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Integrated stress response activator halofuginone protects mice from diabetes-like phenotypes
Shashank Rai1, Maria Szaruga1, Aleksandra P Pitera1
1MRC Laboratory of Molecular Biology , Cambridge, UK.
The Journal of Cell Biology
|August 16, 2024
Summary
Activating the integrated stress response (ISR) via GCN2 with halofuginone improved diabetes symptoms in diet-induced obesity mice. This suggests GCN2 activation as a potential therapeutic strategy for metabolic disorders.
Area of Science:
- Cellular Biology
- Metabolic Disorders
- Pharmacology
Background:
- The integrated stress response (ISR) is a crucial cellular pathway involving kinases like PERK and GCN2, essential for maintaining cell resilience.
- Diabetes and obesity are significant health challenges, and understanding pathways that regulate metabolic homeostasis is critical for developing new treatments.
Purpose of the Study:
- To investigate if enhancing ISR signaling through GCN2 activation can ameliorate diabetes-like phenotypes in a diet-induced obesity (DIO) mouse model.
- To evaluate the therapeutic potential of the GCN2 activator halofuginone (HF) in a DIO mouse model.
Main Methods:
- Administered the GCN2 activator halofuginone (HF) orally to DIO mice.
- Assessed glucose tolerance, body weight, insulin resistance, and serum insulin levels.
- Utilized the ISR inhibitor GSK2656157 to understand the role of ISR inhibition in DIO mice.
Main Results:
- Oral administration of HF activated the ISR in mouse tissues and significantly improved glucose tolerance in DIO mice.
- HF treatment led to reduced weight gain, decreased insulin resistance, and lowered serum insulin levels in DIO mice.
- Inhibition of the ISR with GSK2656157 exacerbated glucose intolerance in DIO mice.
Conclusions:
- Increasing ISR signaling by activating GCN2 with halofuginone demonstrates therapeutic value in reducing diabetes phenotypes in a DIO mouse model.
- These findings highlight GCN2 activation as a promising strategy for managing metabolic dysfunction associated with obesity and diabetes, distinct from the established role of PERK.
