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Published on: November 16, 2011
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.
Abstract:
The integrated stress response (ISR) is a vital signaling pathway initiated by four kinases, PERK, GCN2, HRI and PKR, that ensure cellular resilience and protect cells from challenges. Here, we investigated whether increasing ISR signaling could rescue diabetes-like phenotypes in a mouse model of diet-induced obesity (DIO). We show that the orally available and clinically approved GCN2 activator halofuginone (HF) can activate the ISR in mouse tissues. We found that daily oral administration of HF increases glucose tolerance whilst reducing weight gain, insulin resistance, and serum insulin in DIO mice. Conversely, the ISR inhibitor GSK2656157, used at low doses to optimize its selectivity, aggravates glucose intolerance in DIO mice. Whilst loss of function mutations in mice and humans have revealed that PERK is the essential ISR kinase that protects from diabetes, our work demonstrates the therapeutic value of increasing ISR signaling by activating the related kinase GCN2 to reduce diabetes phenotypes in a DIO mouse model.
Insights
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.
