HSP72 protects against obesity-induced insulin resistance
HSP72 protects against obesity-induced insulin resistance
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DOI：
10.1073/pnas.0705799105
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发表时间：
2008-02-05
影响因子：
11.1
通讯作者：
Febbraio, Mark A.
中科院分区：
文献类型：
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作者：
Chung, Jason;Nguyen, Anh-Khoi;Febbraio, Mark A.
2 型糖尿病患者的热休克蛋白 (HSP) 72 基因表达降低，这与胰岛素敏感性降低相关。热疗可激活 HSP72，改善这些患者的临床参数。多种炎症信号蛋白（例如 c-jun 氨基末端激酶 (JNK)、κ B 激酶抑制剂和肿瘤坏死因子-a）的激活可诱导胰岛素抵抗，但 HSP 72 可以在体外阻断这些分子的诱导。因此，我们研究了 HSP72 的激活是否可以防止胰岛素抵抗的发展。首先，我们发现肥胖、胰岛素抵抗的人骨骼肌中 HSP72 蛋白表达减少，JNK 磷酸化增加。接下来，我们使用热休克疗法、转基因过度表达和药理学手段来特异性地在骨骼肌中或在小鼠中全面过度表达 HSP72。在此，我们表明，无论采用何种手段来实现 HSP72 蛋白的升高，都可以观察到对饮食或肥胖引起的高血糖、高胰岛素血症、葡萄糖不耐受和胰岛素抵抗的保护作用。这种保护与防止 JNK 磷酸化密切相关。这些发现确定了 HSP72 在遗传性肥胖或高脂肪喂养的情况下在阻断炎症和预防胰岛素抵抗方面的重要作用。
Patients with type 2 diabetes have reduced gene expression of heat shock protein (HSP) 72, which correlates with reduced insulin sensitivity. Heat therapy, which activates HSP72, improves clinical parameters in these patients. Activation of several inflammatory signaling proteins such as c-jun amino terminal kinase (JNK), inhibitor of kappa B kinase, and tumor necrosis factor-a, can induce insulin resistance, but HSP 72 can block the induction of these molecules in vitro. Accordingly, we examined whether activation of HSP72 can protect against the development of insulin resistance. First, we show that obese, insulin resistant humans have reduced HSP72 protein expression and increased JNK phosphorylation in skeletal muscle. We next used heat shock therapy, transgenic overexpression, and pharmacologic means to overexpress HSP72 either specifically in skeletal muscle or globally in mice. Herein, we show that regardless of the means used to achieve an elevation in HSP72 protein, protection against diet- or obesity-induced hyperglycemia, hyperinsulinemia, glucose intolerance, and insulin resistance was observed. This protection was tightly associated with the prevention of JNK phosphorylation. These findings identify an essential role for HSP72 in blocking inflammation and preventing insulin resistance in the context of genetic obesity or high-fat feeding.