T. and M.K. Methodology: Y.T., S.T., Y.Y. and K.M. Investigation: Y.T., Y.Y., and K.M. Funding acquisition: R.A. and S.T. Supervision: S.T., J.T. and M.K. Writing original draft: Y.T. Review and editing: S.T., J.T. and M.K. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Seiichi Tomotaki.

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Tomobe, Y., Tomotaki, S., Yoshimura, Y. et al. Downregulation of insulin receptor isoform A in the forebrain of fetal growth-restricted rats. Pediatr Res (2025). https://doi.org/10.1038/s41390-025-04372-8

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