Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University , Kumamoto , Japan.
Department of Molecular Medicine, Faculty of Life Sciences, Global COE "Cell Fate Regulation Research and Education Unit, " Kumamoto University , Kumamoto , Japan.
Am J Physiol Endocrinol Metab. 2019 Feb 1;316(2):E305-E318. doi: 10.1152/ajpendo.00215.2018. Epub 2018 Dec 11.
Heat shock protein 72 (HSP72) is a major inducible molecule in the heat shock response that enhances intracellular stress tolerance. Decreased expression of HSP72 is observed in type 2 diabetes, which may contribute to the development of insulin resistance and chronic inflammation. We used HSP72 knockout (HSP72-KO) mice to investigate the impact of HSP72 on glucose metabolism and endoplasmic reticulum (ER) stress, particularly in the liver. Under a high-fat diet (HFD) condition, HSP72-KO mice showed glucose intolerance, insulin resistance, impaired insulin secretion, and enhanced hepatic gluconeogenic activity. Furthermore, activity of the c-Jun NH-terminal kinase (JNK) was increased and insulin signaling suppressed in the liver. Liver-specific expression of HSP72 by lentivirus (lenti) in HFD-fed HSP72-KO mice ameliorated insulin resistance and hepatic gluconeogenic activity. Furthermore, increased adipocyte size and hepatic steatosis induced by the HFD were suppressed in HSP72-KO lenti-HSP72 mice. Increased JNK activity and ER stress upon HFD were suppressed in the liver as well as the white adipose tissue of HSP72-KO lenti-HSP72 mice. Thus, HSP72 KO caused a deterioration in glucose metabolism, hepatic gluconeogenic activity, and β-cell function. Moreover, liver-specific recovery of HSP72 restored glucose homeostasis. Therefore, hepatic HSP72 may play a critical role in the pathogenesis of type 2 diabetes.
热休克蛋白 72（HSP72）是热休克反应中的主要诱导分子，可增强细胞内应激耐受性。2 型糖尿病患者中观察到 HSP72 的表达降低，这可能导致胰岛素抵抗和慢性炎症的发生。我们使用 HSP72 敲除（HSP72-KO）小鼠来研究 HSP72 对葡萄糖代谢和内质网（ER）应激的影响，特别是在肝脏中。在高脂肪饮食（HFD）条件下，HSP72-KO 小鼠表现出葡萄糖不耐受、胰岛素抵抗、胰岛素分泌受损和肝糖异生活性增强。此外，JNK 的活性增加和胰岛素信号在肝脏中受到抑制。HSP72-KO 小鼠在 HFD 喂养时通过慢病毒（lenti）肝脏特异性表达 HSP72 可改善胰岛素抵抗和肝糖异生活性。此外，HSP72-KO lenti-HSP72 小鼠中 HFD 诱导的脂肪细胞增大和肝脂肪变性得到抑制。HSP72-KO lenti-HSP72 小鼠的肝脏和白色脂肪组织中 JNK 活性和 ER 应激的增加也受到抑制。因此，HSP72 KO 导致葡萄糖代谢、肝糖异生活性和β细胞功能恶化。此外，肝脏特异性恢复 HSP72 可恢复葡萄糖稳态。因此，肝脏 HSP72 可能在 2 型糖尿病的发病机制中起关键作用。
