Shashank Rai, Maria Szaruga, Aleksandra P Pitera, Anne Bertolotti
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引用次数: 0
摘要
综合应激反应(ISR)是由四种激酶(PERK、GCN2、HRI 和 PKR)启动的重要信号通路,可确保细胞恢复能力并保护细胞免受挑战。在这里,我们研究了增加 ISR 信号传导是否能挽救饮食诱导肥胖(DIO)小鼠模型中的糖尿病样表型。我们的研究表明,可口服且已获临床批准的 GCN2 激活剂卤夫酮 (HF) 能激活小鼠组织中的 ISR。我们发现,每天口服 HF 可增加葡萄糖耐量,同时减少 DIO 小鼠的体重增加、胰岛素抵抗和血清胰岛素。相反,低剂量使用以优化其选择性的 ISR 抑制剂 GSK2656157 会加重 DIO 小鼠的葡萄糖耐受性。虽然小鼠和人类的功能缺失突变揭示了 PERK 是防止糖尿病的重要 ISR 激酶,但我们的工作证明了通过激活相关激酶 GCN2 来增加 ISR 信号的治疗价值,从而减少 DIO 小鼠模型中的糖尿病表型。
Integrated stress response activator halofuginone protects mice from diabetes-like phenotypes.
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.
期刊介绍:
The Journal of Cell Biology (JCB) is a comprehensive journal dedicated to publishing original discoveries across all realms of cell biology. We invite papers presenting novel cellular or molecular advancements in various domains of basic cell biology, along with applied cell biology research in diverse systems such as immunology, neurobiology, metabolism, virology, developmental biology, and plant biology. We enthusiastically welcome submissions showcasing significant findings of interest to cell biologists, irrespective of the experimental approach.