Recombinant FGF21 Protects Against Blood-Brain Barrier Leakage Through Nrf2 Upregulation in Type 2 Diabetes Mice

Area of Science:

• Neuroscience
• Metabolic Disorders
• Endocrinology

Background:

• Blood-brain barrier (BBB) damage is a key factor in diabetes-associated neurological complications.
• Current treatments for diabetes-related BBB damage are limited.
• Fibroblast growth factor 21 (FGF21) regulates glucose and lipid metabolism.

Purpose of the Study:

• To investigate the potential of recombinant FGF21 (rFGF21) in mitigating type 2 diabetes (T2D)-induced BBB disruption.
• To explore the role of the NF-E2-related factor-2 (Nrf2) pathway in mediating FGF21's protective effects on the BBB.

Main Methods:

• In vivo studies using db/db mice to assess BBB permeability and junction protein expression after rFGF21 treatment.
• In vitro studies using human brain microvascular endothelial cells (HBMEC) under hyperglycemia and IL1β conditions to evaluate rFGF21's effects.
• Investigating the molecular mechanism involving FGF receptor 1 (FGFR1), Kelch ECH-associating protein 1 (Keap1), and Nrf2.

Main Results:

• rFGF21 treatment significantly reduced BBB permeability and preserved junction protein expression in diabetic mice.
• rFGF21 ameliorated transendothelial permeability and junction protein loss in cultured HBMECs under diabetic conditions.
• rFGF21 was shown to activate FGFR1, leading to reduced Keap1-Nrf2 interaction and subsequent Nrf2 release.

Conclusions:

• rFGF21 administration demonstrates a protective effect against T2D-induced BBB disruption.
• The FGFR1-Keap1-Nrf2 pathway is implicated in mediating the beneficial effects of rFGF21 on the BBB.
• These findings suggest rFGF21 as a potential therapeutic agent for targeting BBB damage in diabetes.