J Clin Invest. 2013 Nov;123(11):4667-80. doi: 10.1172/JCI67615.
Type 2 diabetes is characterized by insulin resistance and mitochondrial dysfunction in classical target tissues such as muscle, fat, and liver. Using a murine model of type 2 diabetes, we show that there is hypothalamic insulin resistance and mitochondrial dysfunction due to downregulation of the mitochondrial chaperone HSP60. HSP60 reduction in obese, diabetic mice was due to a lack of proper leptin signaling and was restored by leptin treatment. Knockdown of Hsp60 in a mouse hypothalamic cell line mimicked the mitochondrial dysfunction observed in diabetic mice and resulted in increased ROS production and insulin resistance, a phenotype that was reversed with antioxidant treatment. Mice with a heterozygous deletion of Hsp60 exhibited mitochondrial dysfunction and hypothalamic insulin resistance. Targeted acute downregulation of Hsp60 in the hypothalamus also induced insulin resistance, indicating that mitochondrial dysfunction can cause insulin resistance in the hypothalamus. Importantly, type 2 diabetic patients exhibited decreased expression of HSP60 in the brain, indicating that this mechanism is relevant to human disease. These data indicate that leptin plays an important role in mitochondrial function and insulin sensitivity in the hypothalamus by regulating HSP60. Moreover, leptin/insulin crosstalk in the hypothalamus impacts energy homeostasis in obesity and insulin-resistant states.
2 型糖尿病的特点是经典靶组织（如肌肉、脂肪和肝脏）中的胰岛素抵抗和线粒体功能障碍。我们使用 2 型糖尿病的鼠模型表明，由于线粒体伴侣 HSP60 的下调，存在下丘脑胰岛素抵抗和线粒体功能障碍。肥胖、糖尿病小鼠中 HSP60 的减少是由于瘦素信号传导不当所致，并用瘦素治疗恢复。在鼠下丘脑细胞系中敲低 Hsp60 可模拟糖尿病小鼠中观察到的线粒体功能障碍，并导致 ROS 产生增加和胰岛素抵抗，抗氧化剂治疗可逆转这种表型。Hsp60 杂合缺失的小鼠表现出线粒体功能障碍和下丘脑胰岛素抵抗。下丘脑 HSP60 的靶向急性下调也会引起胰岛素抵抗，表明线粒体功能障碍可导致下丘脑胰岛素抵抗。重要的是，2 型糖尿病患者的大脑中 HSP60 的表达减少，表明该机制与人类疾病相关。这些数据表明，瘦素通过调节 HSP60 在大脑中发挥重要作用，调节线粒体功能和胰岛素敏感性。此外，下丘脑内的瘦素/胰岛素串扰会影响肥胖和胰岛素抵抗状态下的能量平衡。
