最近的数据表明iNOS在肥胖的ER应激中具有重要作用。然而,iNOS是否足以解释肥胖诱导的内质网应激和未折叠蛋白反应(UPR)尚未被研究.在本研究中,我们使用iNOS基因敲除小鼠研究高脂饮食(HFD)是否仍可诱导残余内质网应激相关胰岛素抵抗.
为此,我们使用腹膜内葡萄糖耐量试验(GTT),正常血糖高胰岛素钳夹,蛋白质印迹和qPCR在肝脏,肌肉,iNOSKO和对照小鼠在HFD上的脂肪组织。
本研究的结果表明,在HFD喂养的小鼠中,iNOS诱导的胰岛素信号改变是肌肉胰岛素抵抗的重要机制,提示iNOS可能是一个重要的靶标,可以被阻断以提高该组织中的胰岛素敏感性。然而,在肝脏和脂肪组织中,HFD诱导的胰岛素抵抗仅部分依赖于iNOS,and,即使在存在iNOS的遗传或药理阻断的情况下,在这些组织中,与胰岛素信号改变相关的明显内质网应激仍然很明显.当这种ER压力在药理学上被阻断时,胰岛素信号得到改善,糖耐量完全恢复。
合照,这些结果加强了肥胖中胰岛素信号的组织特异性调节,iNOS足以解释肌肉中的胰岛素抵抗,但在肝脏和脂肪组织中,内质网应激和胰岛素抵抗可由iNOS依赖性和iNOS非依赖性机制诱导。
Recent data show that iNOS has an essential role in ER stress in obesity. However, whether iNOS is sufficient to account for obesity-induced ER stress and Unfolded Protein Response (UPR) has not yet been investigated. In the present study, we used iNOS knockout mice to investigate whether high-fat diet (HFD) can still induce residual ER stress-associated insulin resistance.
For this purpose, we used the intraperitoneal glucose tolerance test (GTT), euglycemic-hyperinsulinemic clamp, western blotting and qPCR in liver, muscle, and adipose tissue of iNOS KO and control mice on HFD.
The results of the present study demonstrated that, in HFD fed mice, iNOS-induced alteration in insulin signaling is an essential mechanism of insulin resistance in muscle, suggesting that iNOS may represent an important target that could be blocked in order to improve insulin sensitivity in this tissue. However, in liver and adipose tissue, the insulin resistance induced by HFD was only partially dependent on iNOS, and, even in the presence of genetic or pharmacological blockade of iNOS, a clear ER stress associated with altered insulin signaling remained evident in these tissues. When this ER stress was blocked pharmacologically, insulin signaling was improved, and a complete recovery of glucose tolerance was achieved.
Taken together, these results reinforce the tissue-specific regulation of insulin signaling in obesity, with iNOS being sufficient to account for insulin resistance in muscle, but in liver and adipose tissue ER stress and insulin resistance can be induced by both iNOS-dependent and iNOS-independent mechanisms.