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Pharmaceutical Research

, 36:141 | Cite as

Changes of Blood-Brain Barrier and Brain Parenchymal Protein Expression Levels of Mice under Different Insulin-Resistance Conditions Induced by High-Fat Diet

  • Seiryo Ogata
  • Shingo Ito
  • Takeshi Masuda
  • Sumio OhtsukiEmail author
Research Paper

Abstract

Purpose

The purpose of the present study was to investigate changes of blood-brain barrier (BBB) and brain parenchymal protein expression due to type II diabetes mellitus (T2DM) induced by a high-fat diet (HFD) by using SWATH-based quantitative proteomics.

Methods

Mice were fed a HFD for 2 or 10 weeks, and then SWATH-based quantitative proteomic analysis, western blot analysis, immunohistochemistry and functional transport studies were performed.

Results

In brain capillaries, expression levels of BBB transporters (Glut1, P-glycoprotein) and tight-junction proteins (claudin-5, occludin) were significantly reduced in HFD mice at 2 weeks, but recovered to the levels in the normal diet (ND) group at 10 weeks. P-glycoprotein function at the BBB was reduced at 2 weeks. In the cerebral cortex and hippocampus, neurofilament, which is important for neuronal function, was decreased in HFD mice at 2 weeks, but recovered at 10 weeks.

Conclusion

Our results suggest that changes in the status of insulin resistance influence expression of BBB transporters, which in turn may alter the expression of cognitive function-related proteins.

Key Words

Blood-brain barrier central nervous system insulin resistance quantitative proteomics type II diabetes mellitus 

Abbreviations

Amyloid β peptide

AD

Alzheimer’s disease

BBB

Blood-brain barrier

CaMKII

Ca2+/calmodulin-dependent protein kinase

CNS

Central nervous system

GAPDH

Glyceraldehyde-3-phosphate dehydrogenase

Glut1

Glucose transporter 1

hCMEC

human cerebral vascular endothelial cell

HFD

High-fat diet

IDA

Information-dependent acquisition

Lat1

Large neutral amino acids transporter small subunit 1

Lrp1

Low density lipoprotein receptor-related protein 1

Mct1

Monocarboxylate transporter 1

Mdr1a

Multidrug resistance protein 1a

ND

Normal diet

PBS

Phosphate buffered saline

PSD

Post synaptic density

PTS

Phase-transfer surfactant

ROS

Reactive oxygen species

SWATH

Sequential window acquisition of all theoretical fragment-ion spectra

T2DM

Type 2 diabetes mellitus

TCA

Tricarboxylic acid

TfR

Transferrin receptor

TNF-α

Tumor necrosis factor-alpha

VEGF

Vascular endothelial growth factor

Notes

Acknowledgments and Disclosures

We are grateful for partial financial support in the form of three Grants-in-Aid for Scientific Research from the Japanese Society for the Promotion of Science (JSPS) and a Grant-in-Aid for Scientific Research on Innovative Areas (15H01562), as well as a grant from the Mochida Memorial Foundation for Medical and Pharmaceutical Research. Ohtsuki S is a full professor at Kumamoto University and is also a director of Proteomedix Frontiers. This study was not supported by the company, and his position at the company did not influence the design of the study, the collection of the data, the analysis or interpretation of the data, the decision to submit the manuscript for publication, or the writing of the manuscript, and did not present any financial conflicts. The other authors declare no competing interests.

Author Contributions

All authors, Ogata S, Ito S, Masuda T and Ohtsuki S, contributed to study design and manuscript revision. Ogata S conducted experiments and performed data analysis. Ogata S, Ito S. and Ohtsuki S wrote the manuscript. All authors provided final approval of the submitted manuscript.

Supplementary material

11095_2019_2674_MOESM1_ESM.docx (1.2 mb)
ESM 1 (DOCX 1.18 mb)
11095_2019_2674_MOESM2_ESM.xlsx (275 kb)
Table S4 Identified proteins in brain capillary fraction of mice fed with HFD for 2 weeks (A) or 10 weeks (B) by SWATH-MS. (XLSX 275 kb)
11095_2019_2674_MOESM3_ESM.xlsx (980 kb)
Table S5 Identified proteins in cerebral cortex cytosol (A, C) or plasma membrane (B, D) fraction of mice fed with HFD for 2 weeks (A, B) or 10 weeks (C, D) by SWATH-MS. (XLSX 980 kb)
11095_2019_2674_MOESM4_ESM.xlsx (937 kb)
Table S6 Identified proteins in hippocampus cytosol (A, C) or plasma membrane (B, D) fraction of mice fed with HFD for 2 weeks (A, B) or 10 weeks (C, D) by SWATH-MS. (XLSX 936 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pharmaceutical Microbiology, Graduate School of Pharmaceutical SciencesKumamoto UniversityKumamotoJapan
  2. 2.Department of Pharmaceutical Microbiology, Faculty of Life SciencesKumamoto UniversityKumamotoJapan
  3. 3.AMED-CRESTJapan Agency for Medical Research and DevelopmentTokyoJapan

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